# Patent

## Title
Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators

## Abstract

This invention provides potassium channel modulators which are compounds of formula I




where at least one of W and Z is N;

where the moiety





is one of Groups A or B below

A





where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R1 and R2 as defined below, and containing zero or one ring nitrogen atom; and where other substituents are defined herein.

The invention also provides a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of a compound of formula I and ii) a pharmaceutically acceptable salt, ester, or prodrug thereof. The invention also provides a method of preventing or treating a disease or disorder which is affected by activities of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt, ester, or prodrug thereof.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60/934,396, filed Jun. 13, 2007, which is incorporated by reference herein in its entirety.


FIELD OF THE INVENTION
This invention concerns novel compounds that modulate potassium channels. The compounds are useful for the treatment and prevention of diseases and disorders which are affected by activities of potassium ion channels. One such condition is seizure disorders.
BACKGROUND OF THE INVENTION
Retigabine (N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid, ethyl ester] (U.S. Pat. No. 5,384,330) has been found to be an effective treatment of seizure disorders in children. Bialer, M. et al., Epilepsy Research 1999, 34, 1-41. Retigabine has also been found to be useful in treating pain, including neuropathic pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003, 460, 109-116.
A form of epilepsy known as “benign familial neonatal convulsions” has been associated with mutations in the KCNQ2/3 channels. Biervert, C. et al., Science 1998, 27, 403-06; Singh, N. A. et al., Nat. Genet. 1998, 18, 25-29; Charlier, C. et al., Nat. Genet. 1998, 18, 53-55, Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequent investigations have established that the primary site of retigabine action is the KCNQ2/3 channel. Wickenden, A. D. et al., Mol. Pharmacol. 2000, 58, 591-600; Main, M. J. et al., Mol. Pharmcol. 2000, 58, 253-62. Retigabine has been shown to increase the conductance of the channels at the resting membrane potential and to bind the activation gate of the KCNQ 2/3 channel. Wuttke, T. V. et al., Mol. Pharmacol. 2005, 67, 1009-1017.
The recognition of retigabine as a potassium channel modulator has prompted a search for other potassium channel modulators among compounds related to retigabine. Several such searches have been reported in the patent literature, most notably the following: WO 2004/058739; WO 2004/80950; WO 2004/82677; WO 2004/96767; WO 2005/087754; and WO 2006/029623.
BRIEF DESCRIPTION OF THE INVENTION
In one embodiment, this invention provides a compound of formula I




where at least one of W and Z is N;

where the moiety





hereafter denoted “Amine-Ring” is one of Groups A or B below





where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R1 and R2 as defined below, and containing zero or one ring nitrogen atom;





where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R1 and R2 as defined below, and containing zero or one ring nitrogen atom;

where R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl; R′ is H, halogen, CF3, or C1-C3 alkyl; R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl; X═O or S; Y is O or S; q=1 or 0; R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl and all pharmaceutically acceptable salts thereof. Such compounds are potassium channel modulators.

In alternative embodiments, this invention provides a compound of formula I,




where at least one of W and Z is N;

where the moiety





hereafter denoted “Amine-Ring” is one of Groups A or B below





where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R1 and R2 as defined below, and containing zero, one, or two ring nitrogen atom;





where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R1 and R2 as defined below, and containing zero, one, or two ring nitrogen atom;

where R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl; R′ is H, halogen, CF3, or C1-C3 alkyl; R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl; X═O or S; Y is O or S; q=1 or 0; R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl and all pharmaceutically acceptable salts thereof. Such compounds are potassium channel modulators.

In another embodiment, this invention provides a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of a compound of formula I and ii) a pharmaceutically acceptable salt, ester, or prodrug thereof.
In yet another embodiment, this invention provides a method of preventing or treating a disease or disorder which is affected by modulation of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt, ester, or prodrug thereof.
This invention includes all tautomers and salts, as well as all stereoisomeric forms, of compounds of this invention. This invention also includes all compounds of this invention where one or more atoms are replaced by a radioactive isotope thereof.
This invention provides or contemplates compounds of formula I above where NH—C(═X)—(Y)q—R5 is each of the following: NHC(═O)R5, NHC(═O)OR5, NHC(═S)R5, NHC(═S)SR5, NHC(═S)OR5, and NHC(═O)SR5.
Thus, in one embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y)q—R5 is NHC(═O)R5.
In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y)q—R5 is NHC(═S)R5.
In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y)q—R5 is NHC(═S)SR5.
In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y)q—R5 is each NHC(═O)OR5.
In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y)q—R5 is NHC(═S)OR5.
In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y)q—R5 is NHC(═O)SR5.
In one subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group A and NH—C(═X)—(Y)q—R5 is NHC(═O)R5 or NHC(═S)R5.
In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group A and NH—C(═X)—(Y)q—R5 is NHC(═O)SR5 or NHC(═S)OR5.
In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group A and NH—C(═X)—(Y)q—R5 is NHC(═O)OR5 or NHC(═S)SR5.
In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group B and NH—C(═X)—(Y)q—R5 is NHC(═O)R5 or NHC(═S)R5.
In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group B and NH—C(═X)—(Y)q—R5 is NHC(═O)SR5 or NHC(═S)OR5.
In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group B and NH—C(═X)—(Y)q—R5 is NHC(═O)OR5 or NHC(═S)SR5.
In another subgeneric embodiment, this invention provides a compound of formula IA1 below.




