Heterocyclic Benzimidazoles As Trpm8 Modulators Patent Application (2025)

U.S. patent application number 12/576283 was filed with the patent office on 2010-04-15 for heterocyclic benzimidazoles as trpm8 modulators. Invention is credited to Shelley K. Ballentine, Carl R. Illig, Senath K. Meegalla, Daniel J. Parks, William Parsons, Mark R. Player.

HETEROCYCLIC BENZIMIDAZOLES AS TRPM8 MODULATORS

Abstract

Disclosed are compounds, compositions and methods for treatingvarious diseases, syndromes, conditions and disorders, includingpain. Such compounds are represented by Formula I as follows:##STR00001## wherein W.sub.1, W.sub.2, W.sub.3, R.sup.1, R.sup.1a,R.sup.2, R.sup.2a, R.sup.3, V, Q, and X are defined herein.

 PHILIP S. JOHNSON;JOHNSON & JOHNSON ONE JOHNSON & JOHNSON PLAZA NEW BRUNSWICK NJ 08933-7003 US

Related U.S. Patent Documents

Claims

1. A compound of the formula (I) ##STR00178## wherein W.sub.1 isC(R.sup.2a) or N; W.sub.2 is CH or N; W.sub.3 is C(R.sup.2) or N;such that no more than one of W.sub.1, W.sub.2, and W.sub.3 is N;and when one of W.sub.1, W.sub.2, and W.sub.3 is N, then R.sup.2and R.sup.2a are hydrogen; R.sup.1 is fluoro, chloro,trifluoromethyl, (1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl,trifluoromethoxy, or difluoromethoxy; or R.sup.1 and R.sup.3 aretaken together to form a single fused --OCF.sub.2O-- moiety;R.sup.1a is hydrogen, fluoro, chloro, or bromo; R.sup.2 ishydrogen, C.sub.1-4alkyl, fluoro, chloro, bromo, cyano,trifluoromethyl, hydroxy(C.sub.1-6)alkyl,C.sub.1-3alkoxy(C.sub.1-6)alkyl, cyclopropyl,--CH.dbd.CHCH.sub.2OH, or C.sub.2-4alkenyl bound via an unsaturatedcarbon atom; R.sup.2a is hydrogen or methyl; R.sup.3 is hydrogen,fluoro, or taken with R.sup.1 to form --OCF.sub.2O--; V and Q areselected from the group consisting of V is CH(R.sup.4) and Q is O;V is NH and Q is CH.sub.2; and V is O and Q is CH.sub.2; R.sup.4 ishydrogen or C.sub.1-4alkyl; X is CH.sub.2, C(CH.sub.3).sub.2,CF.sub.2, or O; with the proviso that when V is NH, X is other thanO; and enantiomers, diastereomers, and pharmaceutically acceptablesalts thereof.

2. The compound of claim 1 wherein R.sup.1 is fluoro,trifluoromethyl, (1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl,trifluoromethoxy, or difluoromethoxy; or R.sup.1 and R.sup.3 aretaken together to form a single fused --OCF.sub.2O-- moiety.

3. The compound of claim 2 wherein R.sup.1 is fluoro,trifluoromethyl, (1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl,trifluoromethoxy, or difluoromethoxy.

4. The compound of claim 1 wherein R.sup.1a is hydrogen orfluoro.

5. The compound of claim 1 wherein R2 is hydrogen, C1-4alkyl,fluoro, chloro, bromo, cyano, trifluoromethyl, hydroxy(C1-6)alkyl,C1-3alkoxy(C1-6)alkyl, or --CH.dbd.CHCH.sub.2OH.

6. The compound of claim 5 wherein R.sup.2 is C.sub.1-4alkyl,fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, or --CH.dbd.CHCH.sub.2OH.

7. The compound of claim 6 wherein R.sup.2 is methyl, fluoro,chloro, bromo, trifluoromethyl, or hydroxy(C.sub.1-6)alkyl.

8. The compound of claim 1 wherein R.sup.2a is hydrogen ormethyl.

9. The compound of claim 1 wherein R.sup.3 is hydrogen or takenwith R.sup.1 to form --OCF.sub.2O--.

10. The compound of claim 1 wherein R.sup.3 is hydrogen.

11. The compound of claim 1 wherein V and Q are selected from thegroup consisting of V is CH(R.sup.4) and Q is O; V is NH and Q isCH.sub.2; and V is O and Q is CH.sub.2.

12. The compound of claim 11 wherein V and Q are selected from thegroup consisting of V is CH(R.sup.4) and Q is O; and V is O and Qis CH.sub.2.

13. The compound of claim 1 wherein R.sup.4 is hydrogen ormethyl.

14. The compound of claim 1 wherein X is CH.sub.2, CF.sub.2, orO.

15. The compound of claim 1 wherein X is CH.sub.2 or O.

16. A compound of Formula (I) ##STR00179## wherein W.sub.1 isC(R.sup.2a) or N; W.sub.2 is CH or N; W.sub.3 is C(R.sup.2) or N;such that no more than one of W.sub.1, W.sub.2, and W.sub.3 is N;and when one of W.sub.1, W.sub.2, and W.sub.3 is N, then R.sup.2and R.sup.2a are hydrogen; R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; or R.sup.1 and R.sup.3 are taken together toform a single fused --OCF.sub.2O-- moiety; R.sup.1a is hydrogen orfluoro; R.sup.2 is hydrogen, C.sub.1-4alkyl, fluoro, chloro, bromo,cyano, trifluoromethyl, hydroxy(C.sub.1-6)alkyl,C.sub.1-3alkoxy(C.sub.1-6)alkyl, or --CH.dbd.CHCH.sub.2OH; R.sup.2ais hydrogen or methyl; R.sup.3 is hydrogen or taken with R.sup.1 toform --OCF.sub.2O--; V and Q are selected from the group consistingof V is CH(R.sup.4) and Q is O; V is NH and Q is CH.sub.2; and V isO and Q is CH.sub.2; R.sup.4 is hydrogen or methyl; X is CH.sub.2,CF.sub.2, or O; with the proviso that when V is NH, X is other thanO; and enantiomers, diastereomers, and pharmaceutically acceptablesalts thereof.

17. A compound of Formula (I) ##STR00180## wherein W.sub.1 isC(R.sup.2a) or N; W.sub.2 is CH or N; W.sub.3 is C(R.sup.2) or N;such that no more than one of W.sub.1, W.sub.2, and W.sub.3 is N;and when one of W.sub.1, W.sub.2, and W.sub.3 is N, then R.sup.2and R.sup.2a are hydrogen; R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; R.sup.1a is hydrogen or fluoro; R.sup.2 ishydrogen, C.sub.1-4alkyl, fluoro, chloro, bromo, cyano,trifluoromethyl, hydroxy(C.sub.1-6)alkyl,C.sub.1-3alkoxy(C.sub.1-6)alkyl, or --CH.dbd.CHCH.sub.2OH; R.sup.2ais hydrogen or methyl; R.sup.3 is hydrogen; V and Q are selectedfrom the group consisting of V is CH(R.sup.4) and Q is O; and V isO and Q is CH.sub.2; R.sup.4 is hydrogen or methyl; X is CH.sub.2,CF.sub.2, or O; and enantiomers, diastereomers, andpharmaceutically acceptable salts thereof.

18. A compound of Formula (I) ##STR00181## wherein W.sub.1 isC(R.sup.2a) or N; W.sub.2 is CH or N; W.sub.3 is C(R.sup.2) or N;such that no more than one of W.sub.1, W.sub.2, and W.sub.3 is N;and when one of W.sub.1, W.sub.2, and W.sub.3 is N, then R.sup.2and R.sup.2a are hydrogen; R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; R.sup.1a is hydrogen or fluoro; R.sup.2 isC.sub.1-4alkyl, fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, C.sub.1-3 alkoxy(C.sub.1-6)alkyl, or--CH.dbd.CHCH.sub.2OH; R.sup.2a is hydrogen or methyl; R.sup.3 ishydrogen; V and Q are selected from the group consisting of V isCH(R.sup.4) and Q is O; and V is O and Q is CH.sub.2; R.sup.4 ishydrogen or methyl; X is CH.sub.2, CF.sub.2, or O; and enantiomers,diastereomers, and pharmaceutically acceptable salts thereof.

