AU2013211531A1

AU2013211531A1 - Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators

Info

Publication number: AU2013211531A1
Application number: AU2013211531A
Authority: AU
Inventors: Huanming Chen; Ian Wayne Cheney; Martha Alicia De La Rosa; Gary Lee Larson; Jean-Michael Vernier; Jim Zhen Wu
Original assignee: VALEANT PHARMACEUTICALS INT
Current assignee: Bausch Health Americas Inc
Priority date: 2006-08-23
Filing date: 2013-08-02
Publication date: 2013-08-22

Abstract

Abstract This invention provides a compound of formula IA where X = 0 or S; Y is 0 or S; q = I or 0; and other substituents are defined herein. Such compounds can affect the opening of, or otherwise modulate, voltage-gated potassium channels. They are potentially useful for the treatment and prevention of 10 diseases and disorders which are affected by activation or modulation of potassium ion channels. One such condition is seizure disorders,

Description

DERNATIVES OF 4-(N-AZACYCLOALKYL) ANILIDES AS POTASSIUM CHANNEL MODULATORS 5 Field of the Invention This invention concerns novel compounds that activate or otherwise modulate voltage-gated potassium channels. The compounds are useful for the treatment and prevention of diseases anid disorders which are affected by modulation of potassium ion channels. One such condition is seizure disorders. 10 Background of the Invention Epilepsy is a well-known neurological disease, found in about 3% of the population. Approximately 30% of patients with epilepsy do not respond to currently 15 available therapies. Such unfortunate patients - who number hundreds of thousands of people world-wide - must contend with both uncontrolled seizures and the resulting narrowing of their options in such crucial areas of life as health insurance, employment and driving. Retigabine (N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid, ethyl 20 ester) (U.S. Patent No. 5,384,330) has been found to be an effective treatment of seizure disorders and has also been found useful in treating pain. Retigabine has been found to be particularly potent in models for the diug-refractory types of epilepsy. Bialer, M. et aL, Epilepsy Research 1999, 34, 1-41; Blackburn-Munro and Jensen, Eur. J PharmacoL 2003, 460, 109-116; Wickenden, A.D. et at, Expert Opin. Ther. Patents, 2004, 14(4). 25 "Benign familial neonatal convulsions," an inherited fonn of epilepsy, has been associated with mutations in the KCNQ2/3 channels. Biervert, C. et aL, Science 1998, 27, 403-06; Singh, NA., el 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 one important site of action of retigabine 30 is the KCNQ2/3 channel. Wickenden, A.D. et at, Mot PharmacoL 2000, 58,591-600; Main, M.J. et at, Mat Pharmcol, 2000, 58, 253-62. Retigabine has been shown to I a increase the conductance of the channels at the resting membrane potential, with a possible mechanism involving binding of the activation gate of the KCNQ 2/3 channel. Wuttke, T.V, et al, Mac. PharmacoL 2005. Additionally, retigabine has been shown to increase neuronal M currents and to increase the channel open probability of KCNQ 2/3 5 channels. Delmas, P. and Brown, D.A. Nat. Revs Neurasci., vol. 6, 2005, 850-62; Tatulian, L and Brown, D.A., J. Physiol, (2003) 549, 57-63. The seizure type that has been most resistant to therapy is the so-called "complex partial seizure." Retigabine is active in several seizure models, including, as indicated above, models for drug-refractory epilepsy. Because of retigabine's broad spectrum of 10 activity and its unusual molecular mechanism, there is hope that retigabine will be effective in management of several seizure types, including the complex partial seizure, which have been resistant to treatment. Porter, R. J., Nolria, V., and Rundfeldt, C, Neurotherapeutics, 2007, vol. 4, 149-154. The recognition of retigabine as a potassium channel opener has inspired a search 15 among compounds with structural features in common with retigabine for other compounds which can affect the opening of, or otherwise modulate, potassium ion channels. Brief Description of the Invention 20 In their efforts to design a potassium channel modulating compound that is superior to retigabine, shown below, which is a benzyl amine derivative,

NH

2 FH the present inventors have discovered surprising and exceptionally promising properties in a series of tetrahydroisoquinoline derivatives, specifically, para-N-(1,2,3,4-tetrahydro) 25 isoquinolyl anilides and cabamates, and their several sulfur analogues, of the structure of formula IA below These tetrahydroisoquinoline derivatives are, of course, benzyl amines which are restricted to particular conformations because the benzylic nitrogen is a member of a 2 second ring fused to the phenyl ring. Moreover, the present inventors have further discovered that replacement of the primary amino group of retigabine with substituents like halogen, C-C 3 alkyl, OC-C 3 alkyl, and trifluoromethyl also confers surprising and desirable properties. 5 Thus, in one embodiment, this invention provides or contemplates a compound of formula IA H N Ir(Y)jR R2 N Rx [A where R, and R2, are, independently, H, CN, halogen, CH 2 CN, OH, NO2, CH 2 F, CHF2, 10 CF 3 , CF 2 CFj, C-C alkyl, C(=O)CrC 6 alkyl; NH 2 , NH-C-q alkyl; N(C-Csalky)-C-C alkyl, NHC(=0)CrQ alkyl, C(=O)N(CH) 2 , C(=O)N(Et, C(=O)NH2, C(=O)NH-CrC6 alkyL SO 2

NH

2 , NHSOrC-Cs alkyl; C(=O)OCrCs alkyl, OC(=O)C-Csalkyl, OCrC6 alkyl, SCrC6 alkyl, C 3

-C

6 cycloalkyl, (CH2)mCrC6 cycloalkyl, C 3

-C

6 cycloalkenyl,

(CH

2 ),CrC 6 cycloalkenyl, C 2

-C

6 alkenyl, CrCs alkynyl, Ar, (CH 2 ),thienyl, 15 (CH 2 )mfuryl, -(CH 2 ).imidazolyl, (CH2).pyrazy], (CH)2).oxazolyl, (CH 2 )misoxazolyl, (CH2)mthiazolyl, (CH 2 )isothiazoly, (CI)mphenyl, (CH 2 )mpyrrolyl, (CHz)mpyridyl, or

(CH

2 )mpyrinidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoins selected independently from 0, N, and S, and which are optionally substituted as described below; where m is zero, 1, or 2, Ar is a 5- to 10- member mono 20 or bicyclic aromatic group, optionally containing 1 - 4 ring heteroatoms selected independently from N, 0, and S; or R 1 and R2, 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 0, N, and S, and which is optionally substituted as described below; 25 R' is H, halogen, phenyl, 2-(N,N-dixnethylamino)ethyl, CF 3 , OC-C alkyl or C-C 3 alkyl; R3 and R4 are, independently, H, CN, halogen, CF 3 , OCF 3 , OCpC 3 alkyl, or CC 6 alkyl; X o or S; Y is 0 or S; q = I or zero; R, is CrCs alkyl, (CHRs);Cs-C cycloalkyl, 3

(CHR

6 ) CH2C 3 C cycloalkyl, CHI(CHR).C 3

-C

6 cycloalkyl, CR6=CH-CrC cycloalkyl,

CH=CRZ

3 -Cr 6 cycloalkyl, (CHR 6

),C

5 -C cycloalkenyi, CH2(CHR4WCrC cycloalkenyl, C2-C alkenyl, CC6 alkynyl, Ar, (CHR 6 ) Ar, CH2(CHR)Ar, or

(CHR

0 ).CH2Ar, where w = zero, 1, 2, or 3, Ar is a 5- to 10- member mono- or bicyclic 5 aromatic group, optionally containing 1 - 4 ring heteroatoms selected independently from N, 0, and S; R is H or CeC, 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, ary!, and heteroaryl groups in R, R2, R, R,3, R 4 , Rs, R6, and Ar are optionally 10 substituted with one or two substituents selected independently from C-C3 alkyl, halogen, CN, OH , OMe, OEt, CN, CH2F, and trifluoromethyl; and where, additionally. all cycloalkyl and heterocycloalkyl groups are optionally substituted with a carbonyl group. Such compounds are potassium channel activators or modulators. Essentially all combinations of the several variables in formula IA are 15 contemplated by this invention. In another embodiment, this invention provides or contemplates a composition comprising a pharmaceutically acceptable carrier or diluent and at least one of the following: a pharn-maceutically effective amount of a compound of formula IA, a pharmaceutically acceptable salt of a compound of formula IA, a pharmaceutically 20 acceptable solvate of a compound of formula IA, and a pharmaceutically acceptable ester of a compound of formula IA. In yet another embodiment, this invention provides or contemplates a pediatric pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, a syrup for pediatric use, and at least one of the following: a pharmaceutically effective 25 amount of a compound of formula IA, a pharmaceutically acceptable salt of a compound of formula IA, a pharmaceutically acceptable ester of a compound of formula IA, and a pharmaceutically acceptable solvate of a compound of formula IA. In yet another embodiment, this invention provides or contemplates a chewable tablet, suitable for pediatric pharmaceutical use, comprising a phamaceutically 30 acceptable carrier or diluent, and at least one of the following: a pharmaceutically 4 effective amount of a compound of formula IA, a pharmaceutically acceptable salt of a compound of formula IA, a pharmaceutically acceptable solvate of a compound of formula IA, and a phamaceutically acceptable ester of a compound of formula IA. In yet another embodiment, this invention provides or contemplates a method of 5 preventing or treating a disease or disorder which is affected by activation voltage-gated potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IA or a salt or ester or solvate thereof This invention includes all tautomers and salts of compounds of this invention. 10 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 IA above where the group NH-C(=X)-(Y)-Rs is each of the following: NHC(=O)R, NHC(=O)ORs, NHC(=S)R,, NHC(=S)SRs, NHC(=S)OR, and NHC(='O)SR s . 15 Thus, in one embodiment, this invention provides or contemplates a compound of formula IA, where NH-C(=X)-(Y),-Rs is NIC(=O)R3 In another embodiment, this invention provides or contemplates a compound of formula IA, where NH-C(=X)-(Y) 4

R

5 is NHC(=S)Rs. In another embodiment, this invention provides or contemplates a compound of 20 formula IA, where NH-C(=X)-(Y)rRs is NHC(=S)SRS. In another embodiment, this invention provides or contemplates a compound of formula IA, where NH-C(=X)-(Y)-Rs is each NHC(=O)OR 5 . In another embodiment, this invention provides or contemplates a compound of formula IA, where NH-C(=X)-(Y)-R 5 is NHC(=S)ORs. 25 In another embodiment, this invention provides or contemplates a compound of formula- IA, where NH-C(=X)-(Y)qRs is NHC(=0)SRs. In another generic embodiment, this invention provides or contemplates a compound of formula IA, where q is zero and Rs is CrCs alkyl, or (CH14),C-C 6 cycloalkyl. 5 In another subgeneric embodiment, this invention provides or contemplates a compound of formula 1A, where R is H, methyl, ethyl, or halogen In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R is phenyL 5 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is OC 1

-C

3 alkyL In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is 2-dimethylaminoethyl. In another subgeneric embodiment, this invention provides oF contemplates a 10 compound of formula IA, where R' is H. In another subgeneric embodiment, this invention provides ot contemplates a compound of formula IA, where R' halogen. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is methyl or ethyl. 15 In another subgeneric embodiment, R, is located as shown below R4 H H N NS XA T R3 R2 R In another subgenerio embodiment R is located as shown below RR Rl R ~ 20 In another subgeneric embodiment, R is located as shown below )N R4H N )q R5 x N R3 R1 R2 R In another subgeneric embodiment, R, is located as shown below R4 N RS x N R3 R2 SW R, In another subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below. R4 H N (Y5 NH I (Ia x N R3 10 In another subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below. R4H N", RR N

H

In a more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where Rs is C-C 6 alkyl or

(CH

2 )eCs-C 6 cycloalkyl. N 5 H In another more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R5 is C 5

-C

6 alkyl or (CH2),CrC 6 cycloalkyl H N R 5 0 N .OCF 3 N 10 H In another specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R3 and R4 are, independently, H, methyl, or methoxy,

R

4 15 N In a more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R3 and R4 are, independently, H, methyl, or methoxy, and Rs is C 5

-C

6 alkyl or (CHl 2 )CCs 6 cycloalkyl. 8 H N H NNR In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where RS is Cg-CS alkyl or (CHZ). Cs-C 6 cycloalkyl. 5 H N - 0 In another specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R and R4 are, 10 independently, H, methyl, or methoxy, R4 N RY N R3 In another specific subgeneric embodiment, this invention provides or 15 contemplates a compound of the structure shown below, where R.1 and R4 are, independently, H, methyl, or methoxy. R4 H N (Y 5 x 9 In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R 5 is Cr=C 6 alkyl or

(CH

2 ). CS-C 6 cycloalkyl. Me Me- 0 ~ N OMe 5 C In another specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R 3 and R4 are, independently, H, methyl, CI, CF 3 , OCF 3 , or methoxy. 10 R4 H N N R5 In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R5 is C 5

-C

6 alkyl or 15 (CH 2 ), Cs-CE cycloalkyl. H NRS In another specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R 3 and R 4 are, independently, H, methyl, Cl, CFi, OCF 3 , or methoxy. 20 R4 R H- Ra In a more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R$ is C-C alkyl or 5 (CH 2 ), CS-C 6 cycloalkyl. H N In another more specific subgeneric embodiment, this invention provides or 10 contemplates a compound of the structure shown below, where Rs is Cs-C 6 alkyl or

(CH

2 ). CS-C 6 cycloalkyl N 15 In yet another more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R, is (CH 2 ),Ar or C-C 6 alkyl. H N0 1) In another subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R 3 and R 4 are, independently, H, methyl, CI, CF 3 , OCF 3 , or methoxy R4 NR2 5 0 In a more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R 3 and R 4 are, independently, H , methyl, C1, CF 3 , OCF 3 , or methoxy and R is (CH 2 ),Ar or C 3

-C

6 alkyl H N Sr- 0 R3 10 c In another subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where Rs is (CH 2 )Ar or CrC alkyl,

R

4 RR3 - 'x 15 N In yet another more specific subgeneric embodiment, this invention provides or contemplates a compound of the structure shown below, where R 3 and R 4 are, independently, H, methyl, Cl, CF 3 , OCF 3 , or methoxy and where R 5 is (CH2)wAr or CrC6 alkyl 20 H In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R2 is H. In another subgeneric embodiment, this invention provides or contemplates a 5 compound of formula IA, where R2 is halogen. In another, more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R2 is C1 or F. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R2 is trifluoromethyl 10 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R3 and R4 are, independently, H, Cl, methyl, ethyl, trifluoromethyl, or methoxy. In another, more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where q is zero and R3 and R4 are Cl, ethyl, 15 methoxy, or methyl. In another, more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where q is zero and R-3 and R4 are both methyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where W is methyl, halogen, or H; and R3 and R.4 are 20 independently, H, Cl, ethyl, methoxy, or methyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is methoxy; and R3 and R4 are, independently, H, C1, ethyl, metboxy, or methyl. In another more specific subgeneric embodiment, this invention provides or 25 contemplates a compound of formula IA, where I is H; and R3 and R4 are, independently, H, Cl, ethyl, or methyl. 13 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is H, q is zero, and R 5 is C-C 6 alkyl, or (CHR)C 3

-C

6 cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a 5 compound of formula IA, where R'is H; q is 1; Y is O; and R5 is C -Q alkyl, or (CHR4).C 3

-C

6 cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA, where R' is H; q is 1; Y is S; and Rs is CrCsalkyl, or

(CHR),C

3

C

6 cycloalkyl. 10 In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where RL' and R 2 are H and Rs is CrC6 alkyl, or

(CHR

6

),C-C

6 cycloalky. In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' and R 2 are H and RS is Ar, 15 (CHR 6 )WAr, CH 2 (CHR6) Ar, or (CHR)wCH 2 Ar. In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' and R 2 are H and R.s is (CHR 4 )wCC 6 cycloalkenyl, CH 2

(CHR

4

)C.C

6 cycloalkenyl, CrCs alkenyl, or C 2 -C alkynyl. In a more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula IA, where R' and R 2 are H and iR 5 is CR6=CH-C 3

-C

6 cycloalkyl or CH=CR-CrC 6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is halogen; and R ' and 1 4 are H, C ethyl, or methylH 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is C1 or F; and R and 14 are H, C, ethyl, or methyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is CI or F; R 3 and R 4 are H, Cl, ethyl, 30 or methyl; and Rs, is CrC6 alkyl, or (CHR 6 ).CrC 4 cycloalkylt 14 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where Ris phenyl, optionally substituted. In another more-specific subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA, where R' is 1-phenyl, optionally substituted. 5 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is 4-phenyl, optionally substituted. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is phenyl, optionally substituted, and Rs is CrC6 alkyl, or (CHR 6

).C

3

-C

6 cycloalkyl. 10 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R2 is NH-CrC alkyl, N(CI-C& alkyl )-C

C

6 alkyl, C(=Q)NH-C-C alkyl, NH-C(=O)Cr-C alky; O-CI alkyl, C(=O)-CrCsalky, C(=O)-OCr-Cs alkyl, or OC(O)CGCalkyl; R is phenyl, optionally substituted, and R, is C,-C alkyl, or (CHR6),C-C 6 cycloalkyl. 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is H, methyl, or ethyl; and RI is NH-C-C 6 alkyl,

N(C-C

6 alkyl )-C-C alkyl, C(=zO)NH-C-C 6 alkyl, or NH-C(=O)C-C 6 alkyL In yet another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is H, methyl, or ethyl; and R, is C(=O)OCrC alkyl, 20 OC(=O)C-C 6 alkyI, or OCrC6 alkyl. In another specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R§ is H, methyl, methoxy, or halogen, and R! is methyl or ethyl. In another more specific subgeneric embodiment, this invention provides or 25 contemplates a compound of formula IA, where R, is H, methyl, methoxy, or halogen, and R' is phenyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R is H, methyl, methoxy, or halogen, and R' is F. 30 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula ]A, where R, is methoxy, methoxymethyl, ethoxymethyl, or methoxyethyl. In a more specific subgeneric embodiment, this invention provides or 5 contemplates a compound of formula IA, where R, is methoxy, methoxymethyl, ethoxymethyl, or methoxyethyl; R 2 is H, methyl, or halogen; and R 3 is methyl or C1. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R! is 4-phenyl, optionally substituted, and R is H, methyl, methoxy, or halogen. 10 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula [A, where Ris CF 3 or C 1

-C

3 alkyl, and R 2 is H, methyl, methoxy, or halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R' is methoxy, and R 2 is H, methyl, 15 methoxyor halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a coinpound of formula IA, where R' is 2-dimethylamino ethyl, and R 2 is H, methyl, methoxy, or halogen. In another more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula iA, where q is zero, R 2 is H, methyl, methoxy, or halogen, R' is 1-phenyl, optionally substituted; and R 3 and R 4 are H, Cl, ethyl, or methyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where q is zero, R 2 is H, methyl, methoxy, or halogen, R' is 4-phenyl, optionally substituted; and It, and R 4 are H, C, ethyl, or methyl. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where q is zero, R2 is H, methyl, methoxy, or halogen; R* is CF or CrC, alkyl; and R and R 4 are H, Cl, ethyl, or methyl, In another more specific subgeneriC embodiment, this invention provides or contemplates a compound of formula IA, where q is zero, R 2 is H, methyl, methoxy, or 30 halogen; R is methoxy and R 3 and R4 are H, Cl, ethyl, or methyl. 16 In another subgcneric embodiment, this invention provides or contemplates a compound of formula IA, where q is zero; R' is (2-dimethylamino) ethyl; R 2 is H, methyl, methoxy, or halogen; and R 3 and R 4 are H, CI, ethyl, or methyl In a more specific sub-generic embodiment, the invention provides or 5 contemplates a compound of ftnnula IA-I below. Rt 3 R, R1 R2 IA-1 In another more specific embodiment, this invention provides or contemplates a compound of formula IA-2 below. R H N O 0 R6

RR

4 R' 10 tR2 [A-2 In another more specific embodiment, this invention provides or contemplates a compound of formula IA-3 below. 15

R

3 R, R' R2 IA 3 Ft 1

__

In another more specific embodiment, this invention provides or contemplates a compound of formula IA-4 below. R% H NN RR RR R2 IA-4 5 In another more specific embodiment, this invention provides or contemplates a compound of formula IA-5 below Ra N &R4 R, R R2 [A-5 10 In another subgeneric embodiment, this invention provides or contemplates a compound of formula [IA-1 or formula IA-3, where R2 is H, alkyl, or halogen; and Rs is C-Cralkyl, (CHRw).CrC 6 cycloalkyl, (CHRs),CH 2

C

3

-C

6 cycloalkyl, or CH2(CHRa),CyC 6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or 15 contemplates a compound of formula IA-i or formula IA-3, where R, is (CH2).C 3

-C

6 cycloalkyl; R1 is H, alkyl, or halogen; and Rs is C-C 6 alkyl, (CH&),C 3 -Cs cycloalkyl,

(CHR

6

),CH

2

C-C

6 cycloalkyl, or CH 2 (CHR ).CrC 6 cycloalkyL In another more specific subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA-1 or formula IA-3, where R, is methoxy, 20 methoxymethyl, or methoxyethyl; R 2 is H, alkyl, or halogen; and R 5 is Cr-C alkyl,

(CHR

6

).C

3

-C

6 cycloalkyl, (CHR),CH 2

C

3

-C

6 cycloalkyl, or CH2(CHR).C 3 -C cycloalkyL. 18 In yet another more specific subgeneric embodiment this invention provides or contemplates a compound of formula IA-2, where R5 is Ca-C alkyl, (CHR),CrC 6 cycloalkyl, (CHR4),CH 2

C

3 -C cycloalkyi, or CH2(CHR),C 3

-C

6 cycdalkyl. In yet another more specific subgeneric embodiment, this invention provides or 5 contemplates a compound of formula IA-2, where Rs is Ar, (CH)Ar, CH 2

(CHR

6 ).Ar, or (CHR4)JCH 2 Ar. In yet another more specific subgenexic embodiment, this invention provides or contemplates a compound of formula IA-2, where Rs is CR 6

=CH-C

3 -C cycloalkyl,

CH=CR

6

-C

3

-C

6 cycloalkyl, (CHR4Cs-Q cycloalkenyl, CH 2 (CHR4)C.Cs 6 cycloalkenyt 10 C 2 -Q alkenyl, or CrC ynyl. In yet another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R 2 and R' are H; R 3 is methyl; and R is CrCf alkyl, (CHR),,C 3

-C

6 cycloalkyl, (CHR6).CH2C 3 -C cycloalkyl, or CH 2 (CHs).C3

C

6 cycloalkyt 15 In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is H, F, Cl, Br, methoxy, methoxymethy], ethoxymethyl, methoxyethyl, or trifluoromethyl; R 3 is methyl; and R, is