In another subgeneric embodiment, this invention provides a compound of formula IA2 below.




In another subgeneric embodiment, this invention provides a compound of formula IA3 below.




In another subgeneric embodiment, this invention provides a compound of formula IA4 below.




In another subgeneric embodiment, this invention provides a compound of formula IA5 below.




In another subgeneric embodiment, the invention provides a compound of formula IB1 below.




In another subgeneric embodiment, the invention provides a compound of formula IB2 below.




In another subgeneric embodiment, the invention provides a compound of formula IB3 below.




In another subgeneric embodiment, the invention provides a compound of formula IB4 below.




In another subgeneric embodiment, the invention provides a compound of formula IB5 below.




In a more specific subgeneric embodiment, the invention provides a compound of any of formulas IA1-IA5, where W and Z are both N.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where W is N and Z is C.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where W is C and Z is N.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where R′ is H, halogen, CF3, or methyl.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where W and Z are both N and R′ is H, F, or methyl.
In another more specific subgeneric embodiment, the invention provides a compound of any of formulas IB1-IB5, where W and Z are both N.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W is N and Z is C.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W is C and Z is N.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where R′ is H, halogen, CF3, or methyl.
In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W and Z are both N and R′ is H, F, or methyl.
In a more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=1; Y is O; R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl; and R1 is H, CF3, or halogen.
In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=1; Y is O; R5 is C1-C6 alkyl, substituted with methoxy, methylthio, or halogen; and R1 is H, CF3, or halogen.
In another subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is S, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is S, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is S, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=zero; R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl; and R1 is halogen.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=zero; R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl; R′ is halogen or C1-C3 alkyl; and R1 is halogen.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is O, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is O, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is O, and R5 is Ar1, (CHR6)Ar1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=zero, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=zero, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=zero, and R5 is Ar1, (CHR6)Ar1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is O, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA-1, where X is O; q=1; Y is O; and R5 is C1-C6 alkyl, substituted with methoxy, methylthio, or halogen.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is O, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is O, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is S, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is S, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is S, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=zero, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=zero, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=zero, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is O, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is O, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is O, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=zero, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=zero, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=zero, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is S, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is S, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is O, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is O, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is O, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is S, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is S, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is S, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=zero, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=zero, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=zero, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is O, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is O, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is O, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=zero, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=zero, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=zero, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is S, and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is S, and R5 is CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is S, and R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=1, Y is O, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is S, q=1, Y is S, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is S, q=1, Y is O, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=1, Y is S, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q zero, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=zero, and R5 is C5-C6 alkyl, CH2—C5-C6 cycloalkyl, CH2CH2—N-pyrrolidinyl, or CH2CH2—C5-C6 cycloalkyl.
In another still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=1, Y is O, and R5 is C5-C6 alkyl, CH2—C5-C6 cycloalkyl, or CH2CH2—N-pyrrolidinyl, or CH2CH2—C5-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen; R2 is H, halogen, or C1-C4 alkyl; X is O; and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen or halomethyl; R2 is H, halogen, or C1-C4 alkyl; X is O; and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen or halomethyl; R2 is H, halogen, or C1-C4 alkyl; R′ is halogen, methyl, or halomethyl; X is O; and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q zero, and R5 is C3-C6 alkyl, CH2CH2-cyclopentyl or one of the groups below:




In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen or halomethyl; R2 is H, halogen, or C1-C4 alkyl; X is O; and R5 is one of the groups above.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is S, q zero, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, or C(═O)C1-C6 alkyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is C(═O)C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, or OC(═O)C1-C6 alkyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is phenyl, pyridyl, pyrrolyl, (CH2)mpyrazyl, (CH2)mimidazolyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)mpyridyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, or (CH2)mpyrimidyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is C(═O)C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, or OC(═O)C1-C6 alkyl, and R5 is C5-C6 alkyl or CH2—C3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, or C2-C6 alkynyl, and R5 is C5-C6 alkyl or CH2—C3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, and R5 is C5-C6 alkyl or CH2—C3-C6 cycloalkyl.
In a more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R5 is Ar1 or CH2—Ar1, where Ar1 is unsubstituted phenyl, mono substituted phenyl, unsubstituted pyridyl, or unsubstituted pyrrolyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R5 is Ar1 or CH2—Ar1, where Ar1 is unsubstituted phenyl, mono substituted phenyl, unsubstituted pyridyl, or unsubstituted pyrrolyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA or IB, where R1 and R2 form a fused phenyl group, X is O, q=1, Y is O, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA or IB, where R1 and R2 form a fused pyridyl group, X is O, q=1, Y is O, and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen, C1-C6 alkyl, mono-halo C1-C6 alkyl, CN, di-halo C1-C6 alkyl, CF3, CN, or O—C1-C6 alkyl, and R5 is C5-C6 alkyl or CH2—C3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen, cyano, CF3, or methoxy, R2 is H or methyl, R′ is H, halogen, or methyl, and R5 is C5-C6 alkyl or CH2—C3-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R′ is halogen, CF3, or C1-C3 alkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen; R2 is H or methyl, R′ is H, halogen, or methyl; and R5 is C5-C6 alkyl or CH2—C5-C6 cycloalkyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R1 is halogen; R2 is H or methyl, R′ is H, halogen, or methyl; and R5 is CH2—C4-alkyl or CH2—C5— alkyl.
In another subgeneric embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is phenyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, or thiazolyl.
In another subgeneric embodiment, this invention provides a compound of formula I, where R1 and R2 form pyrrolo, imidazolo, oxazolo, or thiazolo.
In another subgeneric embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is isoxazolyl or isothiazolyl.
In another subgeneric embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is quinolyl or isoquinolyl.
In another subgeneric embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is pyrimidyl or purinyl.
In another subgeneric embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is indolyl, isoindolyl, or benzimidazolyl.
In a more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is halo phenyl.
In another more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is dihalophenyl or dihalopyridyl.
In another more specific embodiment, invention provides or contemplates a compound of formula I, where Ar1 is mono- or di-halothienyl, mono- or di-halofuryl, mono- or di-halobenzothienyl, or mono- or di-halobenzofuryl.
In another more specific embodiment, this invention provides or contemplates a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is o-, m-, or p-xylyl or o-, m-, or p-anisyl.
In another more specific embodiment, this invention provides or contemplates a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is m- or p-cyanophenyl or m- or p-cyanomethyl phenyl.
In another more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is C2-C5 alkylphenyl.
In another more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is CH2Ar1 or CH2CH2—Ar1, where Ar1 is 3,5-dichlorophenyl or 3,5-difluorophenyl.
In a more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R3 and R4 are H or C1-C6 alkyl, unsubstituted or substituted with one or two groups selected from OH, OMe; R1 is CN, CH2CN, or halogen; q is 1; and X and Y are both O.
In another subgeneric embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R1 is F, CH2F, CHF2, CF3, or CF2CF3, q is 1, and X and Y are both O.
In a more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R1 is OC1-C6 alkyl or C(═O)C1-C6 alkyl, q is 1, and X and Y are both O.
In a more specific embodiment, this invention provides a compound of formula I, where R1 or R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R1 is C(═O)OC1-C6 alkyl or OC(═O)C1-C6 alkyl, q is 1, and X and Y are both O.
In a more specific embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R1 is C2-C6 alkenyl or C2-C6 alkynyl, q is 1, and X and Y are both O.
In a more specific embodiment, this invention provides a compound of formula I, where where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, Ar1 is phenyl or pyridyl, R1 is SC1-C6 alkyl, q is 1, and X and Y are both O.
In a more specific embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R3 and R4 are H or C1-C3 alkyl, R1 is C1-C6 alkyl, q is zero, and X is O.
In a more specific embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl; R3 and R4 are H or C1-C3 alkyl; R1 is C1-C6 alkyl; q is 1; and X is O.
In a more specific embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is phenyl or pyridyl, R3 and R4 are H or C1-C3 alkyl, R1 is CN, CH2CN, or halogen, q is 1, Y is O, and X is O.
In another embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is thienyl, furyl, benzothienyl, or benzofuryl; R3 and R4 are, independently, H, methyl, or ethyl; and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is pyrrolyl, imidazolyl, oxazolyl, or thiazolyl; R3 and R4 are, independently, H, methyl, or ethyl; and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another embodiment, this invention provides a compound of formula I, where R5 is Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where Ar1 is isoxazolyl or isothiazolyl; R3 and R4 are, independently, H, methyl, or ethyl; and R5 is C1-C6 alkyl or (CHR6)wC3-C6 cycloalkyl.
In another embodiment, this invention provides a compound of formula I, in which R5 is C1-C6 alkyl, where the alkyl group is substituted with one or two groups selected, independently, from OH, OMe, OEt, F, CF3, Cl, or CN.
In another embodiment, this invention provides a compound of formula I, in which R5 is (CHR6)wC3-C6 cycloalkyl, where w is 1 or 2 and R6 is H or methyl, and where the cycloalkyl group is substituted with Me, OH, OMe, OEt, F, CF3, Cl, or CN.
In a more specific embodiment, this invention provides a compound of formula I, in which R5 is (CH2)w—C5-C6 cycloalkyl or (CH2)w—C5-C6 heterocycloalkyl.
In another embodiment, this invention provides a compound of formula I, in which R5 is CH═CH—C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration.
In another embodiment, this invention provides a compound of formula I, in which R5 is CH═CH—C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the Z configuration.
In another embodiment, this invention provides a compound of formula I, in which R5 is CH2—CH═CH—C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration.
In another embodiment, this invention provides a compound of formula I, in which R5 is CH2CH═CH—C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the Z configuration.
In another embodiment, this invention provides a compound of formula I, in which R5 is CH═CH—CH2—C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration. In another embodiment, this invention provides a compound of formula I, in which R5 is CH═CH—CH2—C3-C6 cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the Z configuration.
In another, more specific embodiment, this invention provides a compound of formula I, in which R5 is (CHR6)wC3-C6 cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl group is monosubstituted.
In another embodiment, this invention provides a compound of formula I, in which R5 is CH═CH—CH2—C3-C6 cycloalkyl or heterocycloalkyl or CH═CH—C3-C6 cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl group is monosubstituted.
In another embodiment, this invention provides a compound of formula I, in which R5 is C5-C6 alkyl.
In another embodiment, this invention provides a compound of formula I, in which q is zero and R5 is CH2—C4-alkyl or CH2—C5— alkyl.
In another embodiment, this invention provides a compound of formula I, in which R5 is C2-C6 alkynyl.
In another embodiment, this invention provides a compound of formula I, in which R5 is C2-C6 alkenyl.
In a more specific embodiment, this invention provides a compound of formula IA1, IA2, IA3, IA4, or IA5, where X is O, R2, R′, and R3 are H, and q=zero.
In another embodiment, this invention provides a compound of formula IB1, IB2, IB3, IB4 or IB5, where X is O, R2, R′, and R3 are H, and q=zero.
In a more specific embodiment, this invention provides a compound of formula IA1, IA2, IA3, IA4, or IA5, where X is O, R2, and R′ are H, R3 and R4 are methyl or methoxy, and q=zero.
In another embodiment, this invention provides a compound of formula IB1, IB2, IB3, IB4 or IB5, where X is O, R2, and R′ are H, R3 and R4 are methyl or methoxy, and q=zero.
In a more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IB1-IB5, where X is O; q=1; Y is O; and R5 is C1-C6 alkyl, CH2—C3-C6 cycloalkyl, CH═CH—C3-C6 cycloalkyl or CH═CH—CH2—C3-C6 cycloalkyl.
In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IB1-IB5, where X is O; q=1; Y is O; and R5 is C1-C6 alkyl, substituted with methoxy, methylthio, or halogen.
In a more specific embodiment, this invention provides a compound of formula IA1, IA2, IA3, IA4, or IA5, where X is O, R2, and R′ are H, R3 and R4 are methyl or methoxy, R5 is C5-C6 alkyl, and q=zero.
In another embodiment, this invention provides a compound of formula IB1, IB2, IB3, IB4 or IB5, where X is O, R2, and R′ are H, R3 and R4 are methyl or methoxy, R5 is C5-C6 alkyl, and q=zero.


DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term heterocycloalkyl denotes a saturated carbocyclic moiety in which one or more ring carbon atoms is replaced by an atom selected from O, N, and S. As used herein, the term heterocycloalkenyl denotes a mono- or poly-unsaturated carbocyclic moiety in which one or more ring carbon atoms is replaced by an atom selected from O, N, and S. As used herein, the term heteroaryl denotes a mono- or bi-cyclic aromatic ring system with one or more ring atoms equal to O, N, and/or S.
Prophetic Examples
The examples below are intended to illustrate—but not to limit—the range of compounds contemplated by this invention.











































Preparation of Compounds
Preparation of Compounds as Potential KCNQ Channel Opener
Section I. The preparation of compounds of formula VIII is outlined in Scheme 1.




Section II. The preparation of compounds of formula XI is outlined in Scheme 2.




Section III. The preparation of compound of formula XIV is outlined in Scheme 3.




Section IV. The preparation of compound of formula XV is outlined in Scheme 4.




Section V. The preparation of compound of formula XVI is outlined in Scheme 5.




Section VI. The preparation of compound of formula XX is outlined in Scheme 6.




EXAMPLES
Example 1
N-(6-(3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide




Step 1. Synthesis of 2,4-dimethylnicotinic acid, 1a




A mixture of ethyl 2,4-dimethylnicotinate (3.58 g, 20 mmol) and an aqueous solution of NaOH (10M, 20 ml) in ethanol (20 ml) was stirred at room temperature for 24 hours. The mixture was cooled to 0° C. and methanol (200 ml) was added follow by aqueous HCl (10 M) to adjust pH to 7. The resulting precipitated (NaCl) was filtered off.
The filtrated was concentrated to remain approximately 20 ml and methanol (100 ml) was added again to precipitate the remaining sodium chloride. The precipitation (NaCl) was repeated until all NaCl was removed from methanolic solution of the reaction mixture. The mixture was concentrated to dryness to yield 1a (3.01 g, 19.9 mmol, 99%).
Step 2. Synthesis of 2,4-dimethyl-3-aminopyridine, 1b




A mixture of 1a (0.98 g, 6.5 mmol) and thionyl chloride (5 ml) was heated to 60° C. for 1 hour. The mixture was concentrated to dryness. The mixture was then dissolved in acetone (10 ml) prior to the addition of NaN3 (0.65 g, 10 mmol) and water (5 ml). The solution was heated to 70° C. for 1 hour. Acetone was evaporated from the reaction mixture which was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1b (0.585 g, 4.79 mmol, 74%).
Step 3. Synthesis of 6-bromo-2,4-dimethyl-3-aminopyridine, 1c




A solution of bromine in dichloromethane (0.96 g in 5 ml) was added to a solution of 1b (0.585, 4.79 mmol) in dichloromethane (25 ml) at 0° C. over 5 minutes. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 3c (0.364 g, 1.81 mmol, 38%).
Step 4. Synthesis of N-(6-bromo-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide, 1d




To a mixture of 1c (0.364 g, 1.81 mmol) and pyridine (0.158 ml, 2 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.242 g, 1.8 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1d (0.361 g, 1.64 mmol, 91%).
Step 5. Synthesis of N-(6-(3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide




In a tube, a mixture of 1d (0.299 g, 1.0 mmol), 1,2,3,4-tetrahydroisoquinoline (0.20 g, 1.5 mmol) in toluene (10 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.046 g, 0.05 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.168 g, 1.5 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 2 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title product (0.278 g, 0.79 mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.93 (t, J=6.2 Hz, 2H), 3.84 (t, J=6.2 Hz, 2H), 4.66 (s, 2H), 6.39 (s, 1H), 6.49 (bs, 1H), 7.15-7.19 (m, 4H).
Example 2
N-(6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide




In a tube, a mixture of 1d (0.65 g, 2.15 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.348 g, 2.6 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.052 g, 0.055 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.08 g, 0.2 mmol) and potassium tert-butoxide (0.437 g, 3.9 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.584 g, 1.58 mmol, 73%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.38 (s, 1H), 6.50 (bs, 1H), 6.85-6.92 (m, 2H), 7.09-7.16 (m, 1H).
Example 3
N-(2,4-dimethyl-6-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)-3,3-dimethylbutanamide




In a tube, a mixture of 1d (0.374 g, 1.25 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (0.301 g, 1.5 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.037 g, 0.04 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.326 g, 0.78 mmol, 63%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.39 (s, 1H), 6.55 (bs, 1H), 6.98 (d, J=7.2 Hz, 2H), 7.24 (s, 1H).
Example 4
N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethoxypyrimidin-5-yl)-3,3-dimethylbutanamide




Step 1. Synthesis of 2-chloro-4,6-dimethoxy-5-nitropyrimidine, 4a




Triflic anhydride (4.25 g, 15 mmol) was added to a suspension of tetramethylammonium nitrate (2.04 g, 15 mmol) in dichloromethane (40 ml) at 0° C. over 15 minutes. The mixture was warmed to room temperature and stirred for 2 hours and then a solution of 2-chloro-4,6-dimethoxypyrimidine (1.75 g in 10 ml, 10 mmol) was added to the mixture over 30 minutes. The mixture was stirred for 2 days. The reaction mixture was poured into ice bath, washed with an aqueous solution of NaHCO3 and extracted with dichloromethane. The organic layer was washed with brine, concentrated to dryness to yield 4a (2.13 g, 9.73 mmol, 97%).
Step 2. Synthesis of 2-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline, 4b




1,8-diazabicyclo[5.4.0]undec-7-ene (0.304 g, 2 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.293 g, 2.2 mmol) in DMF (3 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 4b (0.592 g, 1.87 mmol, 94%).
Step 3. Synthesis of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethoxypyrimidin-5-amine, 4c




A suspension of Raney®-Nickel in a methanolic solution of 4b (0.57 g in 50 ml, 1.8 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.51 g, 1.78 mmol, 99%).
Step 4. Synthesis of N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethoxypyrimidin-5-yl)-3,3-dimethylbutanamide. 4d




To a mixture of 4c (0.219 g, 0.76 mmol) and pyridine (0.06 g, 0.76 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.102 g, 0.76 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.262 g, 0.73 mmol, 96%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.90 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J=5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H).
Example 5
N-(4,6-dimethoxy-2-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide




Step 1. Refer to example 4
Step 2. Synthesis of 2-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline, 5b




1,8-diazabicyclo[5.4.0]undec-7-ene (0.669 g, 4.4 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmol) in DMF (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 5b (0.76 g, 1.98 mmol, 99%).
Step 3. Synthesis of 4,6-dimethoxy-2-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-amine, 5c




A suspension of Raney®-Nickel in a methanolic solution of 5b (0.76 g in 50 ml, 1.98 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.69 g, 1.96 mmol, 99%).
Step 4. Synthesis of N-(4,6-dimethoxy-2-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide
To a mixture of 5c (0.69 g, 1.96 mmol) and pyridine (0.156 g, 2.0 mmol) in dichloromethane (20 ml) was added tert-butylacetyl chloride (0.269 g, 2.0 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.657 g, 1.45 mmol, 72%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J=5.8 Hz, 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J=7.8 Hz, 1H).
Example 6
N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-3,3-




Step 1. Synthesis of ethyl 2-hydroxy-4,6-dimethylpyrimidine-5-carboxylate. 6a




A mixture of ethyl diacetoacetate (17.22 g, 100 mmol), urea (9.61 g, 160 mmol) and HCl (10 M, 4 ml) in ethanol (400 ml) was heated to 90° C. for 12 hours. The mixture was concentrated to remain 200 ml and then was cooled to −20° C. to allow precipitation. The mixture was filtered at room temperature to obtained 6a as solid granulate (5.32 g, 2.71 mmol, 27%).
Step 2. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate, 6b




Phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 6a (1.47 g, 7.5 mmol), benzyltriethylammonium chloride (1.71 g, 7.5 mmol) and N,N-dimethylaniline (1.82 g, 15 mmol) in acetonitrile (30 ml). The mixture was reflux for 5 hours. The mixture was poured into ice water and neutralized with NaHCO3. The solution was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, concentrated and chromatographed to obtain 6b, (1.02 g, 4.75 mmol, 63%).
Step 3. Synthesis of ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine-5-carboxylate, 6c