19. A compound of Formula (I) ##STR00182## wherein W.sub.1 isC(R.sup.2a) or N; W.sub.2 is CH or N; W.sub.3 is C(R.sup.2) or N;such that no more than one of W.sub.1, W.sub.2, and W.sub.3 is N;and when one of W.sub.1, W.sub.2, and W.sub.3 is N, then R.sup.2and R.sup.2a are hydrogen; R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; R.sup.1a is hydrogen or fluoro; R.sup.2 ismethyl, fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, C.sub.1-3 alkoxy(C.sub.1-6)alkyl, or--CH.dbd.CHCH.sub.2OH; R.sup.2a is hydrogen or methyl; R.sup.3 ishydrogen; V and Q are selected from the group consisting of V isCH(R.sup.4) and Q is O; and V is O and Q is CH.sub.2; R.sup.4 ishydrogen or methyl; X is CH.sub.2 or O; and enantiomers,diastereomers, and pharmaceutically acceptable salts thereof.

20. A compound of Formula (I) ##STR00183## selected from the groupconsisting of: a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1aR.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethoxy, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is O, Q is CH.sub.2, and X is CH.sub.2; acompound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethoxy, R.sup.1a, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is O, Q is CH.sub.2, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is O, Q is CH.sub.2,and X is CH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a),W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl,R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is O, Q isCH.sub.2, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is fluoro, R.sup.2, R.sup.2a, and R.sup.3are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and Xis CH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethoxy, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethoxy, R.sup.1a is fluoro, R.sup.2, R.sup.2a,and R.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isO; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CF.sub.2; a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is 2,2,2-trifluoroethyl, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is takenwith R.sup.3 to form --OCF.sub.2O--, R.sup.1a, R.sup.2, andR.sup.2a are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isdifluoromethoxy, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is fluoro, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is methyl, and X is CH.sub.2; a compound wherein W.sub.1is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is chloro, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is bromo, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is(1-hydroxy-1-methyl)ethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and Xis CH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is NH, Q isCH.sub.2, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isdifluoromethoxy, R.sup.1a is hydrogen, R.sup.2 is methyl, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is cyano, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is 3-hydroxypropyl,R.sup.2a is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is fluoro, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is hydrogen, R.sup.2a is methyl, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is 1-hydroxy-prop-2-en-3-yl, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is fluoro, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen, R.sup.3is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and Xis CH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen, R.sup.3is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is methyl, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is O, Q is CH.sub.2,and X is O; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is chloro, R.sup.1a is hydrogen,R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is fluoro, R.sup.1a, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is hydrogen, and X is O; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is methyl, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is O; a compound wherein W.sub.1 is C(R.sup.2a),W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl,R.sup.1a is hydrogen, R.sup.2 is bromo, R.sup.2a is hydrogen,R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen,and X is O; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is chloro, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isO; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is cyano, R.sup.2 is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isO; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1aR.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is C(CH.sub.3).sub.2; a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is chloro, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is C(CH.sub.3).sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is fluoro, R.sup.2 is hydrogen, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is O; a compound wherein W.sub.1 is C(R.sup.2a),W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl,R.sup.1a is hydrogen, R.sup.2 is trifluoromethyl, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is C(CH.sub.3).sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 ischloro, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is O; a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is chloro, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isC(CH.sub.3).sub.2; a compound wherein W.sub.1 is C(R.sup.2a),W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl,R.sup.1a is hydrogen, R.sup.2 is trifluoromethyl, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is O; a compound wherein W.sub.1 is C(R.sup.2a),W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl,R.sup.1a is hydrogen, R.sup.2 isCH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, R.sup.2a is hydrogen, R.sup.3is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and Xis CH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is fluoro, R.sup.1a is fluoro,R.sup.2 is chloro, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; acompound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is chloro, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is methyl, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is hydrogen, R.sup.2 is methyl, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is fluoro, R.sup.2 is methyl, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is hydrogen, R.sup.2 is chloro, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethoxy, R.sup.1a is hydrogen, R.sup.2 is chloro, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethoxy, R.sup.1a is hydrogen, R.sup.2 is trifluoromethyl,R.sup.2a is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen, R.sup.2 isCH.sub.2 CH.sub.2 CH.sub.2OCH.sub.3, R.sup.2a is hydrogen, R.sup.3is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and Xis CH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 isCH, W.sub.3 is C(R.sup.2), R.sup.1 is fluoro, R.sup.1a is hydrogen,R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is methyl, R.sup.2a is methyl, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a ishydrogen, R.sup.2 is chloro, R.sup.2a is methyl, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is N, W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is hydrogen, and X is CH.sub.2; a compound wherein W.sub.1is C(R.sup.2a), W.sub.2 is N, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH,W.sub.3 is N, R.sup.1 is trifluoromethyl, R.sup.1a, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; and enantiomers, diastereomers, andpharmaceutically acceptable salts thereof.

21. A compound of formula (I) wherein the compounds have a formulaselected from the group consisting of ##STR00184## or apharmaceutically acceptable salt form thereof.

22. A pharmaceutical composition comprising a compound of claim 1and at least one of a pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and a pharmaceuticallyacceptable diluent.

23. The pharmaceutical composition of claim 22, wherein thecomposition is a solid oral dosage form.

24. The pharmaceutical composition of claim 23, wherein thecomposition is a syrup, an elixir, or a suspension.

25. A method for treating inflammatory pain, inflammatoryhypersensitivity condition, neuropathic pain, anxiety anddepression in a subject in need thereof comprising administering tothe subject a therapeutically effective amount of a compound ofclaim 1.

26. The method of claim 25 wherein the inflammatory pain is due toinflammatory bowel disease, visceral pain, migraine, post operativepain, osteoarthritis, rheumatoid arthritis, back pain, lower backpain, joint pain, abdominal pain, chest pain, labor,musculoskeletal diseases, skin diseases, toothache, pyresis, burn,sunburn, snake bite, venomous snake bite, spider bite, insectsting, neurogenic bladder, interstitial cystitis, urinary tractinfection, rhinitis, contact dermatitis/hypersensitivity, itch,eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy painsyndrome, menstrual pain, endometriosis, sinus headache, tensionheadache, or arachnoiditis.

27. The method of claim 25 wherein the inflammatory pain isinflammatory hyperalgesia.

28. The method of claim 27 wherein the inflammatory hyperalgesia isinflammatory somatic hyperalgesia or inflammatory visceralhyperalgesia.

29. The method of claim 28 wherein the inflammatory hyperalgesia isdue to inflammation, osteoarthritis, rheumatoid arthritis, backpain, joint pain, abdominal pain, musculoskeletal diseases, skindiseases, post operative pain, headaches, fibromyalgia, toothache,burn, sunburn, insect sting, neurogenic bladder, urinaryincontinence, interstitial cystitis, urinary tract infection,cough, asthma, chronic obstructive pulmonary disease, rhinitis,contact dermatitis/hypersensitivity, itch, eczema, pharyngitis,enteritis, irritable bowel syndrome, Crohn's Disease, or ulcerativecolitis.

30. The method of claim 25 wherein said inflammatoryhypersensitivity condition is urinary incontinence, benignprostatic hypertrophy, cough, asthma, rhinitis, nasalhypersensitivity, itch, contact dermatitis, dermal allergy, orchronic obstructive pulmonary disease.

31. The method of claim 25 wherein said neuropathic pain is due tocancer, a neurological disorder, spine or peripheral nerve surgery,a brain tumor, traumatic brain injury (TBI), spinal cord trauma, achronic pain syndrome, fibromyalgia, chronic fatigue syndrome, aneuralgia, lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain,neuropathies associated with spinal cord injury, stroke, ALS,Parkinson's disease, multiple sclerosis, sciatic neuritis,mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, a bony fracture, oral neuropathicpain, Charcot's pain, complex regional pain syndrome I and II (CRPSI/II), radiculopathy, Guillain-barre syndrome, meralgiaparesthetica, burning-mouth syndrome, optic neuritis, postfebrileneuritis, migrating neuritis, segmental neuritis, Gombault'sneuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,geniculate neuralgia, glossopharyngial neuralgia, migrainousneuralgia, idiopathic neuralgia, intercostals neuralgia, mammaryneuralgia, Morton's neuralgia, nasociliary neuralgia, occipitalneuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vulvodynia or vidianneuralgia.