C

4 -C alkyl, (CHRs)XCH 2 C-Q cycloalkyl, or CH 2

(CHR

6 )WCrS& cycloalkyL In another still more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula IA-2, where R, is C4C alkyl, (CHR 6 ).CrC 6 cycloalkyl, or CH 2 (CHR4Cs-C, 6 cycloalkyl; and R, is H, F, Cl, Br, methoxy, methoxymethyl, ethoxymethyl, methoxyethylor trifluoromethyl. In another still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, is H, F, Cl, Br, methoxy, 25 methoxymethyl, ethoxymethyl, methoxyethyl, or trifluoromethyl; R2 is H, methyl, or F; R' is H or methyl; R is methyl; and Rs is CrCs alkyl, (CHR).C,-Q cycloalkyl, or

CH,(CHR

6

).C-C

6 cycloalkyl In another more generic embodiment, this invention provides or contemplates a compound of formula IA-1, where R Tis (CH2)CrC 6 cycloalkyl, Cr-C cycloalkenyl, or 30 (CH2)mCrC& cycloalkenyl; R' is halogen; and R 3 is methyl or CL 19 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R I is (CH2)mCrCs cycloalky, CrC6 cycloalkenyl, or (CH 2

)C

3

-C

6 cycloalkenyl; and R' is F or Cl. In another more specific subgeneric embodiment, this invention provides or 5 contemplates a compound of formula IA-1, where R, is methoxy, methoxymethyl, ethoxymethyl; or methoxyethyl; R 2 is H or F; R3 is methyl; R 4 is methyl or CI; and R5 is

(CHR

6 ),Cs-C 6 cycloalkenyl or (CHR 6 )wAr. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I, where R, is phenyl, optionally substituted 10 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where RI is methyl, halomethyl, ethyl, or haloethyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R'is 2-(dimethylamino) ethyl. 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R' is 1-methyl or 1-ethyl, In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R' is I -fluoro, R5 is C 4 -C alkyl, (CHR),Cs-C 6 cycloalkyl, or CH 2 (CHR4).C 5 -C cycloalkyl; and R, is H, F, Cl, Br, 20 rnethoxy, or trifluoromethyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R' is 4-fluoro, Rs is CrO alkyl, (CHR4),Cs-C 6 cycloalkyl, or CH2(CHR),Cs-C cycloalkyl; and Rj is H, F, Cl, Br, methoxy, or trifluoromethyl. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R I is (CH2)mimidazolyl, (CH2).pyrazyl (CH2)m furyl, (CH 2 )m thienyl, (CH2)moxazolyl, (CH 2 ).isoxazolyI, (CH)mthiazolyl, (CH2)misothiazolyl, (CH 2 )mphenyl, (CH 2 )mpyrrolyl, (CH2).pyridyL, or (CH2).pyrimidyl; and R2 and R' are H. 30 20 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R I is (CH 2 )nimidazolyl, (CH2).pyrazyL

(CH

2 )m furyl, (CH2)m thienyL, (CH 2 )moxazoly1, (CH 2 )misoxazolyl, (CH 2 )mthiazolyl, (CH2)isothiazolylt (CHz)phenyl, (CH2)mpyrrolyl, (CH 2 ).pyridyl, or (CH 2 ).pyrimidyl; and 5 R' is 4-phenyl, optionally substituted. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I, where R' is CF 3 or CrCa alkyl; RS is CvC alkyl, (CHR 6

).CS-C

6 cycloalkyl, or CH2(CHR),CrC cycloaikyl; and RI, is H, F, Cl, Br, methoxy, or trifluoromethyl. 10 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where RI is 4-methyl or 4-ethyl; and R5 is Cc

C

6 alkyl, (CHR.

6 ).Cr-C cycloalkyl, or CH2(CH ),Cs- cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifluoromethyl. In another more specific subgeneric embodiment, this invention provides or 15 contemplates a compound of formula IA-1, where W is methoxy or ethoxy, and Rs is Cc C ak, (CHR6),C 5 C cycloalkyl, or CH 2

(CHR.

6 )s-C 6 cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifluoromethyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA- 1, where T' is I -phenyl, optionally substituted; 20 Rj is C 4

-C

6 alkyl, (CHRsC),C 6 - cycloalkyl, or CH2(CHR),.C-CC cycloalkyl; and R is H, F, Cl, Br, methoxy, or trifluoromethyL In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formul a IA-1, where R' is 4-phenyl, optionally substituted; Rs is C 4 -Cdalky. (CHR4).Cs-C 6 cycloalkyl, or CH 2 (CHR),CrC 6 cycloalkyl; and R, is H, 25 F, Cl, Br, methoxy, or trifluoromethyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R' is CF 3 or CrC 3 alkyl; RS is C4-C alkyl, (CHRs),C 5 -C cycloalkyl, or CHz(CHR 6 )wCrC 6 cycloalkyl; and RI is H, F, Cl, Br, methoxy, or trifluoromethyL In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R' is 4-methyl or 4-ethyl; R5 is CrC alkyl, (CHR 6

).C

5

-C

6 cycloalkyl, or CHz(CHR).Cs-C cycloalkyl; and R I is H, F, C, Br, methoxy, or trifluoromethyL 5 In another more specific subgeneric embodiment, this invention provides or contemplates a cornpound of formula IA-1, where R is methoxy or ethoxy, Rs is C 4

-C

6 alkyl, (CHRs),Cs-C cycloalkyl, or CH(CHR6)AC-Cr cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifluoromethyl. In another more specific subgeneric embodiment, this invention provides or 10 contemplates a compound of formula IA-4, where RE is H, F, CI, Br, methoxy, or trifluormmethyl; Rs is C 4 -Cs alkyl, (CHRs),Cr cycloalkyl, or CH2(CHR 6 )WCS-Cs cycloalkyl; and R is H, F, Cl, Br, methoxy, or trifluoromethyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-4, where R 2 is H, F, or methyl; t; is CeC alky 15 (CHR6),C-4 5 cycloalkyl, or CH 2 (CHRd)Cs-C 6 cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifluoromethyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R' is H. In another subgeneric embodiment, this invention provides or contemplates a 20 compound of formula IA-2, where R' is halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R'! is F. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula 1A-2, where R' is methyl or ethyl. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula UA-2, where R' is methyl or ethyl; R 5 is C 4

-C

6 alkyl,

(CHR

4 ),Cs-C6 cycloalky , or CH 2

(CHR),CS-C

6 cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifIuoromethyL In another more specific subgeneic embodiment, this invention provides or 30 contemplates a compound of formula IA-2, where R is halogen; Rs is C4-Ca alkyl, 22

(CHR

6 ),Cs-C 6 cycloalkyl, or CH 2

(CHR

6

).CSC

6 cycloalkyl; and Rt is H, F, Cl, Br, methoxy, or trifluoromethyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R! is H; R 5 is CeC6 alkyl, (CHR 6 )Cs 5 C6 cycloalkyl, or CH2(CHRlCrCS cycloalkyl; and R is H, F, Cl, Br, methoxy, or trifluoromethyL. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R' is 1-phenyl, optionally substituted. In another more specific subgeneric embodiment, this invention provides or 10, contemplates a compound of formula IA-2, where R' is 4-phenyl, optionally substituted. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R' is CF 3 or CrC alkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R' is H; R 5 is C-eC6 alkyl, (CHR)wC5 15 C6 cycloalkyl, or CH2(CHR 6 ),CS-Q cycloalkyl; and R, is IH, F, Cl, Br, methoxy, or trifluoromethyl, In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R' is F; Rs is CrCs alkyl, (CHR),C, CQ cycloalkyl, or CH2(CHRs),Cs-q cycloalkyl; and R is H, F, Cl, Br, methoxy, or 20 trifluoromethyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R' is 1-phenyl, optionally substituted;

R

5 is C4-0 alkyl, (CHR),Cs-C 6 cycloalkyl, or CH2(CHRS).C5rC cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifluoromethyl. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R' is 4-phenyl, optionally substituted; Rs is C4-4 ak, (CHR )Cs-C cycloalkyl, or CH2(CHR).C-C 6 cycloalkyl; and R, is H, F, Cl, Br, methoxy, or trifluoromethyl. In another more specific subgeneric embodiment, this invention provides or 30 contemplates a compound of formula IA-3, where R' is CF 3 or C-C3 alkyl; R5 is CrC6 23 alkyl, (CHR 6

),C

5

-C

6 cycloalkyl, or CH 2

(CHR

6 ),Cs-C 6 cycloalkyl; and Ra is H, F, Cl, Br, methoxy, or trifluoromethyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-, where R, and R2, are, independently, H, CN, F, Cl, Br, 5 CH 2 CN, OCH 3 , CH 2

OCH

3 , CH 2 CH2OCH,, CH 2

OCH

2 CH3; CH 2 F, CHF 2 , CF 3 , CF 2

CF

3 , or C-C alkyl and R is CrCs alkyl or CHz(CHRe),C-C 6 cycloalkyl, where w =0, 1, or 2. In another still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, RI is H, CN, F, C1, Br, CH 2 CN, OCH 3 , CH2OCH 3 , CH 2

CH

2

OCH

3 , CH 2

OCH

2

CH

3 , CH2F, CHF 2 , CF3, CF 2

CF

3 , or Cr-C 6 alkyl; R2 is 10 H, F, Cl, or methyl; R.3 is methyl or chloro; and R5 is CrZs alkyl or CH 2 (CHR6),CrC6 cycloalkyl, where R6 is H or methyl and w I I or 2. . In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where Rs is Ar, (CHk).Ar, CH 2

(CHR

6 )-Ar, or (CHR4),CH 2 Ar. 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R5 is Ar, (CHR)WAr, CH 2 (CHR)M,Ar, or (CHR)wCH2Arl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R5 is Ar, (CHI&)wAr, CH2(CHR6).Ar, or 20 (CHRs),CH 2 Ar. In another more specific subgeneric embodiment, this invention provides or contemplates compounds of formula IA-1, IA-2, IA-3, IA-4, or IA-S, where R, and R2, are, independently, methyl, ethyl, F, Cl, CF,3, methoxy or methoxymethyl, W is methyl, and Rs is C 4 -C alkyl, (CHRs),Cs-Cs cycloalkyl, or CH 2 (CHR)wC5-C 6 cycloalkyl. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R5 is CR 6 tCHrC 3 -Cs cycloalkyl, CH=CR6-C,-C 6 cycloalkyl, (CHR 6 ).C5-C cycloalkenyl, CH2(CHR).C-C 6 cycloalkenyl, Cz-Cf alkenyl, or CrC 6 alkynyl. In another subgeneric embodiment, this invention provides or contemplates a 30 compound of formula IA, where Rs is haloalkyl. 24 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I, where R5 is haloalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R5 is haloalkyl 5 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where Rs is haloalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R5 is methoxy alkyl. In another subgeneric embodiment, this invention provides or contemplates a 10 compound of formula IA, where R5 is cyano alkyL In a more specific subgeneric embodiment, the invention provides or contemplates a compound of formula IA-4, where Rs is halo alkyl. in a more specific subgeneric embodiment, the invention provides or contemplates a compound of formula IA, where R, is CHcycloalkyl or CH 2

CH

2 r 15 cycloalkyl. In a more specific subgeneric embodiment, the invention provides or contemplates a compound of formula IA-4, where R5 is CH 2 -cycloalkyl or CH2CHr cycloalkyL In a more specific subgeneric embodiment, the invention provides or 20 contemplates a compound of formula IA-5, where Rs is CH 2 -cycloalkyl or CH 2

CH

2 cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA- I, where R3 and R4 are chloro, methoxy, or methyl and RS is CH2-cycloalkyl. 25 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R3 and R4 are chloro, methoxy, or methyl and RS is haloalkyl, hydroxyalkyl, or methoxyalkyl. In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R3 and R4 are chloro, methoxy, or 30 methyl and R-s is methoxy alkyL 25 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R, and R 4 are chloro, methoxy, or methyl and Rs is chioroalkyl. In another subgeneric embodiment, this invention provides or contemplates a 5 compound of formula IA-2, where R3 and R4 are chloro, methoxy, or methyl and R5 is methoxyalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R,3 and R4 are both methyl and Rs is 2-(2-halo cyclopentyl) ethyl. 10 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R3 and R4 are both methyl and R5 is 2-(2-furyl) ethyl, In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where Ra and R 1 4 are both methyl and R5 is 2-(2 tetrahydrofuaryl) ethyl. Is In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R3 and R 4 are both methyl and Rs is 2-phenyl ethyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I, where R(3 and 14 are both methyl and Rs is 3-phenyl propyl. In another subgeneric embodiment, this invention provides or contemplates a 20 compound of formula IA-1, where R3 and R4 are both methyl and R5 is 2-phenyl propyl, In another more specific subgeneric embodiment, this invention provides or contemplates a compound of fomiula IA-1, where R-5 is C-C alkyl, (CHR 6

),C-C

4 cycloalkyl, (CHRE),CH2CrC6 cycloalkyl, or CHz(CHR 6

).C

3

-C

6 cycloalkyl; R' is halogen or C,-C alkyl; and R, is halogen. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where Rf is CrCsalkyl, (CH1),C-C 6 cycloalkyl, (CH1 4

),CH

2

C-C

6 cycloalkyl, or CH4 2 (CHi)Cr-C cycloalkyl; R('is halogen or CrC3 alkyl; R2 is H or halogen; and R is halogen. In another more specific subgeneric embodiment, this invention provides or 30 contemplates a compound of formula IA-1, where R- is C-Q akyl, (CHR6).C-C 6 26 cycloalkyl, (CHRas)CH 2

C

3 -C cycloalkyl, or CH2(CHR 6 ),C-C cycloalkyl;R' is phenyl, optionally substituted; Ra is H or halogen; and R 1 is halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where Rs is CrCi alkyl, (CHR).C 3 -C 5 cycloalkyl, (CH ).CH 2

C

3 -C cycloalkyl, or CHz(CHR 6 )wCrC 6 cycloalkyl; R' is halogen or C-C, alkyl; R 2 is H or halogen; and R, is halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R5 is C 1

C

6 alkyl, (CH ),CrC6 cycloalkyl, (CHR),CH2Cr-C cycloalkyl, or CH 2

(CHR

4

),C-C

6 cycloalk; R' is halogen or 10 C-C 3 alkyl; and R, is halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where Rs is C-C 6 alkyl, (CHR).C 3

-C

6 cycloakyl, (CHR 4

).CH

2

C

3

-C

6 cycloalkyl, or CH 2 (CHR4),C 3 -C cycloalkyl; R' is halogen or CrC3 alkyl; and R, is halogen. 15 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R5 is CR=CH-CrC 6 cycloalkyl, CH=CRj-CC cycloalkyl, (CH%).Cs-Cs cycloalkenyl, CH2(CHM),,Cs cycloalkenyl, CrC alkenyl, or CrC6 alkynyl. In another more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula IA, where Rs is Ar, (CHo),Ar, CH 2 (CHRe).Ar, or

(CHR

6 ),CH2Ar. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA-3, where R, is haloalkyl; R2 is H or F; R3 and R4 are Cl, methoxy, or methyl; and Rs is C-G 6 alkyl, (CH ),CrC cycloalkyl, 25 (CHR 6 )wCH2CrC cycloalkyl, or CH2(CHR)4Z-C 6 cycloaly. in another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is C,-C1 alkyl, halogen, or haloalkyl;

R

2 is H or F; R3 and R4 are H, methyl, or Cl; and Rs is CH 2

CR

6

-C

3

C

6 cycloalkyl,

CRCH-C

3

-C

6 cycloalkyl, CH=CRs.-Cr-C 6 cycloalkyl, (CHRa),Cs-C cycloalkenyl, 30 CH 2 (CH),Cs-G 6 cycloalkenyl, C 4

-C

6 alkyl, C 2

-C

6 alkenyl, or Cr-C6 alkynyl. 27 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where RI is C 1

-C

3 alkyl, halogen, or haloalkyl; R2 is H or F; R, and R4 are H, methyl, or C; and R5 is CH 2 CR-Cr-C cycloalkyl, CRCCH-C-C 6 cycloalkyl, CH=C(t 6

-C

3 -C cycloalkyl, (CHR 6

)XC-C

6 5 cycloalkenyl, CH2(CHRhC4CS cycloalkenyl, CeC6 alkyl, CrC6 alkenyl, or CrCi akynyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R] is C-C3 alkyl, halogen, or haloalkyl; R2 is H or F; R3 and R 4 are H, methyl, or Cl; and Rs is CH 2 CRgCrC cycloalkyl, CR 6

=CH-C

3 4C2 cycloalkyl, CH=CRC-C cycloalkyl, (CHR 4 ) Cs-C 6 10 cycloalkenyl, CH 2 (CHRhC 5 -C cycloalkenyl, CeC, alkyl, C 2

-C

6 alkenyl, or C-Cs alkynyL In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is C 1 -C, alkyl, halogen, or haloalkyl; R2 is H or F; R3 and R4 are H, methyl, or Cl; and R5 is CH2CRs-CrC 6 cycloalkyl, or C-C 6 alkyl. 15 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, is CrC3 alkyl, halogen, or haloalkyl; R2 is H or F; R3 and R4 are H, methyl, or Cl; and Rs is CH2CRS-Cr-Cs cycloalkyl, (CHR 6 )kC-C 6 cycloalkenyl, CH2(CHR4)C-C 6 cycloalkenyl, CrCa alkeny, or

C

2 4Cr alkynyl. 20 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where RI is halogen or haloalkyl; R2 is H or F; and R5 is CRg=CH-C 3

-C

6 cycloalkyl, CH=CR 6

-C-C

6 cycloalky, (CHR4)Cs-Cs cycloalkenyl, CH2(CHR)C-C cycloalkenyl,C 2

-C

6 alkenyl, or Cr-Cs alkyny. In another more specific subgeneric embodiment, this invention provides or 25 contemplates a compound of formula IA-3, where R, is halogen or haloalkyl; R2 is H or F; and Rs is CR4=CH-CrC4 6 cycloalkyl, CH=CR-C3-C 6 cycloalkyl, (CHR6%)Cs cycloalkenyl, CHz(CHR 4 XwCs-C cycloalkenyl, C-C 6 alkenyl, or CrC6 alkynyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, is halogen or haloalkyl; R2 is H or F; R 3 aid R 4 are Cl, methoxy, or methyl; and R 5 is Ci-Cs alkyl, (CHR6).CrCa cycloalkyl, (CHR4).CH 2

C

3

-C

6 cycloalkyl, or CH2(CHLa),CrC6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where RI is halogen or haloalkyl; R? 2 is H or 5 F; and Rs is CRrCH-C3-C 6 cycloalkyl, CH=CRa-CrC6 cycloalkyl, (CHRs)C-Ce, cycloalkenyl, CH2(CHR)wCrCa cycloalkenyl, C 2

-C

6 alkenyl, or C-s alkynyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula 1A-3, where R, is methyl, fluoro, or fluoroalkyl; R 2 is H or F; and R 5 is C-C 6 alkyI, (CHR.),CrC cycloalkyl, (CHR 6

),CH

2

C

3 -C cycloalkyl, 10 or CH2(CHR 6 )wC 3 -Q cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, is Cl, F, or CF 3 ; R 2 is H or F; R' is H or CH 3 ; and Rs is C4=CHC 3

-C

6 cycloalkyl, CH=CRe-C 3 -C cycloalkyl, (CHR 6 ),C-C cycloalkenyl, CH2(CH),C-CS cycloalkenyl, C206 alkenyl, or C2-C6 alkynyl. 15 in another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, is Cl, F, or CF 3 ; R 2 is H or F; R! is H or CH 3 ; and Rs is Ar, (CHSe).Ar, CHz(CHRs).Ar, or (CHR ).CH2Ar. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-A, where R 3 and R4 are 11, methyl, or Cl; and R 20 is C -Q alkyl, (CH ),3-Cr cycloalkyl, (CH ),CH 2

C

3 -Cs cycloalkyl, or CH 2 (CH )wC C6 cycloalkyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-5, where Ra and I4 are H, methyl, or Cl; and Rs is C s=CH-C-C cycloalkyl, CH=CR-C 3

-C

6 cycloalkyl, (CH )Cs-C6 cycloalkenyl, 25 CH 2 (CHR.)C0s-Q cycloalkenyl, CrCa alkenyl, or Cr-Ce alkynyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R and Rt. are H, methyl, or C; and where Ra and R 2 , on adjacent carbons, form a six-membered ring. In another rmore specific subgeneric embodiment, this invention provides or 30 contemplates a compound of formula IA-1, where R 3 and R. are H, methyl, or C; where 29

R

5 is C2-C alkyl, CH-C-C 6 cycloalkyl, CH2CH2-CS-Ct cycloalkyl, CR=CH-C-C 6 cycloalkyl, CH=CR-C 3 -Q cycloalkyl, or Cr-C alkenyl; and where RI and R2, are on adjacent carbons, and are both other than H. In another more specific subgeneric embodiment, this invention provides or 5 contemplates a compound of fonnula IA-1, where R3 and R 4 are H, methyl, or Cl; where

R

5 is CrCs alkyl, CH 2 rG 5

-C

6 cycloalkyl, CH 2

CH

2

-C-C

6 cycloalkyl, QRg=CH-C 3 -C cycloalkyl, CH=CR 4

-C-C

6 cycloalkyl, or Cs-Q alkenyl; and where R, and R2, on adjacent carbons, are both halogen. In another more specific subgeneric embodiment, this invention provides or 10 contemplates a compound of formula IA-1, where R, and R.4 are H, methyl, or Cl; where

R

5 is CrC6 alkyl, CH 2

-C

5 -Cs cycloalkyl, CI3CH 2

-C-C

6 cycloalkyl, CR=CH-C-C 6 cycloalkyl, CH=CR 6 -C1-C 6 cycloalkyl, or CrC6 alkenyl; and where R and R2, on adjacent carbons, are both fluorine. In a more specific subgeneric embodiment, this invention provides or 15 contemplates a compound of formula IA-1, where R' is F, methyl, or H; R3 and R4 are H, methyl, or Cl; and R5 is 01-C alkyl, (CHR),CrC cycloalkyl, (CHR)wCH 2 C-Q cycloalkyl, or CH 2 (CHR4,).C-C6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R' is F, methyl, or H; R5 is CR=CH 20 C3-C6 cycloalkyl, CH=CR 6 -Cr-C 6 cycloalkyl, (CHR).Cs-C6 cycloalkenyl, CH 2 (CH).Cs C6 cycloalkenyl C2-Ce alkenyl, or CrC akynyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I, where R' is halogen and R 5 is Ar, (CH).Ar,

CH

2 (CHR)Ar, or (CHR6).CH2Ar, 25 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-i, where Ri 1 and R2 are on adjacent carbon atoms and are both other than H. In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula [A-1, where Ri and R2, on adjacent cabon atoms are, independently trifluoromethyl or halogen; and where Rs is CeC6 alkyl, (CHR6)CC 6 cycloalkyl, (CHR),CH2C 3 -Q cycloak, or CH 2 (CH4),C-C cycloalky. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where Rs is (CHR),.C-C cycloalkenyl, CH 2

(CHR

6 ),Cs-C 5 cycloalkenyl, CrC6 alkenyl, or CrCe alkynyL In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R is halogen and:R is H, or R 1 i and

R

2 , on adjacent carbon atoms are, independently trifluoromethyl or halogen; and where R5 is CR 6

=CH-C

3

-C

6 cycloalkyl, CH=CR$ 3 C cycloalkyl, (CHR,).