1,8-diazabicyclo[5.4.0]undec-7-ene (1.086 g, 7.15 mmol) was added to a mixture of 6b (1.02 g, 4.75 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.95 g, 7.13 mmol) in DMSO (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 6c (1.43 g, 4.5 mmol, 95%).
Step 4. Synthesis of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine-5-carboxylic acid, 6d




A mixture of 6c (1.43 g, 4.5 mmol) and an aqueous solution of NaOH (10M, 20 ml) in ethanol (20 ml) was refluxed for 6 hours. To the mixture was added 100 ml of water and then the mixture was washed with dichloromethane (100 ml). The aqueous phase was neutralized with hydrochloric acid to pH=6. Product was precipitated at pH=6. After filtration, 6d was obtained as white powder (1.10 g, 3.88 mmol, 86%).
Step 5. Synthesis of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-amine, 6e




To a cold (−20° C.) thionyl chloride (5 ml) was added 9d (0.8 g, 2.82 mmol). The mixture was heated to 70° C. for 1 hour. Excess thionyl chloride was evaporated. The residue was dissolved in THF (3 ml) and acetone (3 ml) and then trimethylsilyl azide (0.55 ml, 4.25 mmol) was added into the mixture. The mixture was heated to 70° C. for 2 hours. The reaction media was washed with brine, extracted with ethyl acetate. Organic layer was dried over MgSO4, concentrated and chromatographed to yield 6e (0.028 g, 0.11 mmol, 4%).
Step 6. Synthesis of N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide, 6f




To a mixture of 6e (0.028 g, 0.11 mmol) and pyridine (0.03 g, 0.4 mmol) in dichloromethane (2 ml) was added tert-butylacetyl chloride (0.053 g, 0.4 mmol). The mixture was stirred at room temperature for 5 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 6f (0.031 g, 0.07 mmol, 63%).
Step 7. Synthesis of N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-3,3-dimethylbutanamide




An aqueous solution of ammonium hydroxide (30%, 1 ml) was added to a solution of 6f (0.031 g, 0.07 mmol) in methanol (1 ml) and stirred for 20 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.019 g, 0.054 mmol, 77%). 1H NMR (CDCl3, 400 MHz) δ 1.11 (s, 9H), 2.23 (s, 2H), 2.30 (s, 6H), 2.91 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 4.89 (s, 2H), 6.68 (s, 1H), 7.17 (dd, J=7.8, 3.4 Hz, 4H).
Example 7
N-(6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide
Step 1. Synthesis of N-(6-bromo-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide




To a mixture of 1c (0.5114 g, 2.54 mmol) and pyridine (0.22 ml, 2.78 mmol) in dichloromethane (5 ml) was added 2-(2-methoxyethoxy)acetyl chloride (0.425 g, 2.78 mmol). The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 7d (0.72 g, 2.27 mmol, 90%).
Step 2. N-(6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide




In a tube, a mixture of 7d (0.245 g, 0.77 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.1876 g, 1.0 mmol) in toluene (5 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.04 g, 0.1 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.259 g, 0.668 mmol, 87%). 1H NMR (CDCl3, 400 MHz) δ 2.19 (s, 3H), 2.36 (s, 3H), 2.92 (t, J=5.7 Hz, 2H), 3.40 (s, 3H), 3.62 (dd, J=4.3, 2.2 Hz, 2H), 3.80-3.84 (m, 4H), 4.19 (s, 2H), 4.64 (s, 2H), 6.40 (s, 1H), 6.85-6.91 (m, 2H), 7.14 (dd, J=7.9, 7.9 Hz, 1H), 8.21 (bs, 1H).
Example 8
N-(2,4-dimethyl-6-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide




In a tube, a mixture of 7d (0.2 g, 0.6 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (0.209 g, 0.88 mmol) in toluene (5 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.04 g, 0.1 mmol) and potassium tert-butoxide (0.224 g, 2.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.262 g, 0.6 mmol, 95%). 1H NMR (CDCl3, 400 MHz) δ 2.18 (s, 3H), 2.35 (s, 3H), 2.96 (t, J=5.5 Hz, 2H), 3.37 (s, 3H), 3.62 (dd, J=3.8, 1.6 Hz, 2H), 3.78-3.84 (m, 4H), 4.17 (s, 2H), 4.71 (s, 2H), 6.41 (s, 1H), 7.27 (d, J=7.7, 1H), 7.40 (s, 1H) 7.41 (d, J=8.4 Hz, 1H), 8.25 (bs, 1H).
Example 9
N-(2,4-dimethyl-6-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)-3,3-dimethylbutanamide




Bis(dibenzylidineacetone)palladium (4 mg, 0.069 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (6.5 mg, 0.014 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (34 mg, 0.3 mmol), 1d (50 mg, 0.17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (28 mg, 0.14 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% ethyl acetate:hexanes) to afford the tittle compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 1.03 (s, 9H), 2.09 (s, 3H), 2.15 (s, 2H), 2.21 (s, 3H), 3.03 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.79 (s, 2H), 6.68 (s, 1H), 8.12 (s, 1H), 8.75 (s, 1H), 9.02 (s, 1H).
Example 10
N-(6-(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide




Bis(dibenzylidineacetone)palladium (5 mg, 0.009 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (9 mg, 0.018 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (46 mg, 0.41 mmol), 1d (66 mg, 0.22 mmol) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (25 mg, 0.19 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford the tittle compound as a solid. 1H NMR (CDCl3, 400 MHz) δ 1.15 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.06 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.73 (s, 2H), 6.48 (s, 1H), 6.55 (s, 1H), 8.55 (s, 1H), 9.01 (s, 1H).
Example 11
N-(2,4-dimethyl-6-(2-(trifluoromethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyridin-3-yl)-3,3-dimethylbutanamide




Bis(dibenzylidineacetone)palladium (4 mg, 0.07 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (6.5 mg, 0.014 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (34 mg, 0.31 mmol), 1d (50 mg, 0.18 mmol) and 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (28 mg, 0.14 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford compound 9 as a solid. 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.17 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.83 (s, 2H), 6.51 (s, 1H), 8.70 (s, 1H).
Biological Results
Compounds of this invention formula were evaluated as potassium channel modulators by measuring rhubidium release in the following assay.
Methods: PC-12 cells were grown at 37° C. and 5% CO2 in DMEM/F12 Medium supplemented with 10% horse serum, 5% fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, 100 U/ml streptomycin. They were plated in poly-D-lysine-coated 96-well cell culture microplates at a density of 40,000 cells/well and differentiated with 100 ng/ml NGF-7s for 2-5 days. For the assay, the medium was aspirated and the cells were washed once with 0.2 ml in wash buffer (25 mM Hepes, pH 7.4, 150 mM NaCl, 1 mM MgCl2, 0.8 mM NaH2PO4, 2 mM CaCl2). The cells were then loaded with 0.2 ml Rb+ loading buffer (wash buffer plus 5.4 mM RbCl2, 5 mM glucose) and incubated at 37° C. for 2 h. Attached cells were quickly washed three times with buffer (same as Rb+ loading buffer, but containing 5.4 mM KCl instead of RbCl) to remove extracellular Rb+. Immediately following the wash, 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCl) with or without compounds was added to the cells to activate efflux of potassium ion channels. After incubation for 10 min at room temperature, the supernatant was carefully removed and collected. Cells were lysed by the addition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1% Triton X-100) and the cell lysates were also collected. If collected samples were not immediately analyzed for Rb+ contents by atomic absorption spectroscopy (see below), they were stored at 4° C. without any negative effects on subsequent Rb+ analysis.
The concentration of Rb+ in the supernatants (Rb+Sup) and cell lysates (Rb+Lys) was quantified using an ICR8000 flame atomic absorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) under conditions defined by the manufacturer. One 0.05 ml samples were processed automatically from microtiter plates by dilution with an equal volume of Rb+ sample analysis buffer and injection into an air-acetylene flame. The amount of Rb+ in the sample was measured by absorption at 780 nm using a hollow cathode lamp as light source and a PMT detector. A calibration curve covering the range 0-5 mg/L Rb+ in sample analysis buffer was generated with each set of plates. The percent Rb+ efflux (F) was defined by F=[Rb+sup/(Rb+sup+Rb+Lys)]×100%.
The effect (E) of a compound was defined by: E=[(Fc−Fb)/(Fs−Fb)]×100% where the Fc is the efflux in the presence of compound in depolarization buffer, Fb is the efflux in basal buffer, and Fs is the efflux in depolarization buffer, and Fc is the efflux in the presence of compound in depolarization buffer. The effect (E) and compound concentration relationship was plotted to calculate an EC50 value, a compound's concentration for 50% of maximal Rb+ efflux. The results are shown below. Legend: A: EC50=1 nM-50 nM; B: EC50=50 nM-100 nM; C: EC50=100-200 nM.







TABLE 1







ACTIVITIES OF EXEMPLARY COMPOUNDS








COMPOUND
ACTIVITY









A


 






A


 






A


 






A


 






A


 






B

## Claims

1. A compound of formula IA-1a



wherein R5 is C3-C6 alkyl or CH2—C3—C6-cycloalkyl and where R5 is optionally substituted with halogen, hydroxy, or methoxy;
at least one of W and Z is N, and the other is C;
R1 is H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2;
R3 and R4 are, independently, H, halogen, methyl, methoxy, or trifluoromethyl;
R′ and R2 are, independently, H, halogen, methyl, or trifluoromethyl;
and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R1 is H, F, methyl, or trifluoromethyl.

3. The compound of claim 1 wherein R3 and R4 are, independently, H, methyl, or methoxy.

4. A compound of formula IA-1b



where at least one of W and Z is N, and the other is C;
R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;
R′ is H, halogen, CF3, or C1-C3 alkyl;
R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl;
R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl; and
pharmaceutically acceptable salts thereof.

5. The compound of claim 4 wherein R3 and R4 are, independently, H, halogen, methyl, methoxy, or trifluoromethyl.

6. The compound of claim 5 wherein R′ and R2 are, independently, H, halogen, methyl, or trifluoromethyl.

7. The compound of claim 6, wherein R5 is C3-C6 alkyl or CH2—C3-C6-cycloalkyl and where R5 is optionally substituted with halogen, hydroxy, or methoxy.

8. The compound of claim 7 wherein R1 is H, F, methyl, or trifluoromethyl.

9. The compound of claim 4 wherein R3 and R4 are, independently, H, methyl, or methoxy.

10. A compound of formula IA2



where at least one of W and Z is N, and the other is C;
R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C66 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;
R′ is H, halogen, CF3, or C1-C3 alkyl;
R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl;
X═O or S; Y is O or S; q=1 or 0;
R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl; and
pharmaceutically acceptable salts thereof.