32. The method of claim 31 wherein the neuralgia is trigeminalneuralgia, glossopharyngeal neuralgia, postherpetic neuralgia, orcausalgia.

33. The method of claim 25 wherein the neuropathic pain isneuropathic cold allodynia.

34. The method of claim 33 wherein the neuropathic cold allodyniais pain arising from spine and peripheral nerve surgery or trauma,traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II), or radiculopathy.

35. The method of claim 25 wherein the anxiety is social anxiety,post traumatic stress disorder, phobias, social phobia, specialphobias, panic disorder, obsessive compulsive disorder, acutestress disorder, separation anxiety disorder, or generalizedanxiety disorder.

36. The method of claim 25 wherein the depression is majordepression, bipolar disorder, seasonal affective disorder, postnatal depression, manic depression, or bipolar depression.

37. A method for treating inflammatory somatic hyperalgesia inwhich a hypersensitivity to thermal stimuli exists, comprisingadministering to the subject a therapeutically effective amount ofa compound of claim 1.

38. A method for treating inflammatory visceral hyperalgesia inwhich a enhanced visceral irritability exists, comprisingadministering to the subject a therapeutically effective amount ofa compound claim 1.

39. A method for treating neuropathic cold allodynia in which ahypersensitivity to cooling stimuli exists, comprisingadministering to the subject a therapeutically effective amount ofa compound of claim 1.

40. A method for treating cardiovascular disease aggravated by coldin a subject in need thereof which comprises administering to thesubject a therapeutically effective amount of a compound of claim1.

41. The method of claim 40 wherein the cardiovascular disease isselected from the group consisting of peripheral vascular disease,vascular hypertension, pulmonary hypertension, Raynaud's disease,and coronary artery disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefits of the filing ofU.S. Provisional Application No. 61/105,449 filed Oct. 15, 2008.The complete disclosures of the aforementioned related patentapplications are hereby incorporated herein by reference for allpurposes.

FIELD OF THE INVENTION

[0002] The present invention relates to heterocyclic benzimidazolesthat act as modulators of the TRPM8 receptor. The present inventionalso relates to processes for the preparation of heterocyclicbenzimidazoles and to their use in treating various diseases,syndromes, and disorders, including those that cause inflammatorypain, neuropathic pain, cold intolerance or cold allodynia,peripheral vascular pain, itch, urinary incontinence, chronicobstructive pulmonary disease, pulmonary hypertension and anxiety,including other stress-related disorders, and combinationsthereof.

BACKGROUND OF THE INVENTION

[0003] Transient receptor potential (TRP) channels arenon-selective cation channels that are activated by a variety ofstimuli. Numerous members of the ion channel family have beenidentified to date, including the cold-menthol receptor, alsocalled TRPM8 (McKemy, D. D. et al. Nature 2002, 416(6876), 52-58).Collectively, the TRP channels and related TRP-like receptorsconnote sensory responsivity to the entire continuum of thermalexposure, selectively responding to threshold temperatures rangingfrom noxious hot through noxious cold as well as to certainchemicals that mimic these sensations. Specifically, TRPM8 is knownto be stimulated by cool to cold temperatures as well as by mentholand icilin, which may be responsible for the therapeutic coolingsensation that these agents provoke.

[0004] TRPM8 is located on primary nociceptive neurons (A-delta andC fibers) and is also modulated by inflammation-mediated secondmessenger signals (Abe, J. et al. Neurosci. Lett. 2006, 397(1-2),140-144; Premkumar, L. S. et al. J. Neurosci. 2005; 25(49),11322-11329). The localization of TRPM8 on both A-delta andC-fibers may provide a basis for abnormal cold sensitivity inpathologic conditions wherein these neurons are altered, resultingin pain, often of a burning nature (Kobayashi, K. et al. J. Comp.Neurol. 2005, 493(4), 596-606; Roza, C. et al. Pain 2006, 120(1-2),24-35; and Xing, H. et al. J. Neurophysiol. 2006, 95, 1221-30).Cold intolerance and paradoxical burning sensations induced bychemical or thermal cooling closely parallel symptoms seen in awide range of clinical disorders and thus provide a strongrationale for the development of TRPM8 modulators as novelantihyperalgesic or antiallodynic agents. TRPM8 is also known to beexpressed in the brain, lung, bladder, gastrointestinal tract,blood vessels, prostate and immune cells, thereby providing thepossibility for therapeutic modulation in a wide range ofmaladies.

[0005] In International patent application WO 2006/040136A1 fromBayer Healthcare AG, Lampe, T. et al. purportedly describessubstituted 4-benzyloxy-phenylmethylamide derivatives as coldmenthol receptor-1 (CMR-1) antagonists for the treatment ofurological disorders. International patent application WO2006/040103A1 from Bayer Healthcare AG purportedly describesmethods and pharmaceutical compositions for treatment and/orprophylaxis of respiratory diseases or disorders. Internationalpatent applications WO 2007/017092A1, WO 2007/017093A1 and WO2007/017094A1, from Bayer Healthcare AG, purportedly describebenzyloxyphenylmethyl carbamate, substituted 2-benzyloxybenzoicacid amide and substituted 4-benzyloxybenzoic acid amidederivatives for the treatment of diseases associated with the ColdMenthol Receptor (CMR), a.k.a. TRPM8.

[0006] There is a need in the art for TRPM8 antagonists that can beused to treat a disease, syndrome, or condition in a mammal inwhich the disease, syndrome, or condition is affected by themodulation of TRPM8 receptors, such as pain, the diseases that leadto such pain, and pulmonary or vascular dysfunction.

SUMMARY OF THE INVENTION

[0007] The present invention is directed to compounds of Formula(I)

##STR00002##

wherein [0008] W.sub.1 is C(R.sup.2a) or N; [0009] W.sub.2 is CH orN; [0010] W.sub.3 is C(R.sup.2) or N; [0011] such that no more thanone of W.sub.1, W.sub.2, and W.sub.3 is N; and when one of W.sub.1,W.sub.2, and W.sub.3 is N, then R.sup.2 and R.sup.2a are hydrogen;[0012] R.sup.1 is fluoro, chloro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; or R.sup.1 and R.sup.3 are taken together toform a single fused --OCF.sub.2O-- moiety; [0013] R.sup.1a ishydrogen, fluoro, chloro, or bromo; [0014] R.sup.2 is hydrogen,C.sub.1-4alkyl, fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, C.sub.1-3alkoxy(C.sub.1-6)alkyl,cyclopropyl, --CH.dbd.CHCH.sub.2OH, or C.sub.2-4alkenyl bound viaan unsaturated carbon atom; [0015] R.sup.2a is hydrogen or methyl;[0016] R.sup.3 is hydrogen, fluoro, or taken with R.sup.1 to form--OCF.sub.2O--; [0017] V and Q are selected from the groupconsisting of [0018] V is CH(R.sup.4) and Q is O; [0019] V is NHand Q is CH.sub.2; and [0020] V is O and Q is CH.sub.2; [0021]R.sup.4 is hydrogen or C.sub.1-4alkyl; [0022] X is CH.sub.2,C(CH.sub.3).sub.2, CF.sub.2, or O; [0023] with the proviso thatwhen V is NH, X is other than O; and enantiomers, diastereomers,solvates, and pharmaceutically acceptable salts thereof.

[0024] The present invention is also directed to a pharmaceuticalcomposition comprising, consisting of and/or consisting essentiallyof a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable excipient, and/or a pharmaceutically acceptable diluentand a compound of Formula (I) or a pharmaceutically acceptable saltform thereof.

[0025] Also provided are processes for making a pharmaceuticalcomposition comprising, consisting of, and/or consistingessentially of admixing a compound of Formula (I) and apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and/or a pharmaceutically acceptable diluent.