6

C-C

6 cycloalkenyl, 10 CH 2 (CHR ),CrC- cycloalkenyl, CrC alkenyl, or CrC alkynyl. In another subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA-1, where Rs is Ar, (CHR ).Ar, CH 2

(CHR

6 ).Ar, or (CHR)CH2Ar. In another more specific subgeneric embodiment, this invention provides or 15 contemplates a compound of formula IA-1, where R is halogen or trifluoronethyl and R2 is H, or R 1 and R 2 , on adjacent carbon atoms are, independently trifluoromethyl or halogen; and where K, is Ar, (CHR6),Ar, CI-1 2 (CHR)wAr, or (CHR),CH 2 Ar. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where X is S, q =i, Y is 0, and R5 is C 1 -C6 20 alkyl, (CHR6),C 3

-C

6 cycloalkyl, (CHR6),CH 2 CyC 6 cycloalkyl, or CH 2 (CHR6),CrC 6 cycloalkyl, In another more specific subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA, where X is S, q =1, Y is 0, and RS is CR6=CH CrC6 cycloalkyl, CH=CR6-Cr3Q cycloalkyl, (CHR6)C,-C.

6 cycloalkenyl, 25 CH 2 (CHR6),Cs-C 6 cycloalkenyl, CrCs alkenyl, or C 2 -C alkynyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where X is S, q =1, Y is 0, and Rs is Ar, (CHR6).Ar, CH(CHR6)WAr, or (CHR6)wCH 2 Ar In another more specific subgeneric embodiment, this invention provides or 30 contemplates a compound of formula TA, where X is S, q zero, and R, is CrCalkyl, 31 (CHR6).CrC 6 cycloalkyl, (CHR6),CH 2

C

3 -C cycloalkyl, or CH 2 (CHR6);CrC cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where X is S, q = zero, and Rs is CR&=CH-C 3 5 C 6 cycloalkyl, CH=CR-C 3

-C

6 cycloalkyl, (CH4),C-C6 cycloalkenyl, CH(CHR),CrC, cycloalkenyl, Cz-C6 alkenyl, or Cr t a alkynyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2 where Rs is C- alkyl or (CHR),C 3 -C cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a 10 compound of formula IA-3, where Rs is CI-C6 alkyl or (CHR).CrC 6 cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA-2, where R, is halogen or trifluoromethyl and Rz is H or R, and

R

2 , on adjacent carbon atoms, are, independently, halogen or trifluoromethyl; and Rs is

C-C

6 alkyl or (CHR),C 3

-C

6 cycloalky. 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, is halogen or trifluoromethyl and R2 is H or R, and R2, on adjacent carbon atoms, are, independently, halogen or trifluoromethyl; and R 5 is C-Cr 6 alkyl or (CHR 4 ),,CrC cycloalkyL In another more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula IA-2, where R, and R2 are, independently, methyl, methoxy, trifluoronethyl, F, Cl, or H; and R5 is 0C-alkyl or (CHR6),C3C 6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where R, and R2 are, independently, methyl, methoxy, trifluoromethyl, F, CI, or H; R' is H; and R 5 is Cj-s alkyl or (CHR46)C 3 -Q 25 cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a compound of fonnula IA-1 or TA-2 or IA-3, where Rl is halogen, C-C 6 alkyl, mono-halo CI-Cr alkyi, CN, di-halo C-C alkyl, CF 3 , CN, or O-0-C 6 alkyl; R' is methyl or ethyl; and R5 is Cs 4 26 alkyl or CH-CrC6 cycloalkyl.

In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I or IA-2 or IA-3, where R, is H, halogen, cyano, CF 3 , or methoxy, R 2 is H, F, or methyl, R' is H, halogen, methyl, ethyl, or methoxy, and Rs is CC alkyl or CH 2

-C

3

C

6 cycloalkyL 5 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is F, Cl, or CF 3 ; R 2 is H; and R' is halogen, methyl, ethyl, or methoxy; R and R 4 are H, methyl, or Cl; and Rs is Cs-C 6 alkyl or CHrCrC cycloalkyl, In another subgeneric embodiment, this invention provides or contemplates a 10 compound of formula IA, where R is halogen or CF 3 ; R 2 is HI, F, or methyl, R' is phenyl;

R

3 and R4 are H, methyl, or Cl; and R 5 is CSC 6 alkyl or CH 2

-C

5 4CS cycloalkyL In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R$ is halogen or CF 3 ; R 2 is H, F, or methyl, R' is halophenyl; R 3 and R 4 are H, methyl, or Cl; and R 5 is C 5 -C alkyl or CH-CrC cycloalky, 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is NH 2 , NH-CrC alkyl; N(CrC 6 alkyl)-CrC alkyl, NHC(=O)Cr-Calkyl, C(=O)N(CH 3

)

2 , C(=O)N(Eth(, C=O)NH 2 , C(=O)NH-C,-C 4 alkyl,

SO

2

NH

2 , NHSO 2

-C-C

6 alkyl. In a more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula IA where R, is NH 2 , NH-C-C 6 alkyl; or N(C-C 6 alkyl)-C-C 6 alkyl; and R 2 is H or halogen. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA where R, is NHC(=O)CrC& 6 alkyl,

C(=O)N(CH

2 , C(=O)N(Eth, C(=O)NH 2 , or C(=O)NH-CrC alkyl. 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1 where R, is NHC(=O)C-C 6 aIkyl, C(=O)N(CH)h, C(=O)N(Et) 2 , C(=O)NH2, or C(=O)NH-C-Cs alkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1 where R 1 is SO 2

NH

2 or NHSO 2 -CrC- alkyl.

In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula iA-2 where R, is SO 2 NH2 or NHSOrCrC6 alkyl, In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R I is C(=O)OC-C alkyl, OC(O)C-C 6 alkyl, OC,-C 6 5 alkyl, or SCrC 6 alkyL In another subgereric embodiment, this invention provides or contemplates a compoud of formula IA, where R, is (CH 2 )mC 3

C

6 cycloalkenyl, C2-C6 alkenyl, or CrC alkynyl. In another subgeneric embodiment, this invention provides or contemplates a 10 compound of formula IA, where R I is CH 2

OCH

3 , CH 2 O CH , OCrC6 alkyl, or SCr C6 alkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where RI is C(=O)OC-C 6 alkyl, OC(=O)C C6 alkyl, OC-C 6 alkyl, or SC -Cc alkyl, 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is CH 2 OCH, CH 2

OCH

2

CH

3 , OCrCs alkyl, or SC, Cr alkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is C(=O)OC-C6 alkyl, OC(=O)C 20 C6 alkyl, OC-C6 alkyl, or SC-C6 alkyl; R 2 is H, F, or methyl, R' is halogen or'methyl; and Rs is Cs-C 6 alkyl or CH2-CCs-Q cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is NH 2 , NH-CrCs alkyl; or N(CrCs alkyl)-Cr alkyl; R2 is H, F, or methyl, R' is halogen or methyl; and R 5 is Cs-CS alkyl or 25 CH-C-C cycloalkyL In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R$ is NHC(=)CrCs alkyl, C(=O)N(CH3)s C(=O)N(Et), CQ=O)NH2, C(=O)NH-CrCs alkyl, SO2NH2, or NHSO-Cr Cs alkyl; R2 is H, F, or methyl, R! is halogen or methyl; and Rs is CCalkyl or CHr-Cr 30 C6 cycloalkyl. 34 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is C 2 -CS alkynyl, optionally substituted. In another subgeneric embodiment, this invention provides 6r contemplates a compound of formula IA, where R, and R 2 form a fused, nitrogen-containing ring. 5 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, and R 2 form a fused, oxygen-containing ring. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R and R 2 form a fused thiazolo or isothiazolo group. In another subgeneric embodiment, this invention provides or contemplates a 10 compound of formula IA, where R and Rz form a fused cyclopentane, optionally substituted. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, and R 2 fora a fused cyclohexane, optionally substituted. 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I or IA-2, where RI and R 2 form a fused, nitrogen-containing ring. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1 or IA-2, where R, and R 2 form a fused, oxygen-containing 20 ring. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-) or IA-2, where RI and R 2 form a fused thiazolo or isothiazolo group, In another subgeneric embodiment, this invention provides or contemplates a 25 compound of formula IA-1 or IA-2, where R, and R 2 form a fused cyclopentane, optionally substituted. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1 or IA-2, where R and R 2 form a fused cyclohexane, optionally substituted.

In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I or IA-2, where R, and R 2 form a fused, nitrogen-containing ring; and Rs is Cs-C 6 alkyl or CH 2

-C

5

-C

6 cycloalkyl. In another subgeneric embodiment, this invention provides or contemplates a 5 compound of formula IA-I or IA-2, where R and R 2 form a fused, oxygen-containing ring; and R 5 is Cs-C 6 alkyl or CH 2

-C

5

-C

6 cycloalkyl, In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I or IA-2, where R I and R 2 form a fused thiazolo or isothiazolo group; and R 5 is CS-C alyl or CH 2 -Cs- cycloalkyl. 10 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I or IA2, where RI and R 2 form a fused cyclopentane, optionally substituted; and Rs is Cs 5 - alkyl or CHrCs-C 6 cycloalkyL In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-I or IA-2, where R, and R 2 form a fused cyclohexane, 15 optionally substituted; and RS is C 5 -C alkyl or CH 2

-CC

6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R I is halogen; R 2 is H, F, or methyl, R' is halogen or methyl; and R 5 is CyC-Qalkyl or CH 2 -0-C cycloalkyl. In another more specific subgeneric embodiment, this invention provides or 20 contemplates a compound of formula IA-1, where R, is halogen; R 2 is H, F, or methyl, R' is 2-(dimethylamino) ethyl; and Rs is Cs-C alkyl or CH-C 5 -C cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R is halogen; R 2 is H, halogen, or methyl, R' is H; and R 5 is CrC alkyl or CHrCsr cycloalkyt 25 In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where RI, is halogen; R 2 is H or methyl, R! is halogen or methyl; and R 5 is C-C 6 akyl or CH 2

-C

5 C cycloalkyl.

C(=O)OC,-C

6 alkyl, OC(=O)C-C( alkyl, OC-C 6 alkyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula 30 IA-1, In another more specific subgeneric embodiment, this invention provides or 36 )I contemplates a compound of formula IA-I, where R, is trifluoromethyl; R 2 is H or methyl, W is halogen or methyl; and R 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 IA-2, where R, where R, is trifluoromethyl; R 2 is H 5 or methyl, R' is halogen or methyl; and R5 is C-C alkyl or CH 2 -C-C cycloalkyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where Rt where R is trifluoromethyl; R 2 is H or methyl, R' is halogen or methyl; and R5 is Cs-C 6 alkyl or CH 2 -Cs-C 6 cycloalkyl. In another more specific subgeneric embodiment, this invention provides or 10 contemplates a compound of formula IA-4 or IA-5, where R, where R is trifluoromethyl;

R

2 is H or methyl, R' is halogen or methyl; and R5 is Cs-C 6 alkyl or CHrCs-C cycloalkyl In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R, is trifluoromethyl; R 2 is F; R' is halogen or methyl; and RS is CrQsalkyl or CHrC-C6 cycloalkyl. 15 In another subgeneric embodiment, this invention provides or contemilates a compound of formula IA, where R, or R 5 is CH 2 Ar or CH 2

CH

2 -Ar, where Ar is phenyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, or thiazolyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R is F. 20 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is Cl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R is Br. In another subgeneric embodiment, this invention provides or contemplates a 25 compound of formula IA-1, where R I is F. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R is CL In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is Br.

In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R , is F and R2 is H, OCH3, or F. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-k, where R, is F; R 3 and R4 are both methyl; and R' is H. 5 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R , is CF 3 ; R 3 and R 4 are both methyl; and P'is H. In another subgeneric embodiment, this invention provides or contemplates a compound of formula [A, where R, and R2 are both F. In another subgeneric embodiment, this invention provides or contemplates a 10 compound of formula IA, where R, is mono-, di-, or tri-halomethyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is CH 2 F, CHF2, or CF 3 . In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, is CH 2 CL 15 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where Rt is CH 2 Br. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where R, and R 2 are both F; R 3 and R4 are both methyl; and R' is H. 20 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where Rj is F. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R, and R 2 are both F. In another subgeneric embodiment, this invention provides or contemplates a 25 compound of formula IA-3, where R, is F. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-3, where RI and R2 are both F. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R, or Rs is CH2Ar or CH 2

CH

2 -Ar, where Ar is 30 isoxazolyl or isothiazolyl. 38 In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, where R 1 or R5 is CH 2 Ar or CHt2CHrAr, where Ar is quinolyl or isoquinolyl. In another subgeneric embodiment, this invention provides or contemplates a 5 compound of formula IA, where R or Rs is CH 2 Ar or CH 2

CH

2 -Ar, where Ar is pyrinidyl or purinyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula [A, where Ra or RS is CH 2 Ar or CH 2 CHr-Ar, where Ar is indolyl, isoindolyl, or benzimidazoly. 10 In a more specific embodiment, this invention provides or contemplates a compound of formula IA, where R 1 or Rs is CH 2 Ar or CH 2 CH-Ar, where Ar is halo phenyL In another more specific embodiment, this invention provides or contemplates a compound of formula IA, where R or R 5 is CH 2 Ar or CH 2

CH

2 -Ar, where Ar is 15 dihalophenyl or dihalopyridyL In another more specific embodiment, invention provides or contemplates a compound of formula IA, where R 1 or R 5 is CH 2 Ar or CH 2

CH

2 -Ar, where Ar is mono- or di-halothienyl, mono- or di-halofuryl, mono- or di-halobenzothienyl, or mono- or di halobenzofuryl. 20 In another more specific embodiment, this invention provides or contemplates a compound of formula IA, where R 1 or Rs is CH 2 Ar or CH 2

CH

2 -Ar, where Ar is o-, M-, or p- xylyl or o-, m- orp-anisyl. In another more specific embodiment, this invention provides or contemplates a compound of formula IA, where R or Rs is CH 2 Ar or CH 2

CH

2 -Ar, where Ar is M- orp 25 cyanophenyl or m- orp-cyanomethyl phenyl. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, in which R3 and R4 are halogen, CF 3 , or CrC, alkyl and Rs is

C

1 -Cralkyl, where the alkyl group is substituted with one or two groups selected, independently, from OH, OMe, OEt, F, CF3, Cl, or CN.

In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA, in which R 3 and 4 are halogen, CF 3 , OCF 3 , C-C 3 alkyl, or OCI-C, alkyl, and Rs is (CH 2 )wC 3

-C

6 cycloalkyl, where w is I or 2, where the cycloalkyl group is substituted with Me, OH, OMe, OEt, F, CF 3 , Cl, or CN. 5 In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, in which R,3 and R4 are halogen, CF 3 , or C

C

3 alkyl, and R5 is (CHz).-Cs-C 6 :cycloalkyl, optionally substituted, or (CH 2 )w-Cs-C 6 heterocycloalkyl, optionally substituted. In another more specific embodiment, this invention provides or contemplates a 10 compound of formula IA-1, where R, is CH2phenyl or CH 2

CH

2 -phenyl. In another more specific embodiment, this invention provides or contemplates a compound of formula IA-I, where R, is Ar, CH 2 Ar or CH 2 CH-Ar, where Ar is 3,5 dichlorophenyl or 3,5-difluorophenyl. In a more'specific embodiment, this invention provides or contemplates a 15 compound of formula IA-1, where R$ is Ar, (CHR 6 ).Ar, CH 2 (CHR6).Ar, or (CHR1).CH 2 Ar, where Ar is phenyl or pyridyl; R3 and R4 are H or C 1

-C

6 alkyl, unsubstituted or substituted with one or two groups selected from OH, OMe; and R.

6 is CN, CH 2 CN, or halogen. In another subgeneric embodiment, this invention provides or contemplates a 20 compound of formula IA-1, where Rs is Ar, (CHR 6 )Ar, CH 2 (CHUs).Ar, or (CH1?),CH 2 Ar, where Ar is phenyl or pyridyl; and R, is F, CH2F, CHF 2 , CF3, or CF 2 CF. In a more specific embodiment, this invention provides or contemplates a compound of formula IA-I, where R5 is Ar, (CH6),Ar, CH 2 (CHRO)wAr, or (CHR4)wCH 2 Ar, where Ar is phenyl or pyridyl, and R is OC-C 6 alkyl or C(=O)C-C 6 25 alkyl. In a more specific embodiment, this invention provides or contemplates a compound of formula IA-I, where Rs is Ar, (CH4).Ar, CH 2 (CHR )wAr, or (CHR6).CH 2 Ar, where Ar is phenyl or pyridyl, and R is C(=0)OC-C 6 alkyl or OC(=O)CeC- alkyl.

In a more specific embodiment, this invention provides or contemplates a compound of formula IA-1, where R, is Ar, (CHR),Ar, CH 2 (CHR6).Ar, or (CHs).CH 2 Ar, where Ar is phenyl or pyridyl, R, is C 2 -C alkenyl or C 2 -C alkynyl, q is 1, and X and Y are both O. 5 In a more specific embodiment, this invention provides or contemplates a compound of formula IA-1, where R 5 is Ar, (CHR).Ar, CH 2 (CHs).Ar, or

(CHR

4

).CH

2 Ar Ar is phenyl or pyridyl, and R 1 is SCrC alky In a more specific embodiment, this invention provides or contemplates a compound of formula [A-1, where Rs is Ar, (CHR 6 ).Ar, CH 2

(CH

6 )XAr, or 10 (CHR4),CAr, where Ar is phenyl or pyridyl, R 3 and R 4 are H, Cl, methoxy, or C-C 3 alkyl, and R 1 is C-C 6 alkyl In a more specific embodiment, this invention provides or contemplates a compound of formula IA-2, where R 5 is Ar, (CHR4),Ar, CH2(CHR).Ar, or (CHR).CH2Ar, where Ar is phenyl or pyridyl; Rk, and R, are H, Cl, metboxy, or CeC2 i5 alkyl, unsubstituted or substituted with one or two groups selected from OH, OMe; and

R

1 is CN, CH 2 CN, or halogen. In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA-2, where R 5 is Ar, (CHR ),Ar, CH 2 (CHR).Ar, or (CHRs).CHzAr, where Ar is phenyl or pyridyl; and RI is F, CH 2 F, CHF 2 , CF 3 , or CF 2

CF

3 . 20 In a more specific embodiment, this invention provides or contemplates a compound of formula IA-1, where R5 is Ar, (CHR4)VAr, CH 2 (CHR4&Ar, or

(CHR

6 ),CH2Ar, where Ar is phenyl or pyridyl, and R, is OC-C alkyl or C(=O)CrCs alkyl. In a more specific embodiment, this invention provides or contemplates a 25 compound of formula IA-2, where Rs is Ar, (CHR 6 )wAr, CH 2 (CHR ).Ar, or (CHR4,CH 2 Ar, where Ar is phenyl or pyridyl, and R, is OC-C 6 alkyl or C(=O)C-Cf alkyl. In a more specific embodiment, this invention provides or contemplates a compound of formula IA-3, where Rs is Ar, (CH ),Ar, CH 2

(CHR

6 )Ar, or :4t )I

(CHR

6

).CH

2 Ar, where Ar is phenyl or pyridyl, and R, is OCC 6 alkyI or C(=O)CrC alkyL. In a more specific embodiment, this invention provides or contemplates a compound of formula IA-3, where R' is phenyl or methoxy, R2 is H, and Rs is Ar, 5 (CHR6).Ar, CH 2 (CH4).Ar, or (CHRg),CH 2 Ar, where Ar is phenyl or pyridyl, and R. is C(=O)OCrC alkyl or OC(=O)CrC alkyL In a more specific embodiment, this invention provides or contemplates a compound of formula IA-2, where R5 is Ar, (CHR4),Ar, CH 2 (CHA).Ar, or (CHR),CH2Ar, Ar is phenyl or pyridyl, and R, is SCrC-Qalkyl. 10 In a more specific embodiment, this invention provides or contemplates a compound of formula IA-2, where Rs is Ar, (CHR),Ar CH2(CH%),Ar, or