11. The compound of claim 10 wherein X is O, Y is O, and q is 0 or 1.

12. The compound of claim 11 wherein R3 and R4 are, independently, H, halogen, methyl, methoxy, or trifluoromethyl.

13. The compound of claim 12 wherein R′ and R2 are, independently, H, halogen, methyl, or trifluoromethyl.

14. The compound of claim 13, wherein R5 is C3-C6 alkyl or CH2—C3-C6-cycloalkyl and where R5 is optionally substituted with halogen, hydroxy, or methoxy.

15. The compound of claim 14 wherein R1 is H, F, methyl, or trifluoromethyl.

16. The compound claim 11 wherein R3 and R4 are, independently, H, methyl, or methoxy.

17. A compound of formula IA3



where at least one of W and Z is N, and the other is C;
R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;
R′ is H, halogen, CF3, or C1-C3 alkyl;
R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl;
X═O or S; Y is O or S; q=1 or 0;
R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl; and
pharmaceutically acceptable salts thereof.

18. The compound of claim 17 wherein X is O, Y is O, and q is 0 or 1.

19. The compound of claim 18 wherein R3 and R4 are, independently, H, halogen, methyl, methoxy, or trifluoromethyl.

20. The compound of claim 19 wherein R′ and R2 are, independently, H, halogen, methyl, or trifluoromethyl.

21. The compound of claim 20, wherein R5 is C3-C6 alkyl or CH2—C3-C6-cycloalkyl and where R5 is optionally substituted with halogen, hydroxy, or methoxy.

22. The compound of claim 21 wherein R1 is H, F, methyl, or trifluoromethyl.

23. The compound of claim 17 wherein R3 and R4 are, independently, H, methyl, or methoxy.

24. A compound of formula IA4



where at least one of W and Z is N, and the other is C;
R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;
R′ is H, halogen, CF3, or C1-C3 alkyl;
R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl;
X═O or S; Y is O or S; q=1 or 0;
R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl; and
pharmaceutically acceptable salts thereof.

25. The compound of claim 24 wherein X is O, Y is O, and q is 0 or 1.

26. The compound of claim 25 wherein R3 and R4 are, independently, H, halogen, methyl, methoxy, or trifluoromethyl.

27. The compound of claim 26 wherein R′ and R2 are, independently, H, halogen, methyl, or trifluoromethyl.

28. The compound of claim 27, wherein R5 is C3-C6 alkyl or CH2—C3-C6-cycloalkyl and where R5 is optionally substituted with halogen, hydroxy, or methoxy.

29. The compound of claim 28 wherein R1 is H, F, methyl, or trifluoromethyl.

30. The compound of claim 24 wherein R3 and R4 are, independently, H, methyl, or methoxy.

31. A compound of formula IA5



where at least one of W and Z is N, and the other is C;
R1 and R2, are, independently, H, CN, halogen, CH2CN, OH, NO2, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, NH—C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH—C1-C6 alkyl, C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mpyrazyl, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, or (CH2)mpyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R1 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 O, N, and S, and which is optionally substituted with halogen, CF3, or C1-C3 alkyl;
R′ is H, halogen, CF3, or C1-C3 alkyl;
R3 and R4 are, independently, H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, or C1-C6 alkyl, all said C1-C3 alkyl groups and said C1-C6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C1-C3 alkyl, OC1-C3 alkyl, or trifluoromethyl;
X═O or S; Y is O or S; q=1 or 0;
R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar1, (CHR6)wAr1, CH2(CHR6)wAr1, or (CHR6)wCH2Ar1, where w=0-3, Ar1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R6 is hydrogen or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, or Ar1 are optionally substituted with one or two substituents selected independently from C1-C3 alkyl, halogen, OH, OMe, SMe, CN, CH2F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C3-C6 cycloalkyl; and
pharmaceutically acceptable salts thereof.

32. The compound of claim 31 wherein X is O, Y is O, and q is 0 or 1.

33. The compound of claim 32 wherein R3 and R4 are, independently, H, halogen, methyl, methoxy, or trifluoromethyl.

34. The compound of claim 33 wherein R′ and R2 are, independently, H, halogen, methyl, or trifluoromethyl.

35. The compound of claim 34, wherein R5 is C3-C6 alkyl or CH2—C3-C6-cycloalkyl and where R5 is optionally substituted with halogen, hydroxy, or methoxy.

36. The compound of claim 35 wherein R1 is H, F, methyl, or trifluoromethyl.

37. The compound of claim 31 wherein R3 and R4 are, independently, H, methyl, or methoxy.

38. A pharmaceutical composition comprising a compound of claim 1 with a pharmaceutically acceptable carrier.

39. A pharmaceutical composition comprising a compound of claim 4 with a pharmaceutically acceptable carrier.

40. A pharmaceutical composition comprising a compound of claim 10 with a pharmaceutically acceptable carrier.

41. A pharmaceutical composition comprising a compound of claim 17 with a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising a compound of claim 24 with a pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising a compound of claim 31 with a pharmaceutically acceptable carrier.