[0026] The present invention is further directed to methods fortreating or ameliorating a TRPM8-modulated disorder in a subject,including a mammal and/or human, in which the disease, syndrome, orcondition is affected by the modulation of TRPM8 receptors, such aspain, the diseases that lead to such pain, and pulmonary orvascular dysfunction using a compound of Formula (I). Inparticular, the methods of the present invention are directed totreating or ameliorating a TRPM8 receptor-modulated disorderincluding inflammatory pain, cold-intolerance or cold allodynia,peripheral vascular pain, itch, urinary incontinence, chronicobstructive pulmonary disease, pulmonary hypertension and anxiety,including other stress-related disorders, using a compound ofFormula (I).

[0027] The present invention is also directed to methods forproducing the instant compounds and pharmaceutical compositions andmedicaments thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The term "independently" means that when more than one ofsuch substituent is possible, such substituents may be the same ordifferent from each other.

[0029] The term "alkyl" whether used alone or as part of asubstituent group refers to straight and branched carbon chainshaving 1 to 8 carbon atoms or any number within this range.Therefore, designated numbers of carbon atoms (e.g. C.sub.1-8)shall refer independently to the number of carbon atoms in an alkylmoiety or to the alkyl portion of a larger alkyl-containingsubstituent. In substituent groups with multiple alkyl groups suchas (C.sub.1-6alkyl).sub.2 amino- the C.sub.1-6alkyl groups of thedialkylamino may be the same or different.

[0030] The term "alkoxy" refers to an O-alkyl substituent group,wherein alkyl is as defined supra. To the extent substituted, analkyl and alkoxy chain may be substituted on a carbon atom.

[0031] The terms "alkenyl" and "alkynyl" refer to straight andbranched carbon chains having 2 or more carbon atoms, wherein analkenyl chain has at least one double bond in the chain and analkynyl chain has at least one triple bond in the chain.

[0032] The term "cycloalkyl" refers to saturated or partiallyunsaturated, monocyclic or polycyclic hydrocarbon rings of from 3to 14 carbon atom members. Examples of such rings include, and arenot limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and adamantyl. Similarly, "cycloalkenyl" refers to acycloalkyl that contains at least one double bond in the ring.Additionally, a "benzofused cycloalkyl" is a cycloalkyl ring thatis fused to a benzene ring. A "heteroaryl-fused cycloalkyl" is acycloalkyl ring that is fused to a 5 or 6-membered heteroaryl ring(containing one of O, S or N and, optionally, one additionalnitrogen).

[0033] The term "heterocyclyl" refers to a nonaromatic cyclic ringof 5 to 7 members in which 1 to 2 members are nitrogen, or anonaromatic cyclic ring of 5 to 7 members in which zero, one or twomembers are nitrogen and up to two members are oxygen or sulfur;wherein, optionally, the ring contains zero to one unsaturatedbonds, and, optionally, when the ring is of 6 or 7 members, itcontains up to two unsaturated bonds. As used herein, "benzofusedheterocyclyl" includes a 5 to 7 membered monocyclic heterocyclicring fused to a benzene ring. As used herein, "heteroaryl-fusedheterocyclyl" refers to 5 to 7 membered monocyclic heterocyclicring fused to a 5 or 6 membered heteroaryl ring (containing one ofO, S or N and, optionally, one additional nitrogen). As usedherein, "cycloalkyl-fused heterocyclyl" refers to a 5 to 7 memberedmonocyclic heterocyclic ring fused to a 5 to 7 membered cycloalkylor cycloalkenyl ring. Furthermore, as used herein,"heterocyclyl-fused heterocycyl" refers to a 5 to 7 memberedmonocyclic heterocyclic ring fused to a 5 to 7 memberedheterocyclyl ring (of the same definition as above but absent theoption of a further fused ring).

For instant compounds of the invention, the carbon atom ringmembers that form the heterocyclyl ring are fully saturated. Othercompounds of the invention may have a partially saturatedheterocyclyl ring. As used herein, "heterocyclyl" also includes a 5to 7 membered monocyclic heterocycle bridged to form bicyclicrings. Such compounds are not considered to be fully aromatic andare not referred to as heteroaryl compounds. Examples ofheterocyclyl groups include, and are not limited to, pyrrolinyl(including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl,2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

[0034] The term "aryl" refers to an unsaturated, aromaticmonocyclic ring of 6 carbon members or to an unsaturated, aromaticpolycyclic ring of from 10 to 14 carbon members. Examples of sucharyl rings include, and are not limited to, phenyl, naphthalenyl oranthracenyl. Preferred aryl groups for the practice of thisinvention are phenyl and naphthalenyl.

[0035] The term "heteroaryl" refers to an aromatic ring of 5 or 6members wherein the ring consists of carbon atoms and has at leastone heteroatom member. Suitable heteroatoms include nitrogen,oxygen or sulfur. In the case of 5 membered rings, the heteroarylring contains one member of nitrogen, oxygen or sulfur and, inaddition, may contain up to three additional nitrogens. In the caseof 6 membered rings, the heteroaryl ring may contain from one tothree nitrogen atoms. For the case wherein the 6 membered ring hasthree nitrogens, at most two nitrogen atoms are adjacent.

[0036] Optionally, the heteroaryl ring is fused to a benzene ringto form a "benzo fused heteroaryl"; similarly, the heteroaryl ringis optionally fused to a 5 or 6 membered heteroaryl ring(containing one of O, S or N and, optionally, one additionalnitrogen) to form a "heteroaryl-fused heteroaryl"; similarly, theheteroaryl ring is optionally fused to a 5 to 7 membered cycloalkylring or a 5 to 7 membered heterocyclo ring (as defined supra butabsent the option of a further fused ring) to form a"cycloalkyl-fused heteroaryl". Examples of heteroaryl groupsinclude, and are not limited to, furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl or pyrazinyl; examples of heteroarylgroups with the optionally fused benzene rings include indolyl,isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl,benzothiadiazolyl, benzotriazolyl, quinolizinyl, quinolinyl,isoquinolinyl or quinazolinyl.

[0037] The term "arylalkyl" means an alkyl group substituted withan aryl group (e.g., benzyl, phenethyl). Similarly, "arylalkoxy"indicates an alkoxy group substituted with an aryl group (e.g.,benzyloxy).

[0038] The term "halogen" refers to fluorine, chlorine, bromine andiodine. Substituents that are substituted with multiple halogensare substituted in a manner that provides compounds that arestable.

[0039] Whenever the terms "alkyl" or "aryl" or either of theirprefix roots appear in a name of a substituent (e.g., arylalkyl,alkylamino) the name is to be interpreted as including thoselimitations given above for "alkyl" and "aryl." Designated numbersof carbon atoms (e.g., C.sub.1-C.sub.6) refer independently to thenumber of carbon atoms in an alkyl moiety, an aryl moiety, or inthe alkyl portion of a larger substituent in which alkyl appears asits prefix root. For alkyl and alkoxy substituents, the designatednumber of carbon atoms includes all of the independent membersincluded within a given range specified. For example C.sub.1-6alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g. C.sub.1-2,C.sub.1-3, C.sub.1-4, C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6,C.sub.5-6, C.sub.2-5, etc.).

[0040] In general, under standard nomenclature rules usedthroughout this disclosure, the terminal portion of the designatedside chain is described first followed by the adjacentfunctionality toward the point of attachment. Thus, for example, a"phenylC.sub.1-C.sub.6 alkylamidoC.sub.1-C.sub.6 alkyl" substituentrefers to a group of the formula:

##STR00003##

[0041] Unless otherwise noted, it is intended that the definitionof any substituent or variable at a particular location in amolecule be independent of its definitions elsewhere in thatmolecule. It is understood that substituents and substitutionpatterns on the compounds of this invention can be selected by oneof ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

[0042] The term "subject" as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been theobject of treatment, observation or experiment.

[0043] The term "therapeutically effective amount" means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal orhuman that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation or partialalleviation of the symptoms of the disease, syndrome, condition ordisorder being treated.

[0044] The term "composition" is intended to encompass a productcomprising the specified ingredients in therapeutically effectiveamounts, as well as any product that results, directly orindirectly, from combinations of the specified ingredients in thespecified amounts.