(CHR),CH

2 Ar, where Ar is phenyl or pyridyl, R3 and R4 are H or C-C 3 alkyl, and R, is CrC6 alkyl. In another embodiment, this invention provides or contemplates a method of treating 15 or preventing a disease, disorder, or condition that is affected by modulation of potassium ion channels in a patient comprising administration of a compound of formula IA in an amount of up to 2000 mg per day. In another embodiment, this invention provides or contemplates a method of treating or preventing a disease, disorder, or condition that is affected by modulation of potassiwn 20 ion channels in a patient comprising administration of a compound of formula IA in an amount of from about 10 mg to about 2000 mg per day. In a more specific embodiment, this invention provides or contemplates a method of treating or preventing a disease, disorder, or condition that is affected by modulation of potassium ion channels in a patient comprising administration of a compound of formula 25 IA-1 in an amount of up to about 2000 mg per day. In a more specific embodiment, this invention provides or contemplates a method of treating or preventing a seizure disorder in patient comprising administration of a compound of formula IA in an amount ofup to about 2000 mg per day. 42 In another embodiment, this invention provides or contemplates a method of treating or preventing a seizure disorder in a patient comprising administration of a compound of formula IA in an amount of from about 10 mg per day to about 2000 mg per day. In another embodiment, this invention provides or contemplates a method of treating 5 or preventing a seizure disorder in a patient comprising administration of a compound of formula 1A in an amount of from about 300 mg per day to about 2000 mg per day. In another embodiment, this invention provides or contemplates a method of treating or preventing a seizure disorder in a patient comprising administration of a compound of formula IA in an amount of from about 300 mg per day to about 1200 mg per day. 10 In another more specific embodiment, this invention provides or contemplates a method of treating or preventing a seizure disorder in a patient comprising administration of a compound of formula IA-1 in an amount of up to 2000 mg per day. In another embodiment, this invention provides or contemplates a method of treating or preventing a seizure disorder in a patient comprising administration of a compound of 15 formula IA-1 in an amount of from about 10 mg per day to about 2000 mg per day. In another embodiment, this invention provides or contemplates a method of treating or preventing a seizure disorder in a patient comprising administration of a compound of formula IA-I in an amount of fror about 300 mg per day to about 2000 mg per day. In another embodiment, this invention provides or contemplates a method of treating 20 or preventing a seizure disorder in a patient comprising administration of a compound of formula IA-I in an amount of from about 300 mg per day to about 1200 mg per day. Detailed Description of Invention As contemplated by this invention, compounds of formula IA are designed for oral 25 or intravenous dosing of up to 2000 mg per day. Yet the high activities of marny of these compounds indicate that dosing of less than 1200 mg per day - the current anticipated dosing level ofretigabine in adults - is possible. Thus, this invention comprises tablets, capsulessolutions, and suspensions of compounds of formula IA which are formulated for oral administration. Similarly, solutions and suspensions suitable for oral pediatric 30 administration, comprising, in addition to compounds of formula IA, a syrup such as 43 sorbitol or propylene glycol, among many other examples, are also contemplated. More specifically, solutions and suspensions comprising, in addition to compounds of formula IA, a syrup such as sorbitol or propylene glycol, along with colorants and flavorings suitable for oral pediatric administration, are also contemplated. Additionally, both chewable and non 5 chewable tablets comprising compounds of formula IA, along with phannaceutically acceptable tabletting agents and other phannaceutically acceptable carriers and excipients, are also contemplated. As used herein, the term pharmaceutically acceptable carrier comprises such recipients, binders, lubricants, letting agents, disintegrants, preservatives, anti-oxidants, flavours and colourants as are typically used in the art of 10 formulation of pharmaceuticals. Examples of such agents include - but are not limited to starch, calcium carbonate, dibasic calcium phosphate, dicalcium phosphate, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose lactose, polyethylene glycols, polysorbates, glycols, safflower oil, sesame oil, soybean oil, and Povidone. Additionally, disintegrants such as sodium starch glycolate; lubricants such as 15 magesium stearate, stearic acid, and Si0; and solubility enhancers such as cyclodextrins, among a great many other examples for each group, are contemplated. Such materials and the methods of using them are well known in the pharmaceutical art. Additional examples are provided in Kibbe, Handbook ofPharmaceuIcal Excipients, London, Pharmaceutical Press, 2000. 20 As used herein, the term "pharmaceutically acceptable acid salts" refers to acid addition salts formed from acids which provide non-toxic anions. The pharmaceutically acceptable anions include, but are not limited to, acetate, aspartate, benzoate, bicarbonate, carbonate, bisulfate, sulfate, chloride, bromide, benzene sulfonate, methyl sulfonate, phosphate, acid phosphate, lactate, maleate, malate, malonate, fumarate, lactate, tartrate, 25 borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, glucuronate, gluconate oxalate, palmitate, pamoate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts; among a great many other examples. Hemi-salts, including but not limited to hemi-sulfate salts, are likewise contemplated. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, 30 Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). 44 As is well known, pharmaceutically acceptable salts of compounds of formula I may be prepared by reaction of a compound of formula I with the desired acid; by removal of a protecting group from a suitable precursor of the compound of formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the 5 desired acid or base; and by conversion of one salt of the compound of formula I to another by reaction. with an appropriate acid or base or by passage through an appropriate ion-exchange column. As used herein, the tern "pharnaceutically acceptable solvate" refers to describe a molecular complex comprising the compound of the invention and a stoichiometric 10 amount of one or more pharmaceutically acceptable solvent molecules, including but not limited to water and ethanol. Thus, the term solvate includes a hydrate as one example and an ethanolate as another example. As used herein, modulation of ion channels refers to activating the ion channels, to affecting the kinetics of opening and closing of the ion channels, or to causing any change 15 in the channel open probability of the ion channels. 45$ Preparation of compounds General Strategy Section . The preparation of compounds of formula VI is outlined in Scheme 1, in 5 which, for convenience, a substituted tetrahydroisoquinoline, N H R2 is symbolized by structure V. RN H R2 Such substituted tetrahydroisoquinolines are either commercially available or are 10 prepared from commercially available materials. A great many substituted tetrahydroisoquinolines are known, including many fused isothiazole, piperidino and pyrrolidino derivatives. Thus, for example, compounds of formula IA where R I is 5 fluoro- can be prepared starting with 5-fluoro-1,2,3,4-tetrahydroisoquinoline. Similarly, as another among many examples, compounds of formula IA where RI or R 2 is 6-methyl 15 can be prepared starting with 6-methyl-1,2,3,4-tetrahydroisoquinoline and, again, in two more examples among many, compounds of formula IA where R1 and R 2 are 6- and 7 chloro, respectively, can be prepared starting with 6-, 7- dichloro-1,2,3,4 tetrahydroisoquinoline; and compounds with a substituent in the 9-positio can be prepared starting with the appropriate 9-substitued tetrahydroisoquinoline. Analogously, 20 compounds with R' other than H can be prepared starting with the appropriate 1-, 3-, or 4 substituted tetrhydroisoquinolines. For examples, compounds in which, in the 1- and 4 positions, R' is phenyl, methoxy, ethyl, methyl, F, or 2-(N-, N-dimethylamino)ethyl are accessible via the commercially available 1- and 4-substituted tetrahydroisoquinolines. 4$.

Scheme 1: R3 CH3CN e NNHR I IIIV V Cy 2 a Pd(dba), teuOK, Toluene R, y R2 In this procedure the aromatic amine I is brominated according to standard $ procedures, including but not limited to the reaction with such reagents as N bromosuccinimide in an aprotic solvent such as acetonitrile. The reaction mixture is typically heated under reflux for a period of from approximately 8 to approximately 48 hours. In a typical procedure, the resulting brorno derivative II is purified by filtration of 10 the crude reaction mixture through Celite. If desired, other standard purification techniques, including flash chromatography, can be used. In the following step, the reaction of a compound I1 with the appropriate acyl chloride III in an aprotic solvent such as acetonitrile produces the aide of general formula IV. This reaction is typically conducted at room temperature for a period of 15 from approximately 4 to approximately 48 hours. The resulting aide of general formula IV can be purified by a standard chromatographic technique such as flash chromatography or thin layer chromatography. The next step of the reaction sequence is to prepare the desired product of general Formula VI using the well-known palladium coupling reaction, employing a phosphine 20 ligand such as the commercially available dicyclohexyl phosphino-2'-(NN dimethylamino)biphenyl. Thus, the amine of general formula V can be coupled to the bromine derivative of general formula IV using a palladium derivative such as, for 47 example, bis(dibenzylidineacetone)palladium, a base such as potassium tert-butoxide and the ligand dicyclohexyl phosphino2(NNdimethyl anino)biphenyl in an aprotic solvent. The reaction mixture is typically heated in an oil bath at 90*C for a period of from approximately 8 to approximately 48 hours, or it can be heated using a microwave 5 apparatus (Horizon unit, Biotage) at a temperature range of from approximately 90* to approximately 250*C. The desired compound of general formula VI is purified by standard chromatographic techniques, such as flash chromatography or thin layer chromatography. It can also be recrystallized from toluene. 10 Section 1L The preparation of compounds of formula IX is outlined in Scheme 2. Scheme 2: cY2

NH

2 RX CSt C N SRs RsH R3 uaNi, DMF Br R3R 3 UNI W 3 Pd(dba), -uCK, VII Tolusne VVA R H R ~ N y SR5 N R3 R1,

R

2 IX 15 In reactions in section 11, the compounds of general Formula IX are prepared in a way similar to that employed in section L The aniline derivative II (section 1) is combined with the haloalkyl compound VII under standard conditions to produce the desired thioester of general formula VIIl. The reaction is typically conducted at a temperature of from approximately 20" to approximately 90"C for a period of from 20 approximately 8 to approximately 48 hours, or in a microwave apparatus (Horizon unit, Biotage) at a temperature range of from approximately 900 to approximately 250*C. As in the previous sequence, the thioester can be purified by standard chromatographic techniques such as flash chromatography or thin layer chromatography. The final step, a 48 palladium coupling reaction to produce the compound of general Formula IX, is identical to that described in the corresponding step in Section 1. Section 1ff. The preparation of compound of formula XII is outlined in Scheme 3. 5 Scheme 3: PCy2 Rs NH 2 N OR 5 R R 3- 0J 2 + 2 Sr Ra CH 2

C

2 Base RR Pd(dba) 2 , t-BuOK Tolmne Sx V R4 H N ORs R RR R2 X in section 111, the carbamate derivative of general Formula XI is obtained from the 10 aniline derivative of general Formula II (see section 1) using standard conditions. Typically, the aniline is allowed to react with an anhydride derivative of general Formula X in the presence of a base such as triethylamine or diisopropyl ethylarnine in an aprotic solvent such as methylene chloride. The reaction is conducted at a temperature in the range of from approximately -20" to approximately 40"C for a period of from 15 approximately 30 min to approximately 48 hours, depending on the particular substrates, The resulting carbamate derivative of general Formula XI can be purified by the usual chromatographic techniques, such as flash chromatography or thin layer chromatography As in sections I and II, the final step is a palladium coupling. 20 Section W. The preparation of compound of formula X111 is outlined in Scheme 4. Scheme 4: 49 H 4 ' ORS N yORs R' R Lawasson's reagent N S NN R

R

1 xIIR Here, a compound of general Formula XII, obtained as in section III, reacts with Lawesson's reagent in an aprotic solvent such as methylene chloride to produce the 5 thiocarbarnate. Depending on the substrates involved, the reaction is stirred at room temperature or is heated under reflux for a period of from approximately 2 to approximately 48 hours. The resulting compound XII can be purified by the usual chromatographic techniques, such as flash chromatography or thin layer chromatography. 10 Section V. The preparation of compound of formula XIV is outlined in Scheme 5. Scheme 5: N R6 RN R Lawesson's reagent R' , NN R3 R, R2 V1 R1 v R2 R2 The com-pound of general Formula XIV is obtained under the same conditions 15 described in se-ction IV. 'The recinis typically heated under reflux or stirred at room temperature for a period of from approximately 2 to approximately 48 hours. The resulting deivative of general Formula XIV can be purified by the usual chromat graphic techniques, such as flash chromatography or thin layer chromatography, 20 Exemplary Compounds Staring materials: bromodimethylaniline was obtained from either AMf Aesar or Sigma Aldrich. Substituted tetrahydroisoquinolines commercially available; those used in exiempiary/ reactions here were obtained from ASW Med(he Iu- nc,, of New Brunswick, 50 NJ. Other substituted tetrahydroisoquinolines may be synthesized from commercially available starting materials via standard synthetic techniques. Example I 5 N-(2-chloro-4-(3,4-dihydroisoginolin-2(1I)-yl)-6-(trifluoromethyl)phenyl)-3,3 dimethylbutanamide Step A: Brs C

NH

2

CF

3 10 N-bromo succinimide (910 mg, 5,1 mmol) was added to a solution of 2-hloro-6 (trifluoromethyl)aniline (1.0 g, 5.1 mmol) and acetic acid (3 mL) in acetonitrile (10 mL) at room temperature. The mixture was heated at reflux, with stining, for 8h. The reaction mixture was then filtered through Celite and concentrated to give the title compound, which was used in the next step without further purification. 15 Step B: 44-bromo-2 ds a triflu thdbent '1 33 dimethylbutanamide: Br C

CF

3 20 3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solution of 4 bromo-2-chloro-6-(trifluoromethy)aniline (2.0 g, 7.3 nmtol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography in dichloromethane 25 afforded the title compound as a powder (1,22 g, 65% over the two steps). Step C: -42-chlor-4.4-dniuriso a in-2/Thsy1-6 51 N C10 N

CF

3 H Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol> and (2-dicyclohexyl phosphany-biphenyl-2-yl)-dimethylamine (3.3 mg, 0,0084 mmol) were added to dry tolUene (10 mL purged with argon), and the solution was stirred for 15 minutes under 5 argon. Potassium tert-butoxide (122 mg, 1.08 mmdo), 1,2,3,4-tetmhydroisoquinoline (87 mg, 0.65 mmol), and N-(2-chloro-4-(3,4-dihydroisoquinolin-2(WH)-yl)-6 (trifiuoromethyl)phenyl)-3,3-dimethylbutanamnide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirredat 90 "C overnight The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography 10 (dichloromethane:methanol 5%) to afford the title compound as a solid. (106 mg, 47%). H NMR (DMSO-d, 300 MHz) 8 1.02 (s, 9H), 2.07 (s, 3H), 2.17 (s, 2H), 2.92 (t, J= 5.4 Hz, 2H), 3,62(t, J- 6 Hz, 2H), 4.48 (s, 2H), 7.33 (m, 6H), 9.30 (s, IH). Example 2 15 N-(4-(3,4-dihydroisoquolin-2(1B)-yl)-2,6-dimethylphenyl)-3,3-dimethy butane de Br 20 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2,6-dimethyl phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate which formed was collected to give the title compound as a powder (7.46 g 100% yield). 25 Step B: N-(34-dihy-i' iLin2 1 v dimethylbutanamide 52 N ,?N H Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2T-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimnethylamine (3.3 mg, 0.0084 mmol) were added to dry 5 toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium :ert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrhydroisoquinoline (107 mg, 0.8 mmol) and N-(4-bromo-2,6-dmmethyl-phenyl)-3,3-dimethyl-butanamide (20.0 mg, 0.67 mmol) were then added, and the reaction mixture was stirred at 90 "C overnight. The reaction was then cooled to room temperature, concentrated and purified by thin layer 10 chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid (13.20 mg, 50%), 'H NMR (DMSO-d 6 , 300 MHz) 8 1.03 (s, 9H), 2,08 (s, 6H), 2.15 (s, 2H), 2.89 (t, J= 5.7 Hz, 2H), 3.49 (t, J= 5,7 Hz, 2H), 431 (s, 2H), 6.8 (s, 2H), 7.2 (m, 4H), 8.86 (s, 1H). 15 Example 3 N-(2-chloro-4-(3,4-dihydroisoquinoin-2(1H)-y)6-(trifluoromet y1)pheny) 3 cyelopentyl propanamide Step A. ommo chlro6fuoromet)aniie C1

NH

2 20 CFa N-bromosuccinimide (910 mg, 51 mol) was added to a solution of 2-chloro-6 (tifluoromethyl)a 'ine (1.0 g, 5.1 mmol) and acetic acid (3 mL) in acetonitile (10 mL) at room temperature- The mixture was stirred at reflux for 18h. The reaction mixture was then termed through Celite and concentrated to lve the title compound, which was used 25 in the next step without further purification. 53 Step B: Nd- I: mo2-choro&4- P lMIMMnILLh-c t propionamide: Br Cl C C N or 3 N 5 3&Cyclopenty propionyl chloride (1.28 g, 8.0 mmol) was added to a solution of 4 bromo-2-chloro-6-(trifluoromethyl)aniline (2,0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded 10 the title compound as a powder. Step C: N- hd q4(3,4 -dih iqu NC 15 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2-dicyclohexyl phosphanyl-biphenyl-2-y)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrahydroisoquinoline (107 rg, 0.8 mmol), and N-(4-bromo-2-chloro-6-trifluoromethyl phenyl)-3-cyclopentyl propionamide (200 20 mg, 0.5 mmol) were then added, and the reaction mixture was stirred at 90 *C overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane: methanol 5%) to afford the title compound as a solid. Yield: 28%. 1H NMR (CDC 3 , 300 MHz) 8 1.15 (in, 2H), 1,65 (m 4H), 1.85 (M, 4H), 25 244 (t, J- 75 Hz, 2H), 3.01 (1,1= 5.7. Hz, 2H), 3.6 (t, J 5.7. Hz, 2H), 4.43 (s, 2H), 6.72 (s, 1H), 7.10 (m, 2H), 7.24 (m, 4H). 54 Example 4 N-(2-chlor4-(6-fluoro-3,4-dihydroisoquinclin-2(1y}yl)-6 (trifluoromethyl)phenyl)-3,3-dimethylbutanamide: 5 Step A: §&f4gg4|4j mygg guinoliodQ e 0 NH Sodium azide (0.870 g, 13.33 nunol) was added in portions to a stirred solution of 5-fluoro-1 -indanone (1.0 g, 6.67 mmol) and methanesulfonic acid (4 mL) in dichloromethane (4 mL) at 0 *C. The reaction mixture was stirred at room temperature 10 for 18 h. The mixture was then cooled to 0 C and neutralized with 2N NaOH. The layers were separated, the aqueous layer extracted with dichloromethane, and the combined organic layers were dried over Na 2

SO

4 and concentrated to give the title compound as a white powder. The crude product was used in the next step. 15 Step B:j A nei a NH Diborane (IM, THF, 24 mL) was added at 0 "C to a solution of 6-fluoro-3,4 dihydro isoquinolin- I (21)-one (11 4g, 6.9 mmol) in THF (8 mL). The mixture was stirred at reflux for 18 h. It was cooled to room temperature and water was added. The 20 mixture was extracted with dichloromethane, and the organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (hexanes: ethyl acetate 1:1) afforded the title compound. Step C: NI 2LMkrir ::dih-Y a9 ninda-nkiQIit4 Y 25 ftrifiuromtyIXheny-33-4im1t-hyutanamidet H

CF

3 F Bis(dibenzylidineacetone)palladium (2 mg 0.0035nmol) and (2'-dicyclohexyl phosphanyl biphenyl-2-yl) dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium 5 tert-butoxide (122 mg, 1.08 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (96 mg, 0.65 mmol), and N-(4-bromo2-chloro-6-(trifluoromethyl)phenyl)-3,3-dinethylbutananide (200 ng, 0.54 mmol) were then added, and the reaction mixture was stirred at 90 "C ovemight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title 10 compound as a solid, m/z 441 [M-1]. Example 5 Nd2-Chloro-4-(3,4-dihydro-H-isoqn ioin-2-yl)-6-methy-phenyl-3,3-dimethyl butananmide 15 Step A:, 4bo tcnoro--methther Br CI H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine 20 (253g, 3.5 mL, 25 mmol) were added to a solution of4-brono-2-chloro-6-nethy phenylamine (5,0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate that formed was collected to give the title compound as a powder (7.46 g, 100% yield). Step : N-C h-1 25 dimethyl-butanide. The synthesis of this compound was performed as described in example 4, step C. 56 zk N, CI H H NMR (DMSOd 6 , 300 MHz) & 103 (s, 9H), 2.12 (s, 3H), 2.15 (s, 2H), 2.89 (t, J 5.7 Hz, 2H), 3.53 (t, J= 5.7 Hz, 2H), 436 (s, 2H), 6.87 (d, J= 9.6, 2H), 7.2 (n 4H), 9.08 (s, 5 1H). Example 6 N-[2-Chloro-4(6-fluoro-34-dihydro-1H-isoquinoin-2-yl)-6-trifluoromethy. phenylbe3-cyclopenty1-propionamide 10 Step A: 4-htr s2 tLdhtidPii Br ~CI

NH

2

CF

3 N-bromosuccinimide (910 mg, 5.1 nunol) was added at room temperature to a solution of 2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) and acetic acid (3 mL) 15 in acetonitrile (10 mL). The mixture was stirred at reflux to 18. The reaction mixture was then filtered through elite and concentrated to give the title compound, which was used in the next step without further purification. Step B: ] j| d ed_ 20 rmpionnamide Br CI C N CF3 H 3-Cyclopentyl propionyl chloride (1.28 g, 8.0 mmol) was added to a solution of 4 bromo-2-chloro-6(trifluoromethyl)aniline (2.0 g, 7.3 no]) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the 57 mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder. 5 Step C: i I-q-ingji &-: t~idu9E 4ab nyhld34yenotv arnponamide:

CF

3 Bis(dibenzylidineacetone)palladium (2 mg, 0.003Smmol) and (2'-dicyclohexyl 10 phosphanylt-biphenyl-2yl)-dimethylamine (3.3 mg, 0.0084 rmmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (140 mg, 1.25 mmol), 6-fluorol ,2,3,4-tetrahydroisoiinoline hydrochloride salt (150 mg, 0.8 mmol) and N-(4-Bromo-2-chloro-6-trifluoromethyl phenyl)-3-cyclopentyl-propionamide (200 mg, 0.5 mmnol) were then added and the 15 reaction mixture was stirred at 90 *C overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. ' NMR (DM80-d 6 , 300 MHz) 6 1.07 (m, 2H), L.57 (m, 6), 1.75 (rn, 3H), 2.31 (m, 2H), 2.93 (t, J= 5.1 Hz, 2H), 3.60 (t, J= 5.4 Hz, 2H), 4.45 (s, 2H), 7.06 (m, 21), 7.15 (s, 20 1H), 7.32 (n, 2H), 9.39 (s, 1H).