[0045] The term "antagonist" is used to refer to a compound capableof producing, depending on the circumstance, a functionalantagonism of the TRPM8 ion channel, including, but not limited to,competitive antagonists, non-competitive antagonists, desensitizingagonists, and partial agonists.

[0046] As used herein, "inflammatory hypersensitivity" is used torefer to a condition that is characterized by one or more hallmarksof inflammation, including edema, erythema, hyperthermia and pain,and/or by an exaggerated physiologic or pathophysiologic responseto one or more than one type of stimulation, including thermal,mechanical, and/or chemical stimulation.

[0047] The term "TRPM8-modulated" is used to refer to the conditionof being affected by the modulation of the TRPM8 receptor,including the state of being mediated by the TRPM8 receptor.

[0048] An embodiment of the invention is a method of treating orpreventing at least one of the following diseases, syndromes, andconditions selected from the group consisting of migraine, postherpetic neuralgia, post traumatic neuralgia, post chemotherapyneuralgia, complex regional pain syndrome I and II (CRPS I/II),fibromyalgia, inflammatory bowel disease, pruritis, asthma, chronicobstructive pulmonary disease, toothache, bone pain and pyresis ina subject, which method comprises, consists of, and/or consistsessentially of administering to the subject, including an animal, amammal, and a human in need of such treatment or prevention, atherapeutically effective amount of a TRPM8 antagonist that is acompound of Formula (I).

[0049] Another embodiment of the invention is a method of treatingor preventing at least one of the following diseases, syndromes,and conditions selected from hypertension, peripheral vasculardisease, Raynaud's disease, reperfusion injury or frostbite in asubject, which method comprises administering to the subject,including an animal, a mammal, and a human in need of suchtreatment or prevention a therapeutically effective amount of aTRPM8 antagonist that is a compound of Formula (I).

[0050] A further embodiment of the invention is a method ofaccelerating post-anesthetic recovery or post-hypothermia recoveryin a subject, including an animal, a mammal, and a human, whichmethod comprises administering to the subject, including an animal,a mammal, and a human in need of such accelerated recovery, atherapeutically effective amount of a TRPM8 antagonist that is acompound of Formula (I).

[0051] An embodiment of the present invention is directed tocompounds of Formula (I)

##STR00004##

wherein [0052] a) W.sub.1 is C(R.sup.2a) or N; W.sub.2 is CH or N;W.sub.3 is C(R.sup.2) or N; [0053] such that no more than one ofW.sub.1, W.sub.2, and W.sub.3 is N; and when one of W.sub.1,W.sub.2, and W.sub.3 is N, then R.sup.2 and R.sup.2a are hydrogen;[0054] b) R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; or R.sup.1 and R.sup.3 are taken together toform a single fused --OCF.sub.2O-- moiety; [0055] c) R.sup.1 isfluoro, trifluoromethyl, (1-hydroxy-1-methyl)ethyl,2,2,2-trifluoroethyl, trifluoromethoxy, or difluoromethoxy; [0056]d) R.sup.1a is hydrogen or fluoro; [0057] e) R.sup.2 is hydrogen,C.sub.1-4alkyl, fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, C.sub.1-3alkoxy(C.sub.1-6)alkyl, or--CH.dbd.CHCH.sub.2OH; [0058] f) R.sup.2 is C.sub.1-4alkyl, fluoro,chloro, bromo, cyano, trifluoromethyl, hydroxy(C.sub.1-6)alkyl, or--CH.dbd.CHCH.sub.2OH; [0059] g) R.sup.2 is methyl, fluoro, chloro,bromo, trifluoromethyl, or hydroxy(C.sub.1-6)alkyl; [0060] h)R.sup.2a is hydrogen or methyl; [0061] i) R.sup.3 is hydrogen ortaken with R.sup.1 to form --OCF.sub.2O--; [0062] j) R.sup.3 ishydrogen; [0063] k) V and Q are selected from the group consistingof [0064] V is CH(R.sup.4) and Q is O; [0065] V is NH and Q isCH.sub.2; and [0066] V is O and Q is CH.sub.2; [0067] l) V and Qare selected from the group consisting of [0068] V is CH(R.sup.4)and Q is O; and [0069] V is O and Q is CH.sub.2; [0070] m) R.sup.4is hydrogen or methyl; [0071] n) X is CH.sub.2, CF.sub.2, or O;[0072] o) X is CH.sub.2 or O; [0073] with the proviso that when Vis NH, X is other than O; and enantiomers, diastereomers, solvates,and pharmaceutically acceptable salts thereof;

[0074] and any combination of embodiments a) through o) above,provided that it is understood that combinations in which differentembodiments of the same substituent would be combined areexcluded.

[0075] An embodiment of the present invention is directed tocompounds of Formula (I)

##STR00005##

wherein [0076] W.sub.1 is C(R.sup.2a) or N; [0077] W.sub.2 is CH orN; [0078] W.sub.3 is C(R.sup.2) or N; [0079] such that no more thanone of W.sub.1, W.sub.2, and W.sub.3 is N; and when one of W.sub.1,W.sub.2, and W.sub.3 is N, then R.sup.2 and R.sup.2a are hydrogen;[0080] R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; or R.sup.1 and R.sup.3 are taken together toform a single fused --OCF.sub.2O-- moiety; [0081] R.sup.1a ishydrogen or fluoro; [0082] R.sup.2 is hydrogen, C.sub.1-4alkyl,fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, C.sub.1-3alkoxy(C.sub.1-6)alkyl, or--CH.dbd.CHCH.sub.2OH; [0083] R.sup.2a is hydrogen or methyl;[0084] R.sup.3 is hydrogen or taken with R.sup.1 to form--OCF.sub.2O--; [0085] V and Q are selected from the groupconsisting of [0086] V is CH(R.sup.4) and Q is O; [0087] V is NHand Q is CH.sub.2; and [0088] V is O and Q is CH.sub.2; [0089]R.sup.4 is hydrogen or methyl; [0090] X is CH.sub.2, CF.sub.2, orO; [0091] with the proviso that when V is NH, X is other than O;and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0092] An embodiment of the present invention is directed tocompounds of Formula (I)

##STR00006##

wherein [0093] W.sub.1 is C(R.sup.2a) or N; [0094] W.sub.2 is CH orN; [0095] W.sub.3 is C(R.sup.2) or N; [0096] such that no more thanone of W.sub.1, W.sub.2, and W.sub.3 is N; and when one of W.sub.1,W.sub.2, and W.sub.3 is N, then R.sup.2 and R.sup.2a are hydrogen;[0097] R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; [0098] R.sup.1a is hydrogen or fluoro; [0099]R.sup.2 is hydrogen, C.sub.1-4alkyl, fluoro, chloro, bromo, cyano,trifluoromethyl, hydroxy(C.sub.1-6)alkyl,C.sub.1-3alkoxy(C.sub.1-6)alkyl, or --CH.dbd.CHCH.sub.2OH; [0100]R.sup.2a is hydrogen or methyl; [0101] R.sup.3 is hydrogen; [0102]V and Q are selected from the group consisting of [0103] V isCH(R.sup.4) and Q is O; and V is O and Q is CH.sub.2; [0104]R.sup.4 is hydrogen or methyl; [0105] X is CH.sub.2, CF.sub.2, orO; and enantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0106] An embodiment of the present invention is directed tocompounds of Formula (I)

##STR00007##

wherein [0107] W.sub.1 is C(R.sup.2a) or N; [0108] W.sub.2 is CH orN; [0109] W.sub.3 is C(R.sup.2) or N; [0110] such that no more thanone of W.sub.1, W.sub.2, and W.sub.3 is N; and when one of W.sub.1,W.sub.2, and W.sub.3 is N, then R.sup.2 and R.sup.2a are hydrogen;[0111] R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; [0112] R.sup.1a is hydrogen or fluoro; [0113]R.sup.2 is C.sub.1-4alkyl, fluoro, chloro, bromo, cyano,trifluoromethyl, hydroxy(C.sub.1-6)alkyl, C.sub.1-3alkoxy(C.sub.1-6)alkyl, or --CH.dbd.CHCH.sub.2OH; [0114] R.sup.2ais hydrogen or methyl; [0115] R.sup.3 is hydrogen; [0116] V and Qare selected from the group consisting of [0117] V is CH(R.sup.4)and Q is O; and V is O and Q is CH.sub.2; [0118] R.sup.4 ishydrogen or methyl; [0119] X is CH.sub.2, CF.sub.2, or O; andenantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0120] An embodiment of the present invention is directed tocompounds of Formula (I)

##STR00008##

wherein [0121] W.sub.1 is C(R.sup.2a) or N; [0122] W.sub.2 is CH orN; [0123] W.sub.3 is C(R.sup.2) or N; [0124] such that no more thanone of W.sub.1, W.sub.2, and W.sub.3 is N; and when one of W.sub.1,W.sub.2, and W.sub.3 is N, then R.sup.2 and R.sup.2a are hydrogen;[0125] R.sup.1 is fluoro, trifluoromethyl,(1-hydroxy-1-methyl)ethyl, 2,2,2-trifluoroethyl, trifluoromethoxy,or difluoromethoxy; [0126] R.sup.1a is hydrogen or fluoro; [0127]R.sup.2 is methyl, fluoro, chloro, bromo, cyano, trifluoromethyl,hydroxy(C.sub.1-6)alkyl, C.sub.1-3alkoxy(C.sub.1-6)alkyl, or--CH.dbd.CHCH.sub.2OH; [0128] R.sup.2a is hydrogen or methyl;[0129] R.sup.3 is hydrogen; [0130] V and Q are selected from thegroup consisting of [0131] V is CH(R.sup.4) and Q is O; and V is Oand Q is CH.sub.2; [0132] R.sup.4 is hydrogen or methyl; [0133] Xis CH.sub.2 or O; and enantiomers, diastereomers, solvates, andpharmaceutically acceptable salts thereof.

[0134] A further embodiment of the present invention is directed toa compound of Formula (I)

##STR00009##

selected from the group consisting of: [0135] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; [0136] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethoxy, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is O, Q is CH.sub.2, and X is CH.sub.2; [0137] acompound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethoxy, R.sup.1a, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is O, Q is CH.sub.2, and X isCH.sub.2; [0138] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is O, Q is CH.sub.2,and X is CH.sub.2; [0139] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is O, Q is CH.sub.2, and X is CH.sub.2; [0140] acompound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is fluoro,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; [0141] a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethoxy, R.sup.1a, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is hydrogen, and X is CH.sub.2; [0142] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethoxy, R.sup.1a, is fluoro, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is hydrogen, and X is CH.sub.2; [0143] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is O; [0144] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCF.sub.2; [0145] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is 2,2,2-trifluoroethyl,R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0146]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is taken with R.sup.3 to form--OCF.sub.2O--, R.sup.1a, R.sup.2, and R.sup.2a are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0147]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is difluoromethoxy, R.sup.1, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is hydrogen, and X is CH.sub.2; [0148] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen, R.sup.2 isfluoro, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0149]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a, R.sup.2,R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is methyl, and X is CH.sub.2; [0150] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen, R.sup.2 ischloro, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0151]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is bromo, R.sup.2 is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0152]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is (1-hydroxy-1-methyl)ethyl, R.sup.1a,R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; [0153] a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1, R.sup.2, R.sup.2a,and R.sup.3 are hydrogen, V is NH, Q is CH.sub.2, and X isCH.sub.2; [0154] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is difluoromethoxy, R.sup.1ais hydrogen, R.sup.2 is methyl, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; [0155] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1ais hydrogen, R.sup.2 is cyano, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; [0156] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1ais hydrogen, R.sup.2 is 3-hydroxypropyl, R.sup.2a is hydrogen,R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen,and X is CH.sub.2; [0157] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0158]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is hydrogen, R.sup.2a is methyl, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0159]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is 1-hydroxy-prop-2-en-3-yl, R.sup.2a is hydrogen, R.sup.3is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and Xis CH.sub.2; [0160] a compound wherein W.sub.1 is C(R.sup.2a),W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 is fluoro, R.sup.1ais fluoro, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0161]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; [0162] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1ais hydrogen, R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen,R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is methyl,and X is CH.sub.2; [0163] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is O, Q is CH.sub.2, and X is O; [0164] a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is chloro, R.sup.1a is hydrogen, R.sup.2 istrifluoromethyl, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0165]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is fluoro, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is O; [0166] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is methyl, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is O; [0167] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is bromo, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is O; [0168] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is chloro, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is O; [0169] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is cyano, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is O; [0170] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 arehydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isC(CH.sub.3).sub.2; [0171] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 ischloro, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isC(CH.sub.3).sub.2; [0172] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is fluoro, R.sup.2 is hydrogen, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is O; [0173] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is trifluoromethyl,R.sup.2a is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is C(CH.sub.3).sub.2; [0174] acompound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is chloro, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is O; [0175] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 istrifluoromethyl, R.sup.1a is hydrogen, R.sup.2 is chloro, R.sup.2ais hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4is hydrogen, and X is C(CH.sub.3).sub.2; [0176] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen, R.sup.2 istrifluoromethyl, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is O; [0177] acompound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is CH.sub.2CH.sub.2C(CH.sub.3).sub.2OH, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; [0178] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 isfluoro, R.sup.1a is fluoro, R.sup.2 is chloro, R.sup.2a ishydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; [0179] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is C(R.sup.2), R.sup.1 ischloro, R.sup.1a, R.sup.2, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0180]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is methyl, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0181]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is fluoro, R.sup.1a is hydrogen, R.sup.2 ismethyl, R.sup.2 is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4),Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0182] a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is fluoro, R.sup.1a is fluoro, R.sup.2 ismethyl, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0183]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is fluoro, R.sup.1a is hydrogen, R.sup.2 ischloro, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0184]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethoxy, R.sup.1a is hydrogen,R.sup.2 is chloro, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0185]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethoxy, R.sup.1a is hydrogen,R.sup.2 is trifluoromethyl, R.sup.2a is hydrogen, R.sup.3 ishydrogen, V is CH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X isCH.sub.2; [0186] a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2is CH, W.sub.3 is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1ais hydrogen, R.sup.2 is CH.sub.2 CH.sub.2 CH.sub.2OCH.sub.3,R.sup.2a is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q isO, R.sup.4 is hydrogen, and X is CH.sub.2; [0187] a compoundwherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is fluoro, R.sup.1a is hydrogen, R.sup.2 istrifluoromethyl, R.sup.2a is hydrogen, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0188]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is methyl, R.sup.2a is methyl, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0189]a compound wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, W.sub.3is C(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is chloro, R.sup.2a is methyl, R.sup.3 is hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; [0190]a compound wherein W.sub.1 is N, W.sub.2 is CH, W.sub.3 isC(R.sup.2), R.sup.1 is trifluoromethyl, R.sup.1a is hydrogen,R.sup.2 is hydrogen, R.sup.3 is hydrogen, V is CH(R.sup.4), Q is O,R.sup.4 is hydrogen, and X is CH.sub.2; [0191] a compound whereinW.sub.1 is C(R.sup.2a), W.sub.2 is N, W.sub.3 is C(R.sup.2),R.sup.1 is trifluoromethyl, R.sup.1a, R.sup.2, R.sup.2a, andR.sup.3 are hydrogen, V is CH(R.sup.4), Q is O, R.sup.4 ishydrogen, and X is CH.sub.2; [0192] a compound wherein W.sub.1 isC(R.sup.2a), W.sub.2 is CH, W.sub.3 is N, R.sup.1 istrifluoromethyl, R.sup.1a, R.sup.2a, and R.sup.3 are hydrogen, V isCH(R.sup.4), Q is O, R.sup.4 is hydrogen, and X is CH.sub.2; andenantiomers, diastereomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0193] A further embodiment of the present invention is directed tocompounds 1-58, pictured below in Table 1.