Example 7 N-2A,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydroeiH-isoquinotin-2-yl)-phenylj-3,3 dimethyl butamandde 5 Step A: 4i Br 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mrmol) and triethylamine (2.53g, 3.5 mL, 25 mmol) were added to a solution of 4-Bromo-2,6-dimethyl 10 phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate which formed was collected to give the title compound as a powder (7.46 g, 100% yield). Step B: N2Dnet-4- 6-ti 4reh-4iyds:JH-soouin9i-2y 15 phenylj3,3'-dimethyl butanamide: F3C N H Bis(dibenzylidineacetone)palladium (390 mg, 0.68 nnol) and (2-dicyclohexyl phosphanyl-bipheny-2-yl-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene 20 (150 mL purged with argon) and stirred for 30 minutes under argon. Potassium vert butoxide (4.75 mg, 42.3 wmnol), 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-bromo-2,6-dimethyl-phenyl)-3,3 dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80 *C overnight The reaction mixture was then cooled to room temperature and 25 recrystallized from toluene to afford the title compound as a solid, (5.55 g, 79%). 59 'H NMR (DMSO-dA, 500 MHz) 8 1.03 (s, 9H), 2.09 (s, 6H), 2,15 (s, 2H), 2.98 (t, J = 5.0 Hz, 2H), 3.52 (t, J= 6.0 Hz, 2H), 4.40 (s, 2H), 6.71 (s, 2H), 7.45 (d, J= 8.0, 1 H), 7.52 (m, 2H), 8.87 (s, IH). 5 Example 8 N-[2-Chloro-6-trifluoromethyl4-(6-tifluromethyl-3,4-dihydo-n-isoquinolin-2 y)-phenylJ-3,3-dimethyl butansaide Step A. - c a Br, JC

NH

2 10 CF 3 N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro-6 (trifluoromethyl)aniline (1.0 g, 5.1 mmol) in acetonitrile (10 mL) and acetic acid (3 mL) at room temperature. The mixture was stirred at reflux to 18b. The reaction mixture was then filtered through celite and concentrated to give the title compound which was used 15 in the next step without further purification Step B - N-- (4hl dinethylbutanamide: Br C 20 CF 3 3,3-dimethylbutanoyl chloride (1 08 g, 8.0 mmol) was added to a solution of 4 bromo-2-chloro-6-(trifiuoromethyl)aniline (2,0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overmight. Water was added to the mixture and then extracted with ethyl acetate. The organic layer was dried over sodium 25 sulfate and concentrated Purification by coAumn chromatography (100% DCM) afforded the title compound as a powder (1.2 g 65%) over the two steps. 60 Step C: N2-Ch -- triormh - -r thyl3 .44idrwo--JH iso not namide F C N I

CF

3 H 5 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (T-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 muL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-trifluoro-1,2,3,44etrahydroisoquinoline (154 mg, 0.65 nmol) and N-(4-bromo-2-chloro-6~(trifluormethyl)phenyl)-3,3 10 dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90 "C ovemight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid 'H NMR (DMSO-d, 500 MHz) & 1 03 (s, 9H), 2.17 (s, 2H), 3.02 (t, J= 5.35 Hz, 2H), 15 3.65 (t, J= 5.0 Hz, 2H), 4.61 (s, 2H), 7.19 (d, J= 2.0 Hz, 1H), 7.38 (d, J= 1.9 Hz, 1H), 7.49 (d, J 8.0 Hz, 1H), 756 (d, J= 8.1 Hz, 1H), 7.59 (s, 1H), 9.32 (s, 1 H). Example 9 20 N-f2-Chior -4-(6-chloro-3,4 dihydro-IH-isoquinoin-2-yl)-6-trifluoromethyl phenylj-3,3-dlmethyl butanamide Step A:- 4:tpmo-2-bj(tdt. -foome -M & lte Br CI 25 CF 3 61 N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro6 (trifiuoromethyl)aninlie (1.0 g, 5.1 mmol) in acetonitrile (10 mL) and acetic acid (3 mL) at room temperature. The mixture was stirred at reflux to I 8h. The reaction mixture was then filtered through Celite and concentrated to give the title compound which was used 5 in the next step without further purification. Step B: N 4m9-2j chior-64uomm 1eth wn-3 3 direthyLutanamide: Br CI N H 10 CF 3 3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmiol) was added to a solution of 4 bromo-2-chloro-6-(trifluoromethyl)aniline (210 g, 7.3 mmol) in acetonitrile (10 ML), The reaction mixture was stirred at room temperature overight. Water was added to the mixture and then extracted with ethyl acetate. The organic layer was'dried over sodium 15 sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder (1.22 & 65%) over the two steps. Step C: N2-Co44choro-dihydro-1Hisuinolin-2-vU-6 20 NN CFa Bis(dibenzylidineacetone)paladium (2 mg, 0.0035mmol) and (2'-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene -(10 mL purged with argon) and stirred for 15 minutes under argon. Potassium 25 ter-butoxide (151 mg, 1.35 nmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline 62 hydrochloride (133 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6 (trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added and the reaction mixture was stirred at 90 "C overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography 5 (dichloromethane:methanol 5*%) to afford the title compound as a solid tH NMR (DMSO-d 6 , 500 MHz) 8 1.02 (s, 9H), 2,17 (s, 21), 2.92 (tJ= 5.35 Hz, 2H), 3.61 (t, J== 5.6 Hz, 2H), 4.47 (s, 2H), 7J16 (s, 111), 7.29 (m, 3H), 7.34 (s, 1H), 9.31(s, 1H). 10 Example 10 N-[4-(6-Chloro-3,4-dlhydro-IH-isoquinolin-2-yl)-2,6-dimethyl-pbenyl-3,3-dimethyl butanamide Step A: 1 g $.'o-,dn hg,bcLv-$3An h ybwgna1imnde-V BrN 15 H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3.5 mL, 25 mrnol) were added to a solution of 4-bromo-2,6dimethyl phenylainine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed 20 collected to give the title compound as a powder (7.46 g, 100% yield). Step B: Nd444 hr %d dihsd nninin-. 2-d elhjphenyly 33a-diMethvl butanamide: CI N 25 H 63 Bis(dibenzylidineacetone)palladium (2 ng, 0.0035mmol) and (2'-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (5 mL purged with argon) and stirred fbr 15 minutes under argon. Potassium tert butoxide (188 mg, 1.7 mmol), 6-chloro-1,2,3,4-tetrahydro isoquinoline hydrochloride salt 5 (165 mg, 0.8 mnmol), and N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) were then added, and the reaction mixture was stirred at 80 C overnight. The reaction mixture was then cooled to room temperature and filtered through silica gel. Purification by preparative thin layer chromatography afforded the title compound as a solid. 10 'H NMR (DMSO-d, 500 MHz) 5 1.03 (s, 911), 2.08 (s, 6H), 2,15 (s,2H), 2.89 (t, J 5.25 Hz, 211), 3.47 (t, J= 5.6 Hz, 2H), 4.30 (s, 2H), 6.68 (s, 2H), 7,25 (mi, 3H), 8.85 (s, 1H1). Example i 15 N-[4-(6-fluora-3,4-dihydro-ZH-isoquinolin-2-yl)-2,6-dimethyl phenylj-3,3-dimethyl butanamide Step A: N-4-Dromo-2 6 thhe nI3-diet-unamide: Br H 20 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2,6-dimethyl phenylamine (5:0 g, 25 mimol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate which formed was collected to give the title compound as a powder (7.46 g, 100% yield). 25 Step B: 446-~uro4-i~d-UU 6 3.3-dimethyl butanamide: 4 H Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mnol) and (2'-dicyclohexyl phosphanylbiphenyl-2-y)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon for 30 minutes) and stirred for 30 minutes under argon. 5 Potassium tert-butoxide (4.75 mg, 42.3 mmol) 6-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (3.2 g, 17.0 mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3 dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80 "C overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.11 g, 83%). 10 'H NMR (DMSO-d, 500 MHz) & 1.03 (s, 9H), 2.08 (s, 6H), 2.15 (s, 2H), 2.89 (t, J= 5.25 Hz, 2H), 3.47 ( J= 5.6 Hz, 2H), 4.30 (s, 211), 6.68 (s, 2H), 6.99 (m, 2H), 7.25 (m, I H) 8. 84 (s, I H). Example 12 15 N-2-Chloro-44(7-fluoro-3,4-dihydro-H-isoquinoin-2-yl)-6-trifluoromethyl phenytj-3,3-dimethylbutanamide Step A:i-ro--hoo6~f~p~tvaiie Br NC NH?

CF

3 20 N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro-6 (trifiuoronethyl)aniline (1.0 g, 5.1 immol) in acetonitrile (10 mL) and acetic acid (3 mL) at room temperature. The mixture was stirred at reflux for 18h, The reaction mixture was then filtered through Celite and concentrated to give the title compound, which was used in the next step without further purification. 25 65 Step B: n dimethylbutanamide: Br C N

CF

3 H 3,3-Dimethylbutanoyl chloride (1 .08 g, 8.0 rmmol) was added to a solution of 4 5 bromo2chloro-6-(trifluornethy)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder (1.22 g, 65%) over the two steps. 10 Step C: N42-Cho47-fluoro4-dhy4d - nin-2-4n6 ill ethyl-phenv3.3-dirthylbutanamide: CF3 H 15 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2'-dicyclohexyl phosphanylbbiphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Pdtassiun tert-butoxide (151 mg, 1.35 mmol), 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (122 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6 20 (trifluoromethyl)phenyl) 3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90 *C overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. 'H NMR (DMSO-d, 500 MHz) 8 1.02 (s, 9H), 2.17 (s, 2H), 2.89 (t, J= 5.1 Hz, 2H), 361 25 (t, J = .5.7 Hz, 2H), 4.49 (s, 2H), 7.03 (dd, J 8.6, 2,3 Hz, 1H), 7.12 (m, 21), 7.16 (d, J= 2.2 Hz, 1H), 7.23 (m, 1H), 7.33 (d, J = 2.6, 1 H), 9.30 (s, 1H). 66 Example 13 N-I4-(7-Fluoro3,4-dihydro-1H-sequinolin-2-y)-26-dimethy-phenyl-3,3-dimethy. butanamide 5 Step A: df44 s2Edenety l-ad -dineth taniie Br H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3.5 mL, 25 mmol) were added to a solution of 4-Bromo-2,6-dimethyl 10 phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate fonned collected to give the title compound as a powder (7.46 g, 100% yield). Step B: 4474luQ 0 4 id 1H ii- -4t 15 3,3-dimethyl-butanamide: 'F 0 H Bis(dibenzylidineacetone)palladium (156 mg, 0,28 mmol) and (2'-dicyclohexyl phosphanyl-bipheny-2-yl)-dimethylamine (320 mg, 0.8 nmol) were added to dry toluene (60 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert 20 butoxide (1.9 g, 16.25 mmol), 7-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride sat (1.28 g, 6.8 mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 6.8 mmol) were then added, and the reaction mixture was stirred at 80 "C overnight The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (1.9 g, 76%). 67 'H NMR (DMSO-d, 400 MHz) S 1.5 (s, 9H), 2.10 (s, 6H), 2.17 (s, 2H), 2.89 (t, J= 5.1 Hz, 2H), 3.49 (t, J= 5.7 Hz, 2H), 4.34 (s, 2H), 670 (s, 2%), 7.0 (m, 1H), 7.1 (m, 1H), 7.2 (m 1H), 8.9 (s, IIH). 5 Example 14 N-[2-Chloro-4-(6-fluoro-3,4-dihydro 1H-isequinolin-2-ylk-6-methylphenylb-3,3 dimethylbutanamide Step A: dm m vethy pjen yBw 3 d i-btn d N Q 10 H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL 3 25 mmol) and triethylanine (2.53g, 3.5 mL; 25 mmol) were added to a solution of 4-Bromo 2-Chloro-6-nethyl phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed 15 collected to give the title compound as a powder (7.46 g, 100% yield). Step B: Ng me thylohnv13.3-dimnethytibutanamnide: F N Nk H 20 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035miniol) and (2'dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 inmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium fert-butoxide (197 mg, 1.75 mmol), 6-fluoro- 1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6methyphenyl)-3,3 25 dinethylbutanamide (200 mg, 0.63-mmol) were then added and the reaction mixture was stirred at 90 *C ovemight. The reaction mixture was then cooled to room temperature, 68 concentrated and purified by thin layer chromatography (dichloronethane~methanol 5%) to afford the title compound as a solid. 'H NMR (DMSO-d, 400 MHz) 6 1.05 (s, 9H), 2.14 (s, 3H), 2.17 (s, 2H), 2.91 (t, J= 5.25 Hz, 2H), 3.52 (t, J= 5.6 Hz, 2H), 4.37 (s, 2H), 6.85 (s, 1H), 6.9 (s, 1H), 7.0 (m, 2H), 5 7.3 (m, 1H), 9.10 (s, 1H). Example IS N-12-C horo4(7-fluoro-3,4-dihydro-1H-isoquinolin-2-y)-6-methylphenylf-3,3 dimethylbutanaimide 10 Step A:,- ~ 2a 6-nty-hovf -t H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3:5 mL, 25 mmol) were added to a solution of 4-Bromo-2-chloro-6-methyl 15 phenylanine (5.0 g, 25 mnol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield). Step B: -olin-2 l6 20 methylohev--imethviut de: NN H Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2'-dicyclohexyl phosphanyl-biphenyl-2-y)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 nL purged with argon) and stirred for 15 minutes under argon. Potassium 25 tert-butoxide (197 mg, 1.75 mmol), 7-fluoro-I,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methyphenyl)-3,3 69 dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90 'C overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. 5 'H NMR (DMSO-d, 400 MHz) 8 1.04 (s, 9H), 2.14 (s, 3H), 2.18 (s, 2H), 2.88 (t, J= 5.25 Hz, 2H), 3.55 (t, J= 5.6 Hz, 2H), 4.4 (s, 2H), 6.88 (s, 1H), 6.9 (s, IH), 7,0 (m, I H) 7.1 (m, 1H), 7.2 (m, 11H), 9. 10 (s, 1H). Example 16 10 N-l2-Chloro-6-methyl4-(6-trifluoromethyl-3,4-dihydro-4H-isequinolin-2-y) phenylf.3,3-dimethylbutanamide Step A:M. Bh m3 t a NK>C 15 H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2,53g, 3.5 mL, 25 mml) were added to a solution of 4-Bromo-2-chloro-6-methyl phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed 20 collected to give the title compound as a powder (7.46 g, 100% yield). Step B; N42-Chloo-methyl-446- tihooethyi4Aihvthoe-IJt-ji, 'n-n FaC 25 H 70 Bis(dibenzylidineacetone)palladiuin (2 mg, 0.0035mmol) and (2-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylaimine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 nL purged with argon) and stirred for 15 minutes under argon. Potassium lert-butoxide (197 mg, 1.75 nnol), 6-trifluoromethy- 1,2,3,4-tetrahydroisoquinoline 5 hydrochloride salt (154 mg, 0.65 imnol) and N-(4-bromo-.2-chloro-6-methyphenyl)-3,3 dimethylbutanamide (200 mg, 0.63 imnol) were then added and the reaction mixture was stirred at 900(C overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. 10 'H NMR (DMSO-d, 400 MHz) S 1.08 (s, 9H), 2.17(s, 3H), 2.21 (s, 211), 3.0 (t, J= 5.25 Iz, 2H), 3.6 (t, J= 5.6 Hz, 2H), 4.5 (s, 2H), 69 (s, 1H), 6.95 (s, 1H), 7.3 (m, IH), 7.5 (m, 211), 9.13 (s, 1H). Example 17 15 N-[2-Chloro-4-(6chloro-3,4-dihydro-H-isequinolin2-yl)-6-methyl-phenyp3,3 dimethylbutanamide Step A: zN Br C Nk< 20 H 3,3-dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3.5 mL, 25 mmol) were added to a solution of 4-Bromo-2-chloro-6-methyl phenylanine (5,0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed 25 collected to give the title compound as a powder (7.46 g, 100% yield). Step: N42-Coro,446-chloro-3 4dihydro-dlisouinoline46methe heny1b3,3-dimethylbutanamide; 71 C1 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mrnol) and (2T-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylainine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium 5 ter-butoxide (197 mg, 1.75 mmol), 6-chloro- I,2,3,44-tetrahydroisoquinoline hydrochloride salt (133 mg, 0,65 mmol), and N-(4-bromo-2-chloro-6-methyphenyl)-3,3 dimethylbutanamide (200 mg, 0.63 mmol) were then added, and the reaction mixture was stirred at 90 "C overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) 10 to afford the title compound as a solid. H NMR (DMSO-d 400 MHz) 6 1.06 (s, 9H), 214 (s, 3H), 2.18 (s, 2H), 2.9 (t, J= 5.25 Hz, 2H), 3.5 (t, J= 5.6 Hz, 2H), 4.4 (s, 2H), 6.85 (s, I H), 6-9 (s, I H), 7.25 (m, 3H), 9.1 (S, Il). 15 Example 18 N-[2-Chloro-4-(6-fluoro-3,4-dihydro-H-isoquinolin-2-y).phenyl3,3 dinethylbutanainde Step A: N44-i ||Xe]| g i mhgbitaat de 20 H 3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added to a solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 rmnol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the 25 mixture and the precipitate fonned collected to give the title compound as a powder (1.04 g, 72% yield), 72 Step B: N-::hM4- -uro-3,44thyd AAIii -AhpenylIkl dimnethylbutanamnide: The synthesis of this compound was performed as described in example 4, step C. Fi' 5 ci H 'H NMR(DMSO-d, 400 MHz) 6 1.04 (s, 91), 219 (s, 2H), 2.93 (tJ= 8Hz, 2H), 3.54 (t, J= 8 Hz, 2H), 4.37 (s, 2H), 6.96 (dd, J= 4, 12 Hz, 11H), 7.04 (m, 3H), 7.27 (m, 1H), 7.34 (d, J 8 Hz, I H), 9.17 (s, 1H). 10 Example 19 N-[4-(6-Fluoro-3,4-dihydro-JH-isoquinolin-2-yi)-2-methyl-phenyl}-3,3 dimethylbutanamide Step A: monB)-2-tLhl Br 15 H 3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, SA mmol) was added to a solution of 4-Bromo-2-methyl-pbenylamine (1.0 g, 5A mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (830 20 mg, 56% yield). Step B: Nh dimethylbutanamide: 25 The synthesis of this compound was perfonned as described in example 4, step C. 73 F N H 'H NMR (DMSO-d 6 , 400 MHz) 8 1.04 (s, 9H), 2.14 (s, 3H), 2.16 (s, 2H), 2,91 (t, J= 8 Hz, 2H), 3.48 (t, J= 8 Hz, 2H), 4.31 (s, 2H), 6. (dd, J= 4, 12 Hz, 1H), 6.85 (s, I H), 7.0 (m, 211), 7.09 (d. J= 8 Hz, 1H), 7.3 (m, 1H1), 8.98 (s, IH). 5 Example 20 N-[4-(6-Fluore-3,4-dihydro-1H-Isoquinoin-2-y)-2-trifluormethylpheny1-3,3 dimethylbutanamide 10 Step A: N- romo2-riuommethybyn 3~imethvh Br KNK)

CF

3 3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to a solution of 4-Brono-2-trifiuoromethyl-phenylamine (1.0 g, 4.16 mmol) in acetonitrile 15 (10 rnL). The reaction mixture was stired at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.1 g, 79% yield). Step B: A 20 phenyll-3,3-dimethylbutanamide: The synthesis of this compound was perfonned as described in example 4, step C. 74 FN

CF

3 'H NMR (DMSO-ds, 400 MHz) 5 1.02 (s, 9H), 2.18 (s, 2H), 2.94 (t, J= 8 Hz, 2H), 3.59 (t,i= 8 Hz, 2H), 4.43 (s, 2H), 7.0 (m, 2H), 7.17 (m, 3H), 7.3 (m, I H), 9.18 (s, IH). 5 Example 21 N-12-Chloro4-(6-triflueremethyl-3,4-dihydro-1H1-squinolin-2-yfl-pheyl3,3 dimethylbutanamkle Step A: N- - 3 ho ed 10 0~' 3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 minol) was added to a solution of 4-Bromo-2-chloro-phenylanine (1.0 g, 4.84 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the 15 mixture and the precipitate formed collected to give the title compound as a powder (1.04 g, 72% yield). Step B: ( yhenv]33-dimethylbutanamide: F3C NN 20 C1 H Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mnmol) and (2T-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) -and stirred for 15 minutes under argon. Potassium 75 tert-butoxide (197 mg, 1.75 mmol), 6trifluoromethybl ,2,3,4-tetrahydroisoquinoline hydrochloride salt (154 mg, 0.65 mmol) and N-(4brono-2-chloro)-3,3 dimethylbutanamide (200 mg, 0.66 mmol) were then added and the reaction mixture was stirred at 90 *C ovemight. The reaction mixture was then cooled to room temperature, 5 concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. 'H NMR (DMSO-d, 400 MHz) 1.03 (s, 9H); 2.19 (s, 2H), 2.99 (t, J= 8 Hz, 2H), 3,58 (t, J= 8 Hz, 2H), 4.48 (s, 21), 6.99 (dd, J= 4, 8 Hz, I H), 708 (d, J= 4 Hz, 1H), 7.35 (dd, J= 4, 8 Hz, I H), 748 (dd, J= 4, 8 Hz, IlH), 7.56 (m, 211), 9.19 (s, I H). Example 22

N-[

4

-(

7 -Fluore-3,4-dihydro1W-isoquinolin-2-yl)-2-trifluormethylphenyl]-3,3 dimnethylbutaunide 15 Step A:. M44rom~-r~q v- y),.d CF3 3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to a solution of 4-Bromo-2-trifluoromethyl-phenylmine (LO g, 4.16 mmol) in acetonitrile 20 (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1 g, 79% yield). Step B:ey , -dit Zunamide:o 25 phenvll-3,3-dimethylbutanainid: F N

CF

3 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2'-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium 5 tertabutoxide (197 mg, 1.75 mmol), 7-Fluoro- 1,2,3,4-tetrahydroisoquinoline hydrochloride salt (122 mg, 0.65 mmol) and N-(4-bromo-2-triffuoromethyl)-3,3 dimethylbutanamide (200 mg, 0.59 mmol) were then added and the reaction mixture was stirred at 90 "C ovemight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane 100%) to 10 afford the title compound as a solid. 'H NMR (DMSO-d 6 , 400 MHz) 5 1.02 (s, 9H), 2.18 (s, 211), 2.90 (t, J= 8 Hz, 2H), 3.60 (t, J= 8 Hz, 211), 4-46 (s, 211), 7.0 (m, 1 H), 7.23 (in, 5R), 9.17(s, 1H). Example 23 15 3,3-Dimethyl-N-[2-trifueromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquino n 2-yi)phenyl-butanamide Step A. N jLyL, H 20 CF 3 3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to a solution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a 25 powder (l.1 g, 79% yield). 77 Step B: .312 u47 isguinolin-2-yD-ohenyl-btanamide: N

CF

3 H 5 Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2dicyclohexyl phosphany-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (154 mg, 0.65 mmol) and N-(4-bromo-2-trifluoromethyl)-3,3 10 dimethylbutanamide (200 mg, 0:59 mmol) were then added and the reaction mixture was stirred at 90 *C overnight. The reaction mixture was then cooled to room temperture, concentrated and purified by thin layer chromatography (Dichloromethane 100%) to afford the title compound as a solid. 'H NMR (DMSO-ds, 400 MHz) 8 1.02 (s, 9R), 2.18 (s, 2H), 3.01 (t, .1=8 Hz, 2H), 3.62 15 (t, J= 8 Hz, 2H), 4.56 (s, 2H), 7.24 (m, 3H), 7.44 (d, J 4 Hz, I H), 7:52 (d, J 4 Hz, IH), 7.67 (s, IH), 9.18 (s, 1H). Example 24 N-14-(6-Methoxy-3,4-dihydro-HH-isoquinoin-2-yl)-2,6-dimethyl-phenyl]-3,3 20 dimethyl butanamide Step A: 25 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmiol) and triethylamine (2.53g, 3.5 mL, 25 mnol) were added to a solution of 4-Bromo-2,6-dimethyl 78 phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield). 5 Step B: -M, AM tt nuhal2inaZdlm4thMty1 phenyl3.3-dimethylbutanamide H Bis(dibenzylidineacetone)palladium (2 mg, 0.0035mmol) and (2-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 nunol) were added to dry 10 toluene (10 nL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (134 mg, 0.67 mnol) and N-(4-bromo-2,6-dimethyphenyl)-3,3 dimethylbutanamide (200 mg, 0.67 mmol) were then added and the reaction mixture was stirred at 80 *C overnight. The reaction mixture was then cooled to room temperature, 15 concentrated, filtered through a pad of silica gel, and recrystallized from toluene to afford the title compound as a solid. 'H NMR (DMSO-d, 400 MHz) S 1.05 (s, 9H), 2.10 (s, 6H), 2.14 (s, 2H), 2.87 (t, J= 8 Hz, 211), 3.48 (t, J= 8 Hz, 2H), 3.72-(s, 314), 4.26 (s, 2H), 6.68 (s, 2H), 6.79 (in, 2H), 7.14 (m, IH), 8.85 (s, I H). 20 Example 25 N-{2,6-Dimethyl-4-(7-trifluoromethyl-3,4dihydro-fH-isequinolin-2-y)-pheny1-3,3~ dimethyl butanamide 25 Step A: t Miy phenyfl-pietdhnbta nameide 79 Br H 3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-brono-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room 5 temperature for 4 hours. Water was added to the mixture, and the precipitate that formed was collected to give the title compound as a powder (7.46 g, 100% yield). Step B:- Nh4 it -n abi--7- md A dji phenvil-3,3-dimethyl-butanamide 10 N H Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2'.dicyclohexyl phosphanyl-bipheny-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert 15 butoxide (4.75 g, 42.3 mmol), 7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (4.82 g, 20.3 mmol) and N-(4-Bromo-2,6-dimethyljphenyl)-3,3 dimethy-butanamide (5 g, 16.8 mmol) were then added and the reaction mixture was stirred at 80 *C overnight. The reaction -mixture was then cooled to room temperature, filtered through silica gel, and recrystallized from toluene to afford the title compound as 20 a solid. (5.94 g, 85%). '11 NMR (DMSO-d, 400 MHz) 8 1.06 (s, 9H), 2.11 (s, 6H), 2.18 (s, 2H), 2,89 (t, J= 4 Hz, 2H), 3.54 (t, J= 4 Hz, 2H), 4,44 (s, 2H), 6,73 (s, 2H), 7.40 (d, J= 8 Hz, 1 H), 7.51 (d, J= 8 Hz, I H), 7.62 (s, 1H), 8.87 (s, IfH), 25 80 Example 26 N-{4-(3,4-Dihydro-1H-isoquinolin-2-ylr2-methoxy-6-methy -pheny3,.3-dimethy. butananide 5 Step 6 -a To an ice-water cooled solution of 2-methoxy-6-methylaniline (10 g, 72.9 nmol) in 30 mL of methanol and 10 mL of acetic acid was added dropwise bromine (3 75 mL, 10 72.9 mmol). The reaction mixture was allowed to stand for overnight. The solvent was removed under reduced pressure and the residue was suspended in 60 mL of IN NaOH and extracted with ethyl acetate and dried over sodium sulfate and evaporated to dryness to give reddish crude product, which was recrystallized from hexane to give pure product (14.3 g, 91%) 15 Step B:-, m mo-2-teth x4-meth y1eya-3,-dimethvi u anamide: Br To a solution of 4-bronio-2-methoxy-6-methyl-aniline (22 g, 10mmol) and 20 triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6g, 12mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction mixture was diluted with dichloromethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was 25 purified by silica gel column (1SCO, hexane/EtOAc, 040%, 40 min) to give a white solid (2.8 g, 89%). 81 Step C:N{ 4 %y~hy tk wxalZ2vt-mchoxv-6 mty- en 33-dimethyl-butanamide: N Toluene (6m!) was degassed with nitrogen for 15 min in a 10 mL of microwave 5 tube, then (4-bromo-2-methoxy-6-methyl-pheny)-3,3-dimethyl-butam ide (188mg, 0.6nmol) and 1,2,3,4-tetmhydroisoquinoline (96 mg, 0.72 mmol) Was added, followed by potassium tert-butoxide (101mg, 0.9mmol), bis(dibenzylidene acetonie)palladium (17 mg, 0.03 mmol), and 2-dicyclohexyphosphino-2-(NN-dimethylamiho)biphenyl (24 mg, 0.06 mmol). The reaction tube was sealed and reacted in microwave at 100 "C for 2 10 hours. The reaction mixture was purified by silica gel column (ISCO, hexane/EtOAc, 0 40%, 40 min) to give pure compound as a white solid. 'H-NMR (DMSO-d, 400MHz): 8 8.64 (brs, 1H, exchangeable with D2O), 7.20 (m, 4H), 6.48 (s, 1H), 6.43 (s, IH), 4.37 (s, 2H), 3.73 (s, 3H), 3.52 (t, J=6.OHz, 2H), 2.92 (t, J=6OHz, 2H), 2.13 (s, 2H), 2.08 (S, 3H), 1.04 (s, 9H). MS: 367 (M-1). 15 Example 27 N-12-Choro4-(3,4-dihydro-H-isoquino n-2-y)-6-trifluoromethoxy-phenyll-3,3 dimethyl-butanainde 20 Step A: -N.4-m butananide: Sr CI 0 H 8 2 To a solution of 4-bromo-2-chloro-6-trifluorometihoxy-aniline (29 g, 10 mmol) and triethylamine ( .5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction 5 mixture was diluted with dichiorornethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.6 g, 93%). 10 Step B: N-42-Ch o--44- boxy phenyl]3,3-dimethylbutanaimide S

CF

3 Synthesized according to example 26: 'H-NMR (DMSO-d, 400MHz): 5 9,28 15 (brs, 1H, exchangeable with D20), 7.20 (m, 4H), 7.10 (s, 1H), 6.89 (s, 1H), 4.45 (s, 2H), 3.57 (t, 3=6.0Hz, 2H), 2.92 (t, J=6.0Hz, 2H), 2.18 (s, 2H), 1.04 (s, 9H). MS: 441 (M+1). Example 28 N-{4-(3,4-Dihydro-1H-isequinoli-2-yl)-2,6-dimethoxy-phenyll-3,3-dimethyl 20 butanamide Step A: 5-Bmr Br O

-

NO

2 1 -Bromo-3,5dimethoxybenzene (10.9 g, SO mmol) was dissolved in 100 mL of acetic anhydride and cooled to 0 'C. A cooled solution of 70% HN03 (6.4 mL, 100 mmol) in 20 mL of acetic anhydride was added dropwise and the resulting mixture was 5 stirred for 1 hour at 0 *C and for 3 hours at room temperature The reaction mixture was poured into ice-water with strong stirring and the yelloW solid was filtered and washed with water. The solid as a mixture of two isomers was separated by silica gel column (ISCO, hexane/EtOAc, 0-30%, 40 min) to give 3.3 g (25%) of pure 5-bromo-1,3 dimethoxy-2-nitro-benzene as an yellow solid. 'H-NMR (DMS0-d4 400MHz): S 7.17 (s, 10 2H), 3.89 (s, 6H). Step B:I5romo- k7dime xv2-minogenizne Br O

NH

2 ON 5-Brorno-1,3-dimethoxy-2-nitro-benzene (2.6 g, 10 mmol) was dissolved in 200 15 mL of methanol and 40 nL of water was added, followed by 2.5 g of Fe powder and 2.5 g of aronium chlorid&. The mixture was heated to reflux at 80 "C for 2 hours and the cooled reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduce pressure to give the crude product, which was used for next step without further purification. 20 Step C:JN-4-4-4rom 2 eh imethmetha tnamid: 84 To a solution of the crude 5-bromo-1,3-dimethoxy-2-amino-benzene from above and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butyl acetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Then the reaction 5 mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (1SCO, hexanefEtOAc, 0-40%, 40 min) to give a white solid (3.0 g, 91%). 'H-NMR (DMSO-d, 400MHz): 5 8.69 (bra, 1H, exchangeable with D 2 0), 6.87 (s, 2H), 3.73 (s, 6H), 2.11 (s, 2H), 1.02 (s, 9H). 10 Step D: N444A4Dihydrp- Misuni-2-vI-2,6dmethoxv-henvI dimethyl-butanamide: Me S N Toluene (6 mL) was degassed with nitrogen for 15 min in a 10 mL of microwave 15 tube, then N-(4-bromo-2,6-dimethoxy phenyl)-3,3-dimethyl butanamide (200 mg, 0.6 mmnol) and 1,2,3,4-tetrahydroisoquinoline (96 mg, 0.72 mmol) was added, followed by potassium ter-butoxide (101 mg, 0.9 mmol), bis(dibenzylidene acetone)palladium (17 mg, 0.03 mmol), and 2-dicyclohexyphosphino-2-(NN-dimethylamino)biphenyl (24 mg" 0.06 mmol). The reaction tube was sealed and reacted in microwave at 100 "C for 2 20 hours. The reaction mixture was purified by silica gel column (ISCO, hexane/EtOAc, 0 40%, 40 min) to give pure compound as a White solid. 'H-NMR (DMSO-d 6 , 400MHz): 6 8.36 (brs, 1H, exchangeable with D2O), 7.20 (m, 4H), 615 (s, 2H), 4.41 (s, 21H), 3.72 (s, 6H), 3.55 (t, 1=6.0Hz, 2H), 2.95 (t, J=6OHz, 2H), 2.07 (s, 2H), 1.03 (s, 9H). MS: 383 (M+1). 25 Example 28 N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1N-isoquinofin32-yl)-phenylb-33 dimethyl-thiobutanamide 5 Step A: N4-e Br 3,3-dimethylbutanoyl chloride (3,37 g, 3.5 mL, 25 mmol) and triethylamine (2.53g, 3.5 mL, 25 mmol) were added to a solution of 4-Bromo-2,6-dimethyl phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at 10 room temperature for 4 hours, Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield). Step B: pheny1V3,3-dimethy -butanamide: 15

F

3 C N N0 N Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2% dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon) and stirred for 15 minutes under argon. 20 Potassiumi tert-butoxide.(4.75 mg, 42.3 mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro isoquinoline hydrochloride salt (4.82 g, 20.3 nnol) and N-(4-Bromo-2,6-dimethyl phenyl)-3,3-dimethyl-butyramide (5 g, 16.8 mmol) were then added and the reaction mixture was stirred at 80 "C over night. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.55 25 g, 79%). 86 'H NMR (DMSO-d, 500 MHz) 8 1.03 (s, 9H), 2.09 (s, 6H), 2.15 (s, 211), 2.98 (t, J= 5.0 Hz, 2H), 3.52 (t, J = 6.0 Hz, 2H), 4.40 (s, 2H), 6.1 (s, 2H), 7.45 (d,J= 8.0, 1 H), 7.52 (m, 2H), 8.87 (s, I H). 5 Step C: tj{2( D heny0l-3,3-dimethyl4hiobutanamide:

F

a C N H To a solution of N-[2,6-Dimethy4-(6-trifluoromethyl-3,4-dihydro-1H isoquinolin-2-yl)-phenyl]-3,3-dimethyl-butyramide (200 mg, 0.48 mmol) in 10 dichloroethane (10 mL) was added Lawesson's reagent (193 mg, 0.48 mmol) and the reaction mixture was stirred at reflux for 2h. The mixture was then cooled to room temperature and concentrate. Purification by preparative thin layer chromatography (dichloromethane 100%) afforded the desired compound as a solid. 'H NMR (DMSO-d4 400 MHz) 8 1 12 (s, 9H), 2.11 (s, 6H), 2.73 (s, 2H), 3.0 (t, J= 5.0 15 Hz, 2H), 3.57 (t, J= 4.0 Hz, 2H), 4.46 (s, 211), 6.75 (s, 2H), 747 (d, = 8.0, 1H), 7.56 (n, 2H), 10.7 (s, 1H). Example 29 [26Dmethyl4-6-trifluoromethy-3,4-dhydro-H1Hsqunoln-2-yw)penyub 20 carbamic acid ethyl ester: Step A: (44-roiwt2,imethyl-phenvleeatbando arid eth e*e Br . NO H Ethyl chloroformate (0.55g, 0.48 mL, 5 nmol) was added to a solution of 4 25 brorno-2,6-dimethyl-phenylamine (1.0 g, 5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at reflux for 16 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.32 g, 97% yield). Step B: .6-D4tifuorety- 4hy isoninoi-l 5 yhicarbaic acid ethl ester: F3C N O H Bis(dibenzylidineacetone)palladium (17 mg, 0.03 mmol) and (2' dicyclohexylphosphany-biphenyl2-yl)-dimethylamine (35 mg, 0.09 mmol) were added 10 to dry t6luene (5 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (166 mg, 1.8 mmol), 6-Trifluoromethyl-1,2,3,4-tetrahydro isoquinoline hydrochloride salt (176 mg, 0.74 mmol) and (4-Bromo-2,6-dimethyl phenyl)-carbamic acid ethyl ester (200 rmg, 0.74 mmol) were then added and the reaction mixture was stirred at 80 *C ovemight. The reaction mixture was then cooled to room 15 temperature filtered through silica gel and purified by preparative thin layer chromatography (DCM 100%) to give the desired compound as a solid. 'H NMR (DMSO-d 6 , 400 MHz) 8 1.23 (t, J = 7.2 Hz, 3H), 2.12 (s, 6H), 3.0 (t, J= 6.4 Hz, 2H), 3.52 (t, J= 6.3 Hz, 2H), 4.08 (q, J= 13.6, 8.3 Hz, 2H), 4.42 (s, 2H) 6.73 (s, 2H), 7.46 (d, J =7.4, 1H), 7.54 (m, 2H), 8.32 (s, IH). 20 Biological Results Compounds of this invention formula were evaluated for activity toward potassium channels in a cell-based Rb* efflux assay This cellular bioassay is believed to 25 faithfully represent the M current channel activities identified with KCNQ2/3 heteromultimers. The most active compounds of this invention have EC 50 s in the single digit aM range, which represents a 40- to 400-fold improvement over retigabine. Additionally, antiseizure activity in vivo was evaluated in a mouse maximal electroshock 88 seizure (MES) model, and neurotoxicities were determined from a rotorod neurocognitive motor impairment model. Methods: 5 Rubidium Efflux Test PC-12 cells were grown at 37 *C and 5 % C07 in DMEMIF12 Medium (Dulbecco's Modified Eagle Medium with Nutrient Mix F-12, available from Invitrogen of Carlsbad, CA), supplemented with 10 % horse serum, 5 % fetal bovine serum, 2 mM glutamine, 100 U/mI penicillin, and 100 U/nil streptomycin. They were plated in poly-D 10 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 mil in wash buffer (25 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM MgC 2 , 0.8 mM NaH2PO 4 , 2 MM CaC 2 ). The cells were then loaded with 0.2 ml Rb 4 loading buffer (wash buffer plus 5.4 mM RbC 2 , 5 mM 15 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 KCI instead of RbCl) to remove extracellular Rbt Immediately following the wash, 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCI) with or without compounds was added to the cells to activate efflux of potassium ion channels. After incubation for 10 min at room 20 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 4 contents by atomic absorption spectroscopy (see below), they were stored at 4 0 C without any negative effects on subsequent Rb analysis. 25 The concentrations of Rb in the supematants (Rbts,,) and the cell lysates (Rbcy,,) were quantified using an ICR8000 flame atomic absorption spectrometer (Aurora Biomed Inc., Vancouver,-BC.) under conditions defined by the manufacturer. Samples 0.05 ml in volume were processed automatically from microtiter plates by dilution with an equal volume of Rb* sample analysis buffer and injection into an air 30 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 89 covering the range 0-5 mg/L Rb 4 in sample analysis buffer was generated with each set of plates. The percent Rb 4 efflux (F) was defined by F = [Rb'sv / (Rb's + RbtLj] X 100 %. where the F is the efflux in the presence of compound in depolarization buffer, P% is the 5 efflux in basal buffer, and F, is the eftlux in depolarization buffer, and F is the efflux in the presence of compound in depolarization buffer. The efflux (F) and compound concentration relationship was plotted to calculate an EC0 value, a compound's concentration for 50% of maximal Rb* efflux. The results are shown below. 10 Maximal Electroshock Seizure (MES) and Acute Toxicity Tests MES Test The MES testing protocol is based on procedures established at the National Institute of Neurological Disorders and Stroke in conjunction with the Anticonvulsant Screening Program (ASP) at the University of Utah (White, H.S., Woodhead, J.H 15 Wilcox, K.S., Stables, J., Kupferberg, HJ and Wolf, H.H. 2002, "General Principles: Discovery and Preclinical Development of Antiepileptic Drugs, "in Antiepileptic Drugs, 5 h Edition, R.H. Levy, ed.; R.H. Mattson, B.S. Meldrum, and E. Perucca. Philadelphia, Lippincott Williams & Wilkins.), The goal of the test rapid identification and characterization of the in vivo anticonvulsant activity of any compounds that have been 20 shown active in PC-12 cellular based Re efflux assay. Adult male CF-I albino mice (18-25 g, Charles River Laboratories) are exclusively used for in-house MES screen of compounds. Male Sprague-Dawley albino rats (100-125g, Charles River Laboratories) are also used to test anticonvulsant compounds. Variability of test outcomes is reduced by using animals of the same sex, 25 age, and weight. Animals are permitted to rest and recover from transit for at least 48 hr prior to experimentation. Animals are used for AED testing only once, In some instances, the animals may be anesthetized prior to blood collection and/or whole brain extraction for pharmacokinetic assay. All animals are maintained and handled as outlined in standard animal care guidelines. 90 In the experiments, testing compounds are prepared as suspensions in 0,5% methyl cellulose (Sigma, Cat # M0512, Viscosity 4000 cP at 20C) in water, regardless of solubility. Dry powder compounds are initially ground with a glass rod in a test tube in several drops of methyl cellulose to create a paste and to break down any large chunks. 5 After several minutes of grinding, the volume of the suspension is increased to the final concentration desired. The suspension is then sonicated using a Branson sonicator model 3510 in a water bath at room temperature for 15 minutes. Compound suspensions are further vortexed prior to animal dosing. In some of the cases, DMSO is used to initially solubilize compounds in small volumes and then this solution is added to the 0.5% 10 methyl cellulose solution, in order to create more even and less aggregated compound suspensions. The final concentration of DMSO is 3.75%, an amount with no apparent toxicity or neuroprotective effects in our usual rotarod and MES tests. Methyl cellulose/DMSO compound suspensions are identically prepared for intraperitoneally (i.p.) to mice or orally (p.o.) to rat dosing. 15 Initially the animals are weighed with an electronic scale and then marked. Data recording sheets are generated for each compound assessment. Mice or rats are dosed with the compound suspension at 0.01 mUg of body weight. The typical injection volume range is between 180-250 pl for mice. Compounds are dosed by i.p. to mice using a -25 or 22 gauge needle, depending on the viscosity of the suspension. Rats are p.o. 20 dosed using a flexible feeding tube, typically starting at a compound dose of 5 mg/kg. A Rodent Electroconvulsive Stimulator (Model 200, Hamit-Darvin-Freesh, Snow Canyon Clinic, Ivins, UT) is used for MES testing. A 60-Hz alternating current (50 mA for mice; 150 mA for rats) is delivered for 0.2 seconds through corneal electrodes to the mice. A drop of 0.5% tetracaine (Sigma, Cat. # T-7508) solution is placed on the eye 25 prior to current delivery. The electrodes are subsequently placed gently onto the eyes of the animal and the electrical shock is initiated by triggering through a foot-pedal activator. The animals are restrained by hand and gently released as the shock is delivered and the seizure commences, Animals are monitored for hind limb tonic extension as the end point for this test. Current delivery is recorded as a measure of 30 overall seizure-induction potential. Electrical current delivery can vary from 91 approximately 30-55 mA (mice) or 90-160 mA (rats) depending on impedance in the animal and quality of the current delivery (ic. correct placement of the electrodes on the cornea). Seizures will be successfully induced in control animals throughout this current range. Tonic extension is considered abolished if the hind limbs fail to become fully 5 extended at I SOP with the plane of the body. Lack of tonic extension suggests that the test compound has prevented the spread of seizure discharge through neural tissue. Although unnecessary in mice, the rats are pre-screened for seizure induction potential using the MES 24hr prior to compound dosing and the subsequent MES test. A success rate of 92-100% has been determined for the rat seizure induction potential, Rats that fail 10 to develop tonic/clonic seizures during the pre-screening are not used for drug testing. For a compound testing, time-to-peak effect studies are initially perf6nned using 0,5, 1, 2,4, 8 and 24 hr time points, typically using a single 5 or 25 mg/kg dose. The determined time-to-peak effect is used for further titration of a compound's potency (EDo, the dose of a drug that protects 50% of animals from electrical induced seizure) in 15 both mouse and rat models. For titrations, 8 animals are used per concentration and dose (normal 5 concentrations) is varied until a full dose response curve can be obtained. Probit analysis (ASP method) or non-linear regression analysis on Graph Pad (constraining the lower dose/effect value) is used to calculate an EDso value for the test compound. 20 Retarod Test Prior to MES testing, compound dosed mice are scrutinized for abnormal neurologic status as defined by motor impairment on a slowly turning (6 rpm) rotarod apparatus (Model 755, Series 8, HTC Life Sciences, Woodland Hills, CA). The inability 25 of a mouse to maintain its balance on the rotarod over a period of one minute (three falls failure) signifies motor impairment and hence acute toxicity. These measurements are done at the same time points as the MES assay. Untreated normal mice are able to maintain balance on the rotarod for at least one minute without falling. Median toxicity of a compound (TD5o, the dose of a drug that results in motor impairment in 50% of 30 animals) is determined. 92 Open Field Test Before MES test, compound treated rats are visually observed for acute toxicity signs for approximately one minute in the open field test Here, rats are gently placed into a plexiglass enclosure and are monitored for behavior consistent with toxicity including 5 ataxia, trembling, hypoactivity (including failure to seek the walls), hypersensitivity, lack of exploratory behavior and lack of avoidance of the open area, Typically if the rats exhibits two or more of these abnonnal behaviors they are scored as toxic.

TABLE I ACTIVITIES OF EXEMPLARY COMPOUNDS Legend: A: ECso:S1 nM; B: 1 nM < ECsol 10 nM; C:10 nM <EC 5 50 nM; D: 50 nM <EC5 5500 nM 5 a0.12< EDSO5 1.2 1.2<ED50512 y: 12 < ED50 COMPOUND Mouse Rat EDsa ACTIVITY ED-% (mg/kg) ECso C y NA B

CF

3 cIX2~CW NA B N

C

3 H

F

3 y NA C 0 NA C NAc p NA B Ny9 COMPOUND) Mouse Rat E0 5 q ACTIVITYj HNA B . Ny NA B NC, N y , a B NA A Fj:: O(..