TABLE-US-00001 TABLE 1 Cpd No. Structure 1 ##STR00010## 2##STR00011## 3 ##STR00012## 4 ##STR00013## 5 ##STR00014## 6##STR00015## 7 ##STR00016## 8 ##STR00017## 9 ##STR00018## 10##STR00019## 11 ##STR00020## 12 ##STR00021## 13 ##STR00022## 14##STR00023## 15 ##STR00024## 16 ##STR00025## 17 ##STR00026## 18##STR00027## 19 ##STR00028## 20 ##STR00029## 21 ##STR00030## 22##STR00031## 23 ##STR00032## 24 ##STR00033## 25 ##STR00034## 26##STR00035## 27 ##STR00036## 28 ##STR00037## 29 ##STR00038## 30##STR00039## 31 ##STR00040## 32 ##STR00041## 33 ##STR00042## 34##STR00043## 35 ##STR00044## 36 ##STR00045## 37 ##STR00046## 38##STR00047## 39 ##STR00048## 40 ##STR00049## 41 ##STR00050## 42##STR00051## 43 ##STR00052## 44 ##STR00053## 45 ##STR00054## 46##STR00055## 47 ##STR00056## 48 ##STR00057## 49 ##STR00058## 50##STR00059## 51 ##STR00060## 52 ##STR00061## 53 ##STR00062## 54##STR00063## 55 ##STR00064## 56 ##STR00065## 57 ##STR00066## 58##STR00067##

[0194] An even further embodiment of the present invention isdirected to compounds of Formula (I) wherein the compounds have aformula selected from the group consisting of

##STR00068##

[0195] For use in medicine, salts of compounds of Formula (I) referto non-toxic "pharmaceutically acceptable salts." Other salts may,however, be useful in the preparation of compounds of Formula (I)or of their pharmaceutically acceptable salts thereof. Suitablepharmaceutically acceptable salts of compounds of Formula (I)include acid addition salts which can, for example, be formed bymixing a solution of the compound with a solution of apharmaceutically acceptable acid such as hydrochloric acid,sulfuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of Formula (I)carry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include alkali metal salts, such as sodium or potassiumsalts; alkaline earth metal salts, such as calcium or magnesiumsalts; and salts formed with suitable organic ligands, such asquaternary ammonium salts. Thus, representative pharmaceuticallyacceptable salts include acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,laurate, malate, maleate, mandelate, mesylate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate,tartrate, teoclate, tosylate, triethiodide and valerate.

[0196] Representative acids and bases that may be used in thepreparation of pharmaceutically acceptable salts include acidsincluding acetic acid, 2,2-dichloroacetic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,caprylic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaricacid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloricacid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelicacid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid,succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; andbases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0197] Embodiments of the present invention include prodrugs ofcompounds of Formula (I). In general, such prodrugs will befunctional derivatives of the compounds that are readilyconvertible in vivo into the required compound. Thus, in themethods of treating or preventing embodiments of the presentinvention, the term "administering" encompasses the treatment orprevention of the various diseases, conditions, syndromes anddisorders described with the compound specifically disclosed orwith a compound that may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration toa patient. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, forexample, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,1985.

[0198] Where the compounds according to embodiments of thisinvention have at least one chiral center, they may accordinglyexist as enantiomers. Where the compounds possess two or morechiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore,some of the crystalline forms for the compounds may exist aspolymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope ofthis invention. The skilled artisan will understand that the termcompound as used herein, is meant to include solvated compounds ofFormula I.

[0199] Where the processes for the preparation of the compoundsaccording to certain embodiments of the invention give rise to amixture of stereoisomers, these isomers may be separated byconventional techniques such as preparative chromatography. Thecompounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis orby resolution. The compounds may, for example, be resolved intotheir component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with anoptically active acid, such as (-)-di-p-toluoyl-d-tartaric acidand/or (+)-di-p-toluoyl-l-tartaric acid followed by fractionalcrystallization and regeneration of the free base. The compoundsmay also be resolved by formation of diastereomeric esters oramides, followed by chromatographic separation and removal of thechiral auxiliary. Alternatively, the compounds may be resolvedusing a chiral HPLC column.

[0200] One embodiment of the present invention is directed to acomposition, including a pharmaceutical composition, comprising,consisting of, and/or consisting essentially of the (+)-enantiomerof a compound of Formula (I) wherein said composition issubstantially free from the (-)-isomer of said compound. In thepresent context, substantially free means less than about 25%,preferably less than about 10%, more preferably less than about 5%,even more preferably less than about 2% and even more preferablyless than about 1% of the (-)-isomer calculated as

% ( + ) - enantiomer = ( mass ( + ) - enantiomer ) ( mass ( + ) -enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.##EQU00001##

[0201] Another embodiment of the present invention is acomposition, including a pharmaceutical composition, comprising,consisting of, and consisting essentially of the (-)-enantiomer ofa compound of Formula (I) wherein said composition is substantiallyfree from the (+)-isomer of said compound. In the present context,substantially free from means less than about 25%, preferably lessthan about 10%, more preferably less than about 5%, even morepreferably less than about 2% and even more preferably less thanabout 1% of the (+)-isomer calculated as

% ( - ) - enantiomer = ( mass ( - ) - enantiomer ) ( mass ( + ) -enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.##EQU00002##

[0202] During any of the processes for preparation of the compoundsof the various embodiments of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groupson any of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described inProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stageusing methods known from the art.

[0203] Even though the compounds of embodiments of the presentinvention (including their pharmaceutically acceptable salts andpharmaceutically acceptable solvates) can be administered alone,they will generally be administered in admixture with apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and/or a pharmaceutically acceptable diluent selectedwith regard to the intended route of administration and standardpharmaceutical or veterinary practice. Thus, particular embodimentsof the present invention are directed to pharmaceutical andveterinary compositions comprising compounds of Formula (I) and atleast one pharmaceutically acceptable carrier, pharmaceuticallyacceptable excipient, and/or pharmaceutically acceptablediluent

[0204] By way of example, in the pharmaceutical compositions ofembodiments of the present invention, the compounds of Formula (I)may be admixed with any suitable binder(s), lubricant(s),suspending agent(s), coating agent(s), solubilizing agent(s), andcombinations thereof.

[0205] Solid oral dosage forms, such as tablets or capsules,containing the compounds of the present invention may beadministered in at least one dosage form at a time, as appropriate.It is also possible to administer the compounds in sustainedrelease formulations.

[0206] Additional oral forms in which the present inventivecompounds may be administered include elixirs, solutions, syrups,and suspensions; each optionally containing flavoring agents andcoloring agents.

[0207] Alternatively, compounds of Formula (I) can be administeredby inhalation (intratracheal or intranasal) or in the form of asuppository or pessary, or they may be applied topically in theform of a lotion, solution, cream, ointment or dusting powder. Forexample, they can be incorporated into a cream comprising,consisting of, and/or consisting essentially of an aqueous emulsionof polyethylene glycols or liquid paraffin. They can also beincorporated, at a concentration of between about 1% and about 10%by weight of the cream, into an ointment comprising, consisting of,and/or consisting essentially of a white wax or white soft paraffinbase together with any stabilizers and preservatives as may berequired. An alternative means of administration includestransdermal administration by using a skin or transdermalpatch.

[0208] The pharmaceutical compositions of the present invention (aswell as the compounds of the present invention alone) can also beinjected parenterally, for example intracavernosally,intravenously, intramuscularly, subcutaneously, intradermally orintrathecally. In this case, the compositions will also include atleast one of a suitable carrier, a suitable excipient, and asuitable diluent.

[0209] For parenteral administration, the pharmaceuticalcompositions of the present invention are best used in the form ofa sterile aqueous solution that may contain other substances, forexample, enough salts and monosaccharides to make the solutionisotonic with blood.

[0210] For buccal or sublingual administration, the pharmaceuticalcompositions of the present invention may be administered in theform of tablets or lozenges, which can be formulated in aconventional manner.