COMPOUND Mos a D 0 ACT lvrry NA 0 NN y NA B HNA C NA 0 I Hy N xp, NllI 09 UNDMouse Rt EDs 0 ACTIVITY F3NA, D H yNA D Ny

F

3 0 N N N c F~cK 7 H 95 COMPOUND Mouse Rat ED 5 . ACTIVITY EDso (mg/kg) ECso NA D

F

3 C NA D N FHNA NA D H N~o F O H NA NA C

F

3 C H NA NA ;D N Studies of KCNQ2/3 opening activity and KCNQ subtype selectivity using electrophysiological patch clamp in Xenopus oocytes 5 Expression in Xenapus laevis oocytes Female Xenopus laevis extracted ovaries were purchased from eNASCO (LM00935MX, eNASCO Fort Atkinson, WI). Following manual dissection of the oocytes into smaller groups, the oocytes were defolliculated by enzymatic treatment with 10 collagenase type 2 (LS004177, Worthington, Lakewood , NJ) for 1-1/2 hour in the presence of calcium-free Culture Bath solution (88 rM NaCl, 1 mM KCI, 0.82 mM MgSO 4 , 2.4 mM NaHCO, and 5 mM HEPES, pH 75). Qocytes were then kept in 98 supplemented Culture Bath solution (88 mM NaCl, 1 mM KCI, 0.82 mM MgSO 4 , 09 mM CaC 2 , 2.4 mM NaHCO 3 , I mM sodium pyruvate, 0.05 mg/mI Geneticin, 100 U/inl penicillin, 0.1 mg/ml streptomycin and 5 mM HEPES, pH 7.5) at 19*C for 24 hours before injection of cRNA. Approximately 50 nl cRNA (about 50 ng) was injected for 5 KCNQI, KCNQ4, and KCNQ5 using a Nanoject microinjector (Dmmmond, Broomall, PA, USA). For co-expression of KCNQ2 and KCNQ3 and of KCNQI and KCNEl, cRNA's were mixed in equal molar ratios before injection of approximately 50 ni. The mixtures contained about 10 + 10 ng and 12.5 + 2.5 ng (RNA, respectively. The smaller amounts are needed because larger currents arise when KCNQ2/KCNQ3 and 10 KCNQI/KCNEI are co-expressed. Oocytes were kept in Culture Barth solution at 191C which was changed daily and currents were recorded after 3 to 5 days. Electrophyslology 15 KCNQ channel currents expressed in Xenopus laevis oocytes were recorded using a two-electrode voltage-clamp. Tie recordings were made at room temperature in recording solution (96 mM NaCI, 2 mM KC1, I mM MgC2 1. 8 mM CaCl 2 , and 5 mM HEPES, pH 7.5) using a two-electrode voltage-clamp amplifier (OC0725C, Warner Instrument, Hamden, CT, USA). The oocytes were placed in custom built perfusion 20 chambers connected to a continuous flow system and impaled with a current electrode and a voltage-clamp electrode pulled from borosilicate glass on a Flaming/Brown Micropipette Puller (Sutter Instrunents Co, Novato, CA, USA). Recording electrodes were filled with 3 M KCl and had a resistance of 0.5 to 2.5 MO. 25 Compounds All compounds were dissolved in DMSO to obtain concentrated stock solutions. On the day of electrophysiological experiments the stock solutions were thawed and diluted in recording solution to-their final concentrations. The final DMSO concentration 30 never exceeded 0.1%. Compound delivery was performed using a custom built multi barrel apparatus connected to the flow system.

Calculations Data were acquired by means of an Axograph X software (Axograph Scientific, Sydney, AU) and analyzed using Graph Pad Prism (GraphPad Software Inc., CA, USA). 5 Concentration - response curves were constructed by plotting the increase in steady-state current expressed in percentages as a function of drug concentration. During the course of the experiment, while various concentrations of the drug were being dosed, the resting voltage was held at -90 mV and pulsed to -60 mV, -40 mV, and -50 mV for 5 s for KCNQ2/KCNQ3, KCNQ4 and KCNQS channels respectively. The plot was then 10 fitted to a Hill function: Response = R2 + (R I-R2)/[l+(C/ECso)^nH] where R1I is the initial response, R2 is the maximum response, C is the drug concentration and nl is the slope (Hill coefficient) of the curve. 15 The efficacy of compounds of this invention in comparison with Retigabine (as a positive control) was determined by recording the steady current using the above voltage protocol for the channels in the presence of the EC 7 s of the drugs. After steady channel current was recorded in the presence of Retigabine at its EC75, recorded occyte was washed with the recording solution until its steady current returned to its normal level 20 without the presence of any drugs. Then the channel steady current was recorded in the presence of the test compound at its EC 7 s. The percent efficacy was then expressed as: % efficacy = (C2/CI) X 100 % 25 where C2 is the recorded steady current in the presence of follow-on compound at its ECns and Cl is the recorded steady current in the presence of Retigabine at its EC 3

.

Claims

1. A compound of formula IA R3H NN (Y) R2 5 IA where R, and R 2 , are, independently, H, CN, halogen, NH 2 , CH 2 CN, OH, NO 2 , CH 2 F, CHF 2 , CF,, CF 2 CF 3 , C-C alkyl, C(=O)Ci-C alkyl; NH-Cr 1 C 6 alkyl; N(C-C 6 alkyl)-C-C6 alkyl, NHC(=O)C-C 6 alkyl, C(=O)N(CH3)2, C(=O)N(Et)2, C(=0)NH 2 , C(=O)NH-CrC 6 alkyl, S0 2 NH 2 , NHSO 2 -C-C 6 alkyl; C(*O)OCr-C 6 alkyl, OC(=0)C-C6 alkyl, OC-C6 10 alkyl, SC-C 6 alkyl, C3-C6 cycloalkyl, (CH2)mCrC cycloalkyl, C-C6 cycloalkenyl, (CH2).CrC cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CH2)mthienyl, (CH2)mimidazolyl, (CH2).pyrazyl, (CH2).oxazolyl, (CH2)misoxazolyl, (CH 2 ).thiazolyl, (CH2).isothiazolyl, (CH 2 ).phenyl, -(CH2).pyrrolyl, (CH 2 ).pyridyl, or (CH2).pyrimidyl, where m = zero, 1, or 2, Ar is a 5- to 10- member mono- or bicyclic aromatic group, 15 optionally containing 1 - 4 ring heteroatoms selected independently from N, 0, and S; or RI 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 beteroatoms selected independently from 0, N, and S; R' is H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF3, OC-C3 alkyl or C-C3 alkyl; R3 and R 4 are, 20 independently, H, CN, halogen, CF,, OCF,, OCi-C alkyl, or C 1 .C3 alkyl; X is 0 or S; Y is o or S; q = I or zero; Rs is CI-C 6 alkyl, (CHR 6 ).CrC 6 cycloalkyl, (CHR),CH 2 C-C 6 cycloalkyl, CH2(CHRs)O,C-C 6 cycloalkyl, CR=CH-C-C 6 cycloalkyl, CH=CR 6 -C-C 6 cycloalkyl, (CHR 6 )wCs-Cs cycloalkenyl, CH 2 (CHR),Cs-C 6 cycloalkenyl, C2-C6 alkenyl, C2-C alkynyl, Ar,, (CHR 6 ).Ar, CH2(CHRo),Ar, or (CHR)OH2Ar, where w = zero, 1, 2, or 25 3, Ar is a 5- to 10- member mono- or bicyclic aromatic group, optionally containing 1 - 4 ring heteroatorns selected independently from N, 0, and S; R 4 is H or C-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms 101 selected independently from N, 0, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in RII, R2, R', R3, R 4 , R5, R 6 , and Ar are optionally substituted with one or two substituents selected independently from C 1 -C3 alkyl, halogen, OH, OEt, OMe, CN, CH 2 F, OCF3, and CF3; and 5 where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with a carbonyl group.

2. The compound of claim 1, where R, and R2, are, independently, H, halogen, CF3, CrC6 alkyl, C(=O)CI-C6 alkyl, C(=O)OCC alkyl, OC(=O)C-C6 alkyl, OCrC, alkyl, 10 SCH 3 , C-C 6 cycloalkyl, (CH2).C-C6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CHz).phenyl, (CH 2 ).pyrrolyl, or (CH2)mpyridyl, said cycloalkyl groups optionally containing one or two heteroatoms selected independently from 0, N, and S, and said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups optionally substituted with one or two groups selected, independently, from halogen, methyl, ethyl, or trifluoromethyl, where m is 15 zero, 1, or 2; R' is H, halogen, phenyl, 2-(NN-dimethylamino)ethyl, CF3, OC-C3 alkyl or C-C, alkyl; where R3 and 14 are, independently, H, halogen, CF3, OCF3, OC-C3 alkyl, or C,.C3 alkyl; X = 0 or S; Y is 0 or S; q = I or 0; R 5 is C-C 6 alkyl, (CHR 4 ).C 3 -C 6 cycloalkyl, (CHB),CH 2 C-C 6 cycloalkyl, CH2(CH4),C-C 6 cycloalkyl, CR 6 =CH-C 3 - 6 cycloalkyl, CH='CR 6 -C-C 6 cycloalkyl, (CHRe).CS-C 6 cycloalkenyl, CH 2 (CHR).Cs-C 6 20 cycloalkenyl, C2-C6 alkenyl, CrC6 alkynyl, Ar, (CHR)Ar, CH2(CHIo).Ar, or (CHR 7 ).CH2Ar, where w = 0 -3, Ar is phenyl, pyrimidyl, or pyridyl, or a 5- member heteroaromatic ring, containing 1 or 2 ring heteroatoms selected independently from N, 0, and S; R6 is H or methyl; where all cycloalkyl and cycloalkenyl groups in Rs optionally contain one or two ring heteroatoms selected independently from N, 0, and S; and where all 25 alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R,, RZ, R3, 14, R 5 , Rs, and Ar are optionally substituted with one or two substituents selected independently from C-C3 alkyl, halogen, Ot, OMe, and trifluoromethyl. 102

3. The compound of claim 1, where R and R 2 , are, independently, H, halogen, CF 3 , C 1 -C 6 alkyl, C(=O)C-C6 alkyl, C(=O)OC-C 6 alkyl, OC(=O)C-C 6 alkyl, OC-C 6 alkyl, SCH 3 , (CH 2 ). cyclopropyl, (CH2).cyclobutyl, (CH 2 ). cyclopentyl, (CH2)m cyclohexyl, (CHz)moxazolyl, (CH2).,isoxazolyl, (CH 2 ).thiazolyl, (CH 2 )misothiazolyl, (CH 2 ).phenyl, 5 (CH2)mpyrrolyl, (CH2) 0 pyridyl, or (CH 2 )mpyrimidyl, said cyclopentyl and said cyclohexyl groups optionally containing one or two ring heteroatoms selected independently from 0, N, and S, and said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups optionally substituted with one or two groups selected, independently, from halogen, CH 3 , ethyl, or CF 3 , where m is zero, 1, or 2; R' is H, halogen, CF 3 , or C-C 3 alkyl; R3 and 14 are, independently, H, 10 halogen, CF 3 , OCF 3 , OC-C 3 alkyl, or C 1 .C 3 alkyl; X = 0 or S; Y is 0; q = I or 0; R is C-C 6 alkyl, (CHR4)C 3 -C 6 cycloalkyl, (CHR4),CH2C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ),C 3 -C6 cycloalkyl, CR 6 =CH-C 3 -C cycloalkyl, CH=CR-C 3 -C cycloalkyl, (CHR 6 ).Cs-C 6 cycloalkenyl, CH2(CHR 6 ).Cs-C6 cycloalkenyl, C2-6 alkenyl, C 2 -C 6 alkynyl, Ar, (CHR6).Ar, CH 2 (CHR 6 ).Ar, or (CHR)wCH 2 Ar, where w = 0 - 3, Ar is phenyl, pyridyl, or 15 a 5-member heteroaronatic ring, containing 1 or 2 ring heteroatoms selected independently from N, 0, and S; R 6 is H or methyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, 0, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R:, R2, Rj, R4, R5, R 6 , and Ar are 20 optionally substituted with one or two substituents selected independently from C-C 3 alkyl, halogen, OMe, OEt, and CF 3 .

4. The compound of claim 2, where RI and R 2 , are, independently, H, halogen, CF 3 , OCj-C 3 alkyl, CI-C 6 alkyl, C(=O)OCI-C 3 alkyl, OC(-0)C-C 3 alkyl, or C(=0)C-C 3 alkyl; R' 25 is H, F, CH3, or ethyl; R3 and 14 are, independently, H, F, Cl, CF 3 , OCF 3 , OC-C 3 alkyl, or C 1 .C 3 alkyl; and R5 is CI-C 6 alkyl, (CHR)wC 3 -C 6 cycloalkyl, (CHR 6 ),CH2C 3 -C 6 cycloalkyl, CH 2 (CHR 6 )C 3 -C 6 cycloalkyl, or (CHRg).Ar, CH 2 (CHR 6 ).Ar, or (CHR6).CH 2 Ar. 103

5. The compound of claim 1, where R 2 is H or F; R' is H; R 3 is H, CH 3 , OCH 3 , CF 3 , OCF 3 ,or Cl; R 4 is OH 3 , OCH3, CF 3 , OCF 3 , or Cl; and R 5 is C 3 -C 6 alkyl or (CH 2 )C 3 -C cycloalkyl. 5

6. The compound of claim I or claim 2, where R is halogen or CF 3 ; R 2 is H or F; R' is H; R3 and R4 are, independently, H, CH 3 , OCH, CF 3 , OCF 3 , or Cl; and Rs is C-C 6 alkyl, (CHR6).C-C 6 cycloalkyl, (CHRe).CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR)wC 3 -C cycloalkyl, CRr=CH-C-Cs cycloalkyl, CH=CR6-C-C 6 cycloalkyl, (CHR 6 )C-C 6 cycloalkenyl, CH2(CHR 6 ).Cs-C 6 cycloalkenyl, C-6 alkenyl, C2-C6 alkynyl, Ar, (CHR 6 ),Ar, 10 CH 2 (CHR 6 )wAr, or (CHR4)wCH 2 Ar.

7. The compound of claim I which is a compound of formula IA-I ARc RI N TRs IA-I 15 where R, is H, halogen, CN, CH2CN, CF3, C-C 6 alkyl, OCH, (C=O)OCH, O(C-0)CH3, OCF3, (CH 2 ).Cr-C 6 cycloalkyl, phenyl, or pyridyl; R2 is H, F, OCH3, CH3, or CF3; R3 and R4 are, independently, H, F, Cl, CF3, OCF3, OC-C3 alkyl, or CI..C3; and Rs is C-C alkyl, (CHR 6 )wCrC 6 cycloalkyl, (CHR 6 ),CH 2 C-C 6 cycloalkyl, CH2(CHR 6 ).C,-C 6 cycloalkyl, CRo=CH-C-0 cycloalkyl, CH=CR 6 -O,-C 6 cycloalkyl, (CHR4)wCs-C 6 cycloalkenyl, 20 CH 2 (CHR6).Cs-C 6 cycloalkenyl, CrC6 alkenyl, CrC6 alkynyl, Ar, (CHR4),Ar, CH 2 (CHR)wAr, or (CHR4).CHzAr, where w = 0 - 3, Ar is phenyl, firyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl; and R6 is Cr1C3 alkyl; where all alkyl, cycloalkyl, aryl, and heteroaryl groups in RI, R 2 , R3, R4, Rs, Rs, and Ar are optionally substituted with one or two substituents selected independently from C-C, alkyl, halogen, OCH3, 25 OCH 2 CH3, CN, and CF 3 . 104

8. The compound of claim 7, where Ri is H, F, Cl, Br, CF 3 , C-C alkyl, OCH 3 , CH 2 0CH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , OCH 2 CH 3 , or CH 2 OCH3; R' is H, CH 3 , CH 2 CH, or halogen; R 3 and R4 are, independently, H, F, Cl, CF 3 , OCF 3 , OCH 3 , or CH 3 ; and R5 is C-C 6 alkyl, CH 2 C 3 -C 6 cycloalkyl, CH 2 CH 2 C 3 -C 6 cycloalkyl, CH=CH-C 3 -C 6 5 cycloalkyl, CH=CH-C-C 6 cycloalkenyl, CH 2 C-C 6 cycloalkenyl, CH 2 CH 2 C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, or (CH 2 )wAr, where w = 1 or 2; Ar is phenyl,.oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, fury!, thienyl, pyrrolyl, or pyridyl; where all alkyl, cycloalkyl, aryl, and heteroaryl groups in RI, R2, R 3 , R4, R 5 , R 6 , and Ar are optionally substituted with one or two substituents selected independently from CH 3 , halogen, OCH 3 , 10 OCH 2 CH 3 , CN, and CF 3 .

9. The compound of claim 1 which is a compound of formula IA-2. R3 N Os1 R, R' 4 R2 IA-2 15 where R, and R 2 , are, independently, H, halogen, CH 2 CN, CF 3 , C-C 6 alkyl, (CH2).C 3 -C 6 cycloalkyl, or phenyl, said alkyl and cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, CN, CH 3 , CH 2 CH 3 , or CF 3 , where m is zero, 1, or 2; R' is H, F, Cl, or C)-C 3 alkyl; where R 3 and R 4 are, independently, H, F, Cl, CF 3 , OCF 3 , OCH,, or C 1 .C 3 alkyl, all said alkyl groups optionally substituted with one 20 or two groups selected, independently, from OH, halogen, C-C 3 alkyl, OC-C 3 alkyl, or CF 3 ; R5 is CrC alkyl, (CHR 6 ).C 3 -C6 cycloalkyl, (CHR)wCH2CC cycloalkyl, CH2(CHR 6 )wC 3 -C 6 cycloalkyl, CR 6 =CH-C 3 -C 6 cycloalkyl, CH=CR 6 -C 3 -C 6 cycloalkyl, (CHRo).Cs-C 6 cycloalkenyl, CH 2 (CHR 6 )-Cs-C 6 cycloalkenyl, CrC6 alkenyl, CrC6 alkynyl, Ar, (CHR).Ar, CH2(CHR6).Ar, or (CHR4).CH 2 Ar, where w =0 -3, Ar is phenyl, furyl, 25 pyrrolyl, or pyridyl; R 6 is C-C 3 alkyl; wheie all alkyl, cycloalkyl, aryl, and heteroaryl 105 groups in R 4 , R5, R6, and Ar are optionally substituted with one or two substituents selected independently from CI-C 3 alkyl, halogen, OMe, OEt, CN, and CF 3 .

10. The compound of claim 8, where R, is F, CF 3 , Cl, CH 3 , CH 2 CH 3 , SCH 3 , OCH 3 , 5 CH 2 OCH 3 , CH 2 0CH 2 CH 3 , OCF3, phenyl, thienyl, or H; R2 is H, F, Cl, or OCH 3 ; R' is H, F, CH 2 CH 3 , or CH 3 ; R3 and R4 are, independently, H, Cl, CH 3 , CF 3 , OCH 3 , or OCF 3 ; and RS is C 4 -C 6 alkyl, (CH 2 ).Ar, or (CH 2 )wC 5 -C 6 cycloalkyl, where w is 1, 2, or 3.

11. The compound of claim 10, where R, is F, CF 3 , Cl, CH 3 , OCH 3 , CH 2 OCH 3 , or H; 10 R2 is H, F, CH 3 , or Cl; R' is H; R3 is H, Cl, CH 3 , CF 3 , OCH 3 , or OCF 3 ; R4 is Cl, OCH 3 , or CH 3 ; and Rs is C 4 -C 6 alkyl or 2-cyclopentyl ethyl.

12. The compound of claim 11, where R3 and R4 are both CH 3 or both OCH 3 ; and R 5 is CS-C4 alkyl. 15

13. The compound of claim 1 which is a compound of formula IA-3 R3 H R. R R2 IA-3 where R, is F, CF 3 , Cl, CH 3 , CH 2 CH 3 , SCH 3 , OCH 3 , CH 2 0CH 3 , CH 2 OCH 2 CH3, OCF3, 20 phenyl, thienyl, or H; R2 is H, F, Cl, or methyl; R' is H, F, ethyl, or methyl; R3 and R4 are, independently, H, Cl, CH 3 , CF 3 , OCH 3 , or OCF 3 ; and R5 is CrC6 alkyl, (CH2)wAr, or (CH 2 )wC 5 -C 6 cycloalkyl, where w is 1, 2, or 3.

14. The compound of claim I which is a compound of formula [A-4 106 R3 H N S'RS RR IA-4 where R, is F, CF 3 , Cl, CH 3 , CH 2 CH 3 , SCH 3 , OCH, CH 2 OCH,, CH 2 OCH 2 CH 3 , OCF 3 , phenyl, thienyl, or H; R 2 is H, F, Cl, or methyl; R' is H, F, ethyl, or methyl; R3 and R4 are, 5 independently, H, Cl, CH 3 , CF3, OCH,, or OCF 3 ; and RS is CrC6 alkyl, (CH 2 )wAr. or (CH 2 )wC 5 -C 6 cycloalkyl, where w is 1, 2, or 3.

15. The compound of claim 3, where R' and R2 are H; R3 and R 4 are both methyl; and R 5 is C 5 -C 6 alkyl or (CH2).C5-C 6 cycloalkyl, where w is 1, 2, or 3. 10

16. A composition comprising a pharmaceutically acceptable carrier and one or more of the following: i. a compound of formula IA; ii. a pharmaceutically acceptable solvate of a compound of formula IA; 15 iii. a pharmaceutically acceptable salt of a compound of formula IA; and iv. a pharmaceutically acceptable ester of a compound of formula IA.

17. The composition of claim 16, wherein the compound of formula IA is a compound of formula LA-I. 20

18. The composition according to either of claims 16 or 17, where RI is F, CF 3 , Cl, or H; R2 is H; R' is H; R3 and R4 are CH3 or OCH 3 ; and R5 is C4-C6 alkyl or 2-cyclopentyl ethyl. 25

19. A compound which is one of the following: N-( 2 -chloro-4-(3,4-dihydroisoquinolin-2(H)-y)-6-(trifluoromethyl)phenyl)-3,3 dimethylbutanamide 107 N-(4-(3,4-dihydroisoquinolin-2(IH)-yI)-2,6-dimethylphenyl)-3,3 dimethylbutanamide N-(2-chloro-4-(3,4.-dihydroisoquinolin-2(IH)-yl)-6-Qrifluorometbyl)phenyl)-3 cyclopentyipropanamide 5 N-(2-chloro-4-(6-fluoro-3,4-dihydroisoquinolin-2(JR)-yl)-6 (trifluoromethyiphenyl)-3 ,3-dimetbybutanamide N-[2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-metbyl pbenyl]-3,3 dimethylbutanamnide N-[2-cblomo-4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-y)-6-trifluorometbyl 10 pbenylj-3-cyclopentylpropionamide N-[2,6-dimethyl-4-(6-trifluorornethyl-3,4-dihydro-Jf-isoquinolin-2-yI)-pbenylj 3,3-dimethytbutanamide N-[2-chloro-6-trifluoromethyl-4-(6-tritluoromethyl-3,4-dihydroq]H-isoquinolin 2-yl)-phenyl]-3,3-dimethylbutananiide 15 N-[2-chloro-4-(6-chloro-3,4-dihydro-JH-isoquinolin-2-yI)-6-tirifluorometmyl phenylJ-3,3-dimethylbutanamide N-[4-(6-chloro-3,4-dibydro-1tI-isoquinoin-2-yI)-2,&dimethy-pheny]-3 ,3 dimethylbutanandde N-t4-(6-fluoro-3.4-dihydro-)H-isoquinolin-2-yI)-2,6-dimethyl phenylj-3,3 20 dimechylbuzanamide N-12-chloro-4-(7-fluoro-3,4-dihydro-JH-isoquinolin-2-yI)-6-tifluoromethyl. phenyl]-3,3-dimethylbutanamide N-[4-(7-fluoro-3,4-dihydro-IH-isoquinolin-2-yI)-2,6.dinicthy-pheny]-3 ,3 dimnethylbutanamide 25 N-I2-chloroA4-(6-fluoro-3,4-dihydro-)H-isoquinolin-2-yI)-6-methylphenyl]J3,3 dimnethylbutanamide N-[ 2 -chloroA4-(7-luoro-3,4-dihydro-H-isoquinolin-2.yl.&-methylphenyl].3 ,3 dimethylbutanamide N-[2-chloro-6-nethy-4-(6-hrifluoromcthyI-3,4-dihydro-H-ioquinoin-2.y) 30 phenyl]-3,3-diinethylbutmnamide 108 N-[2-chloro-4-(6-chloro-3,4-dihydro-JH-isoquinolin-2-yl)-6-methyl-phenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-y)-phenyl]-3,3 dimethylbutanamide 5 N-[4-(6-fluoro-3,4-dihydro-IH-isoquinolin-2-y)-2-methyl-phenyl]-3,3 dimethylbutanamide N-[4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-H-isoquinolin-2-yl)-phenyl]-3,3 10 dimethylbutanamide N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-y)-2-trifluoromethyl-phenyl]-3,3 dimethylbutanamide 3,3-dimethyl-N-(2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-IH isoquinolin-2-yl)-phenyl]butanamide 15 N-(4-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3 dimethylbutanamide N-[4-(3,4-dihydro-IH-isoquinolin-2-y)-2-methoxy-6-methy-phenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(3,4-dihydro-)H-isoquinolin-2-yl)-6-trifluorometboxy-phenyl]-3,3 20 dimethylbutanamide, and N-[4-(3,4-dihydro-JH-isoquinolin-2-yl)-2,6-dimethoxy-phenyl]-3,3 dimethylbutanamide.

20. The composition of claim 16, where the compound of formula IA is chosen from 25 the following: N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1)-yl)-6-(trifluoromethyl)phenyl)-3,3 dimethyl butanamide N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3 dimethylbutanamide 109 N-(2-chloro-4-(3,4-dihydroisoquinolin-2(JR)-y)-6-(trifluorornethyl)phenyl)-3 cyclopentylpropanwnide N-(2-chloroA4-(6-fluoro-3,4-dihydroisoquinoin-2(U)-y)-6-Qrifluoromffiy pbenyl)-3,3-dimethylbutanamidc 5 N-[2-cbloro-4-(3 ,4-dihydro-lH-isoquinolin-2-yI)-6-metbyl phenyl]-3,3 dimetbylbutanamide N-[2-chloro-4-(6-fluoro-3,4-clihydro-1H-isoquinolia-2-yI)-6-trifluoromethyI phenyl]-3-cyclopentylpropioriamide N-(2,6-dimethyl-4-(6-trifluorometbyl-3,4-dihydro-IH-isoquinolin-2-yI)-phenylJ 10 3,3-dimethylbutananiide N-(2-chloro-6-trifluoromethyl-4-(6-ti-ifluoromethyl-3,4..dihydro-n-I-isoquinolin 2-yl)-phenylj-3 ,3-dirnetbylbutanamide N-[2-chloroA4-(6-chloro-3,4-dihydro-IH-isoquinolin-2-yI)-6-trifluoromethy phenyl]-3,3-dimethylbutanamide 15 N-[4-(6-chloro-3,4-dihydro-lH-isoquinolin-2-yI)-2,6-dimetyl-pheny].3,3. dimethylbutanainide N-[4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-y)-2,6-dimethy phenylJ-3,3 dimethylbutananiide N-[2-chloro-4-(7-fluoro-3,4-dihydro-)H-isoquinolin-2-yl)-6-trifluoromcthyl 20 phenyl]-3,3-dimcthylbutanamide N-[4-(7-fluoro-3,4-dibydro-)H-isoquinolin-2-y)-2,6-dimethyphenylj-33 dimethylbutanamide N-(2-chloro-4-(6-fluoro-3,4-dibydro-)H-isoquinolin-2-yI)-6-niethylphenyl]-3,3 diinethylbutanamide 25 N-[2-chloro-4-.{7-fluoro-3 ,4-dihydro-JHf-isoquinolin-2-y)-6-methylphenylJ-3,3 dirnethylbutanamide N-[2-chloro-6-methyI-4-(6-trifluorometby1-3,4-dihydro-1H-igoquinolin-2 yI)phenyl]-3,3-dimethylbutanamide N-[2-chloro-4-(6-chloro-3,4-dihydro-IH-isoquinoin-2-yl)-6-methylphenyl].3,3 30 dimethylbuzanainide 110 N-f2-chloro-4-(6-fluoro-3,4-dihydro-IH-isoquinolin-2-yl)phenyl]-3,3 dimethylbutanamide N-[4-(6-fluoro-3,4-dihydro-IH-isoquinolin-2-yl)-2-methylphenyl]-3,3 dimethylbutanamide 5 N-[4-(6-fluoro-3,4-dihydro-H-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-IH-isoquinolin-2-yl)phenyl]-3,3 dimethylbutanamide N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3 10 dimethylbutanamide 3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H isoquinolin-2-yl)-phenyl]butanamide N-{4-(6-methoxy-3,4-dihydro-IH-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3 dimethylbutanamide 15 N-[4-(3,4-dihydro-JH-isoquinolin-2-y)-2-methoxy-6-methylphenyl]-3,3 dimethyl-butanamide N-[2-chloro-4-(3,4-dihydro-JH-isoquinolin-2-yl)-6-trifluoromethoxyphenyl]-3,3 dimethyl-butanamide, and N-[4-(3,4-dihydro-JH-isoquinolin-2-y)-2,6-dimethoxy-phenyl]-3,3 20 dimethylbutanamide.

21. 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 IA or a salt or solvate 25 thereof.

22. The method of claim 20, where the compound of formula IA is a compound of formula TA-1. 30

23. The method of claim 20, where the compound of formula IA is chosen from the following: - 11 N-(2-chloro-4-(3,4-dihydroisoquinolin-2(JH-y)-6-(trifluoromethy1)pheuyI)-3,3 dimetbylbutanainide N-(4-(3,4-dihydroisoquinolin-2(JH)-yl)-2,6-dimethylphenyl)-3,3 dimethylbutanamide 5 N-(2-chloro4-(3,Adihydroisoquinolin-2(JH-y)-&(trifluoomethy)pheny>.3. cyclopcntylpropanamide N-(2-chloro-4-(6-fluoro-3 ,4-dihydroisoquinolin-2(JH)-yl)-6 (trifluoromcthylphenyl)-3,3-dimetbylbutanamide N-(2-chloroA-(3,4-dihydro-JH-isoquinolin-2-y)-6-methylphenyl]-3,3-dimethyl. 10 butanamide N-[2-chloro-4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-yI)-6 trifluoromethylphenyl]-3-cyclopentylpropionamide N-[2,6-dimethy1-4-(6-trifluoromethy1-3,4-dihydro-JH-isoquinolin-2-y)phenylj.. 3,3-dimethylbutananide 15 N-[2-chloro-6-triflunromethyl-4-(6-trifluoromethyl-3,4-dihydro-Hi-isoquinolin. 2-yi)-pbenyl]-3,3-dimethylbutanaxnidc N-[2-cbloroA4-(6-chloro-3,4-dibydro-H-isoquinolin.2yI)-6, trifluoromethyiphenyl]-3,3-dimethyl butanamide N-[4-(6-ehloro-3,4-dihydro-JH-isoquinolin-2tyl)-2,&-dimethylphenyl]p3,3. 20 dimethylb-utanwnide N-[ 4 -(6-fluoro-3,4-dihydro-JH-isoquinolin-2yl).z,6dimethylphenyl..3,3. dimethylbutanamide N-[2-chloroA4-(7-fluoro-3,4.-dihydro-JH-isaquinolin-2-yl)-6 trifluoromethylpheayl]-3,3-dimethylbutanarnide 25 N-I 4 -(7-fluoro-3,4-dihydro-IH-isoquinoin-2-y)-z,6-imetypheny]-3 3 dimethylbutanamide N1[2-chloro-4-(6-fluoro-3,4-dibydro-IH-isoquinolin-2-yl)-&-methylphenyl]-3 13 dimethylbutanamide N-L2-chlor-4-(7-fluoro-3,4-dihydro4]H-isoquinoin-2-y)-6.methiylphenyI]-3,3. 30 dimethylbutanamride 112 N-[2-chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoin-2 yl)phenyl]-3,3-dimethylbutanamide N-[2-chloro-4-(6-chloro-3,4-dihydro-)H-isoquinolin-2-yl)-6-methylphenyl]-3,3 dimethylbutanamide 5 N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)phenyl]-3,3 dimethylbutanamide N-[4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-yl)-2-methylphenyl]-3,3 dimethylbutanamide N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl)-3,3 10 dimethylbutanamide N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)phenyl]-3,3 dimethylbutanamide N-[4-(7-fluoro-3,4-dihydro-IH-isoquinolin-2-y)-2-trifluoromethylphenyl-3,3 dimethylbutanamide 15 3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-IH isoquinolin-2-yl)-phenyl]butananide N-[4-(6-methoxy-3,4-dihydro-JH-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3 dimethylbutanamide N-[ 4 -(3, 4 -dihydro-)H-isoquinolin-2-yl)-2-methoxy-6-methylphenyl]-3,3 20 dimethylbutanamide N-[2-chloro-4-(3,4-dihydro-H-isoquinolin-2-yl)-6-trifluoromethoxyphenyl-3,3 dimethylbutanamide, and N-[ 4 -(3,4-dihydro-H-isoquinolii-2-yl)-2,6-dimethoxyphenyl]-3,3 dimethylbutanamide. 25

24. A method of preventing or treating a disease or disorder which is affected by activation of voltage-gated potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IA or a salt or ester or solvate thereof. 30 113

25. A method of preventing or treating a seizure or seizure disorder, comprising administering to a patient in need thereof a therapeutically effective amount of one of more of the following: a compound of formula IA a salt of a compound of formula IA or a solvate of a compound of formula IA. 5

26. A method of treating or preventing a disorder characterized by hyperexcitability of the nervous system comprising administering to a patient in need thereof an effective amount of a compound of formula IA or a salt or solvate thereof. 10

27. A method of increasing the channel open probability of KCNQ2/3 channels in a mammal comprising administering to said mammal to an effective amount of a compound of formula IA-I or a salt or solvate thereof.

28. A method of increasing neuronal M currents in a mammal comprising 15 administering to said mammal an effective amount of a compound of formula IA-I or a salt, solvate, or ester thereof.

29. The method of any of claims 24,25, and 26, where the compound of formula IA is a compound of formula IA-1. 20

30. The method of any of claims 24, 25, 26, 27, or 28 where the compound administered is a compound chosen from the following: N-( 2 -chloro-4-(3,4-dihydroisoquinolin-2(H)-yl)-6-(trifluoromethyl)phenyl)-3,3 dimethylbutanamide 25 N-(4-(3,4-dihydroisoquinolin-2(]H)-y)-2,6-dimethylphenyl)-3,3 dimethylbutanamide N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3 cyclopentylpropanamide N-(2-chloro-4-(6-fluoro-3,4-dihydroisoquinolin-2(IH)-yl)-6 30 (trifluoromethylphenyl)-3,3-dimethylbutanamide 114 N-[2-chloro-4-(3 , 4 -dihydro-1H-isoquinolin-2-yl)-6-methylphcnyl]-3,3 dimethylbutanamide N-[2-chloroA-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-yI)-6 trifluoromethylphenyl]-3-cyclopentylpropionaniide 5 N-[2,6-dimcthyl-4-(6-trifluoroniethyl-3,4-dihydro-JH-isoquinolin-2-yl)-phenyl] 3,3-dimethylbutanainide N-[2-chloro-6-trifluoromethyl-4-(6-trifluoromezhyl-3,4-dibydroq]H-isoquinolin 2-yl)-phenylJ-3,3-dimetbylbutanamide N-[2-chlowo-4-(6-ohloro-3,4-dihydro-IH-isoquinolin-2-yI)-6 10 trifluoromnethylphenyl]-3,3-dimethylbutanaznide N-(4-(6-chloro-3,4-dihydro-H-isoquinoin-2-y)-2,6-dimethylpheny]-3,3 dimethylbutanarnide N-[4-(6-fluoro -3,4-dihydro-JH-isoquinolin-2-yl)-2,6-dimethylphenylj-3,3 dimethylbutanamide 15 N-(2-chloro-4-(7-fluoro-3,4-dihydro-JH-isoquinolin-2-yI)-6 trifluoromethylphcnylj-3,3-dimethylbutanamide. N-[4-(7-fluoro-3,4-dihydro-JH-isoquinolin-2-yI)-2,6-dimcthylphenyfl4,3 dimethylbutanainide N-[2-chloro-4-(6-fluoro-3,4-dihydro-)H-isoquinolin-2-yl)-6-melhylphenylj-3,3 20 dimethylbutanainide N-[2-chloro-4-(7-fluoro-3,4-dihydro-)H-isoquinotin-2-yl)-6-methylphenylj-3,3 dimethylbutananiide N-r2-chlowo-6-methyI-4-(6-trifluoromethy1-3,4-dihydroIHisoquinoin.2 yI)phenyl]-3 ,3-diniethylbutanamide 25 N-[2-vhloro-4-(6-chloro-3,4-dihydro-JH-isoquinoin-2-y)-6-methylpheny]-3,3 dixnethylbutanarnide N-[2-chloro-4-(6-fluoro-3,4-dihydro-IH-isoquinolin-2-yl)phenyl]-3,3 dimethylbutanarnide N-[4-(6-fluoro-3,4-dihydro-IH-isoquinolin-2-yl)-2-methylphenyl]-3,3 30 dimethylbutanainide 115 N-[4-(6-fluoro-3,4-dihydro-H-isoquinoin-2-yl)-2-trifluoromethylphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-IH-isoquinolin-2-yl)phenyl]-3,3 dimethylbutanamide 5 N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl-3,3 dimethylbutanamide 3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H isoquinolin-2-yI)-phenyl]butanamide N-[4-(6-methoxy-3,4-dihydro-IH-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3 10 dimethylbutanamide N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methylphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(3,4-dihydro-JH-isoquinolin-2-yl)-6-trifluoromethoxyphenyl]-3,3 dimethyl-butanamide, and 15 N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)2,6-dimethoxyphenyl]-3,3 dimethylbutanamide.

31. 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 20 a therapeutically effective amount of a compound of fonnula IA or a salt or solvate thereof.

32. The method of claim 31, where the compound of formula IA is a compound of formula IA-1. 25

33. The method of claim 20, where the compound of formula IA is chosen from the following: N-(2-chloro-4-(3,4-dihydroisoquinolin-2(IH)-yl)-6-(trifluoromethyl)phenyl)-3,3 dimethylbutanamide 116 N-(4-(3 ,4-dihydroisoquinolin-2(1H)-yI)-2,6-dimezhylphenylj-3 13 dimethylbutanamide N-(2-chloro-4-(3,4-dihydroisoquinolin-2(IH)-y)-6-Qriifluorornethyl)phenyl)-3 cyclopentylpropanamnide 5 N-(2-chloro-4-(6-fluaro-3,4-dihydroisoquinolin-2(JB)-yl)-6 (tifluaromethylphenyl)-3,3-dimethylbutananiide N-[2-chloroA4-(3,4-dihydro-1Jf-isoquinolin-2-yi)-6-methylpbcnyl]-3,3-dimethyl butanamide N-[2-chloro-4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-yl)-6 10 trifluoromethylphcnyl]-3-cyclopenzylpropionainide N-[2,6-dimethyl-4-(6-trifluoromethyl-3,4-dihydro-IH-isoquinolin-2-yl)phenyl] 3,3 -dimnethylbutanainide N-[2-chloro-6-trifluoromethyl-4-(6-trifluoromeffiyl-3,4-dihydro-Jftisoquinolin 2-yI)-phenylj-3,3-dimethylbutanamide 15 N-[2-chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-y)-6 trifluoromethylphenyl]-3,3-dimcthylbutanamide N-(4-(6-ohloro-3,4-dihydro-JH-isoquinolin-2-yl)-2,6-dimehylpienyl-3 93 diinetylbutanamide, N-[4-(6-fluoro-3,4-dihydro- IH-isoquinolia-2-yI)-2,6-dimethylphenylj-3,3 20 dimetbylbutananiide N-[2-chloro-4-(7-fluoro-3,4-dihydro-)JI-isoquinolin-2-yl)-6 trifluoroanethylphenyl]-3,3-dimethylbutanamide N-[4-(7-ifluoro-3,4-dihydro-H-isoquinoin-2-yl)-2,6-dimetbyphemylj-3,3 diznethylbutananiide 25 N-12-chloroA4-(6-fluoro-3,4-dihydro-JH-isoquinolin-2-yl)-6-nethylphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinoin-2-y)-6-methylpbenyI].3,3 dixnethylbutanamidc N-[2-chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2 30 yI)phenyl]-3,3-dimethylbutanaznide 117 N-[2-clloro-4-(6-chloro-3,4-dihydro-JH-isoquinolin-2-yl)-6-methyphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(6-fluoro-3,4-dihydro-IH-isoquinolin-2-y)phenyl-3,3 dimethylbutanamide 5 N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-methylphenyl]-3,3 dimethylbutanamide N-(4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-y)-2-trifluoromethylphenyl]-3,3 dimethylbutanamide N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-IH-isoquinolin-2-yl)phenyl]-3.3 10 dimethylbutanamide N-[4-(7-fluoro-3,4-dihydro-)H-isoquinolin-2-yl)-2-trifluoromethylphenyl-3,3 dimethylbutanamide 3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H isoquinolin-2-yl)-phenyllbutanamide 15 N-[4-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3 dimethylbutanamide N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methy-phenyl]-3,3 dimethylbutanamide N-[ 2 -chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethoxyphenyl]-3,3 20 dimethylbutanamide, and N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethoxyphenyl}-3,3 dimethylbutanamide.

34. The product resulting from the reaction of N-(4-bromo-2,6-dimethyl-phenyl)-3,3 25 dimethyl-butanamide with a tetrahydroisoquinoline derivative of formula Q below, in RNH R2 R' Q where R, and R 2 , are, independently, H, CN, halogen, CH 2 CN, OH, NO2, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C-C 6 alkyl, C(=O)Cg-C 6 alkyl; NH 2 , NH-CI-Ce alkyl; N(CI-C 6 aIkyI)-CI-C 6 118 alkyl, NHC(=O)CI-C 6 alkyl, C(=0)N(CH3) 2 , C(=0)N(Et)2, C(=O)NH 2 , C(=0)NH-Ci-Q alkyl, SO 2 NH 2 , NHSO 2 -C-Cs alkyl; C(=Q)OC I-C6 alkyl, OC(=O)C-C( alkyl, OC-C 6 alkyl, SC-C 6 alkyl, 0,-C 6 cycloalkyl, (CH 2 ).CC 6 cycloalkyl, CrC6 cycloalkenyl, (CH2),Cr-C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (CH 2 )mthienyl, (CH2),furyl, 5 (CH 2 )mimidazolyl, (CH 2 )mpyrazyl, (CH2)moxazolyl, (CH2)misoxazolyI, (CH 2 )mthiazolyl, (CH 2 )misothiazolyl, (CH 2 )mphenyl, (CH2)mpyrrolyl, (CH 2 ).pyridyl, or (CH 2 )mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from 0, N, and S; where m is zero, 1, or 2; or R, and R 2 , together with the ring carbon atoms to which they-are attached, form a 5- or 6- member fused ring, 10 which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from 0, N, and S; R' is H, halogen, phenyl, 2 (N,N-dimethylamino)ethyl, CF3, OC-C3 alkyl or C-C 3 alkyl; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R,, R 2 , and R' are optionally substituted with one or two substituents selected 15 independently from C,-C, alkyl, halogen, CN, OH, OMe, OEt, CN, CH 2 F, and trifluoromethyl; and where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with a carbonyl group; in the presence of bis(dibenzylidineacetone)palladium, (2'-dicyclohexyl phospbanyl-biphenyl-2-yl) dimethylamine, and potassium t-butoxide in dry toluene. 20

35. The product of claim 31, where R' is H, halogen, CF3, OC-C 3 alkyl or Cl-C3 alkyl.

36. A composition comprising a pharmaceutically acceptable carrier or diluent, a syrup for pediatric use, and a pharmaceutically effective amount of at least one of the 25 following: a compound of formula IA, a pharmaceutically acceptable -salt of a compound of formula IA, and a pharmaceutically acceptable solvate of a compound of formula I.

37. A tablet comprising a pharmaceutically acceptable carrier or diluent, and a pharmaceutically effective amount of at least one of the following: a compound of 119 formula IA-1, a pharmaceutically acceptable salt of a compound of formula IA-1, and a pharmaceutically acceptable solvate of a compound of formula IA-I.

38. The tablet of claim 32, where the tablet is chewable. 5

39. A capsule comprising a pharmaceutically acceptable carrier or diluent, and a pharmaceutically effective amount of at least one of the following: a compound of formula IA-1, a pharmaceutically acceptable salt of a compound of formula IA-1, and a pharmaceutically acceptable solvate of a compound of formula IA-1. 10

40. The compound of claim I which is a compound of formula IA-1, where R 1 and R 2 form a fused 5- or 6- member ring, optionally substituted with methyl or halogen, and where R3 and R 4 are, independently, H, F, Cl, CF,, OCE, OCI-C3 alkyl, or C 1 .. C 3 ; and Rs is Ci-C 6 alkyl, (CHR)wC-C 6 cycloalkyl, (CHR6)wCH 2 C-C 6 cycloalkyl, CH 2 (CHR6)wC3-C 6 15 cycloalkyl, CR=CH-C-C 6 cycloalkyl, CH=CR 6 -C-C 6 cycloalkyl, (CHR),C-C 6 cycloalkenyl, CH 2 (CHR 6 ).C,-C 6 cycloalkenyl, C 2 -Cg alkenyl, C2-C 6 alkynyl, Ar, (CHR 4 ).Ar, CH2(CHR 6 )wAr, or (CHR).CH2Ar, where w =0 - 3, Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl; and R6 is CI-C3 alkyl; where all alkyl, cycloalkyl, aryl, and heteroaryl groups in R3, R 4 , R5, R&, and Ar are optionally substituted 20 with one or two substituents selected independently from CI-C3 alkyl, halogen, OCH, OCH 2 CH3, CN, and CF3.

41. A method of treating or preventing a disease, disorder, or condition that is affected by modulation of potassium ion channels in a patient comprising administration of a 25 compound of formula IA in an amount of from about 10 mg to about 2000 mg per day to a patient in need thereof. 120