[0211] By way of further example, pharmaceutical compositionscontaining at least one of the compounds of Formula (I) as theactive ingredient can be prepared by mixing the compound(s) with apharmaceutically acceptable carrier, a pharmaceutically acceptablediluent, and/or a pharmaceutically acceptable excipient accordingto conventional pharmaceutical compounding techniques. The carrier,excipient, and diluent may take a wide variety of forms dependingupon the desired route of administration (e.g., oral, parenteral,etc.). Thus for liquid oral preparations, such as suspensions,syrups, elixirs and solutions, suitable carriers, excipients anddiluents include water, glycols, oils, alcohols, flavoring agents,preservatives, stabilizers, coloring agents and the like; for solidoral preparations, such as powders, capsules and tablets, suitablecarriers, excipients and diluents include starches, sugars,diluents, granulating agents, lubricants, binders, disintegratingagents and the like. Solid oral preparations also may be optionallycoated with substances, such as sugars, or be enterically-coated soas to modulate the major site of absorption and disintegration. Forparenteral administration, the carrier, excipient and diluent willusually include sterile water, and other ingredients may be addedto increase solubility and preservation of the composition.Injectable suspensions or solutions may also be prepared utilizingaqueous carriers along with appropriate additives, such assolubilizers and preservatives.

[0212] A therapeutically effective amount of a compound of Formula(I) or a pharmaceutical composition thereof includes a dose rangefrom about 0.1 mg to about 3000 mg, in particular from about 1 mgto about 1000 mg or, more particularly, from about 10 mg to about500 mg of active ingredient in a regimen of about 1 to 4 times perday for an average (70 kg) human; although, it is apparent to oneskilled in the art that the therapeutically effective amount foractive compounds of the invention will vary as will the diseases,syndromes, conditions, and disorders being treated.

[0213] For oral administration, a pharmaceutical composition ispreferably provided in the form of tablets containing about 0.01,about 10, about 50, about 100, about 150, about 200, about 250, andabout 500 milligrams of the inventive compound as the activeingredient.

[0214] Advantageously, a compound of Formula (I) may beadministered in a single daily dose, or the total daily dosage maybe administered in divided doses of two, three and four timesdaily.

[0215] Optimal dosages of a compound of Formula (I) to beadministered may be readily determined and will vary with theparticular compound used, the mode of administration, the strengthof the preparation, and the advancement of the disease, syndrome,condition, or disorder. In addition, factors associated with theparticular subject being treated, including subject age, weight,diet and time of administration, will result in the need to adjustthe dose to achieve an appropriate therapeutic level. The abovedosages are thus exemplary of the average case. There can be, ofcourse, individual instances wherein higher or lower dosage rangesare merited, and such are within the scope of this invention.

[0216] Compounds of Formula (I) may be administered in any of theforegoing compositions and dosage regimens or by means of thosecompositions and dosage regimens established in the art wheneveruse of a compound of Formula (I) is required for a subject in needthereof.

[0217] As antagonists of the TRPM8 ion channel, the compounds ofFormula (I) are useful in methods for treating and preventing adisease, a syndrome, a condition, or a disorder in a subject,including an animal, a mammal and a human in which the disease, thesyndrome, the condition, or the disorder is affected by themodulation of TRPM8 receptors. Such methods comprise, consist of,and consist essentially of administering to a subject, including ananimal, a mammal, and a human in need of such treatment orprevention a therapeutically effective amount of a compound, salt,or solvate of Formula (I). In particular, the compounds of Formula(I) are useful for preventing or treating pain, or diseases,syndromes, conditions, or disorders causing such pain, or pulmonaryor vascular dysfunction. More particularly, the compounds ofFormula (I) are useful for preventing or treating inflammatorypain, inflammatory hypersensitivity conditions, neuropathic pain,anxiety, depression, and cardiovascular disease aggravated by cold,including peripheral vascular disease, vascular hypertension,pulmonary hypertension, Raynaud's disease, and coronary arterydisease, by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I).

[0218] Examples of inflammatory pain include pain due to a disease,condition, syndrome, disorder, or a pain state includinginflammatory bowel disease, visceral pain, migraine, post-operativepain, osteoarthritis, rheumatoid arthritis, back pain, lower backpain, joint pain, abdominal pain, chest pain, labor,musculoskeletal diseases, skin diseases, toothache, pyresis, burn,sunburn, snake bite, venomous snake bite, spider bite, insectsting, neurogenic bladder, interstitial cystitis, urinary tractinfection, rhinitis, contact dermatitis/hypersensitivity, itch,eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy painsyndrome, menstrual pain, endometriosis, sinus headache, tensionheadache, or arachnoiditis.

[0219] One type of inflammatory pain is inflammatory hyperalgesia,which can be further distinguished as inflammatory somatichyperalgesia or inflammatory visceral hyperalgesia. Inflammatorysomatic hyperalgesia can be characterized by the presence of aninflammatory hyperalgesic state in which a hypersensitivity tothermal, mechanical and/or chemical stimuli exists. Inflammatoryvisceral hyperalgesia can also be characterized by the presence ofan inflammatory hyperalgesic state, in which an enhanced visceralirritability exists.

[0220] Examples of inflammatory hyperalgesia include a disease,syndrome, condition, disorder, or pain state includinginflammation, osteoarthritis, rheumatoid arthritis, back pain,joint pain, abdominal pain, musculoskeletal diseases, skindiseases, post operative pain, headaches, toothache, burn, sunburn,insect sting, neurogenic bladder, urinary incontinence,interstitial cystitis, urinary tract infection, cough, asthma,chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis,irritable bowel syndrome, inflammatory bowel diseases includingCrohn's Disease or ulcerative colitis.

[0221] One embodiment of the present invention is directed to amethod for treating inflammatory somatic hyperalgesia in which ahypersensitivity to thermal, mechanical and/or chemical stimuliexists, comprising the step of administering to a subject in needof such treatment a therapeutically effective amount of a compound,salt or solvate of Formula (I).

[0222] A further embodiment of the present invention is directed toa method for treating inflammatory visceral hyperalgesia in which aenhanced visceral irritability exists, comprising, consisting of,and/or consisting essentially of the step of administering to asubject in need of such treatment a therapeutically effectiveamount of a compound, salt or solvate of Formula (I).

[0223] A further embodiment of the present invention is directed toa method for treating neuropathic cold allodynia in which ahypersensitivity to a cooling stimuli exists, comprising,consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment atherapeutically effective amount of a compound, salt or solvate ofFormula (I).

[0224] Examples of an inflammatory hypersensitivity conditioninclude urinary incontinence, benign prostatic hypertrophy, cough,asthma, rhinitis and nasal hypersensitivity, itch, contactdermatitis and/or dermal allergy, and chronic obstructive pulmonarydisease.

[0225] Examples of a neuropathic pain include pain due to adisease, syndrome, condition, disorder, or pain state includingcancer, neurological disorders, spine and peripheral nerve surgery,brain tumor, traumatic brain injury (TBI), spinal cord trauma,chronic pain syndrome, fibromyalgia, chronic fatigue syndrome,neuralgias (trigeminal neuralgia, glossopharyngeal neuralgia,postherpetic neuralgia and causalgia), lupus, sarcoidosis,peripheral neuropathy, bilateral peripheral neuropathy, diabeticneuropathy, central pain, neuropathies associated with spinal cordinjury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson'sdisease, multiple sclerosis, sciatic neuritis, mandibular jointneuralgia, peripheral neuritis, polyneuritis, stump pain, phantomlimb pain, bony fractures, oral neuropathic pain, Charcot's pain,complex regional pain syndrome I and II (CRPS I/II), radiculopathy,Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathicneuralgia, intercostals neuralgia, mammary neuralgia, Morton'sneuralgia, nasociliary neuralgia, occipital neuralgia, redneuralgia, Sluder's neuralgia, splenopalatine neuralgia,supraorbital neuralgia, vulvodynia, or vidian neuralgia.

[0226] One type of neuropathic pain is neuropathic cold allodynia,which can be characterized by the presence of aneuropathy-associated allodynic state in which a hypersensitivityto cooling stimuli exists. Examples of neuropathic cold allodyniainclude allodynia due to a disease, condition, syndrome, disorderor pain state including neuropathic pain (neuralgia), pain arisingfrom spine and peripheral nerve surgery or trauma, traumatic braininjury (TBI), trigeminal neuralgia, postherpetic neuralgia,causalgia, peripheral neuropathy, diabetic neuropathy, centralpain, stroke, peripheral neuritis, polyneuritis, complex regionalpain syndrome I and II (CRPS I/II) and radiculopathy.

[0227] Examples of anxiety include social anxiety, post-traumaticstress disorder, phobias, social phobia, special phobias, panicdisorder, obsessive-compulsive disorder, acute stress disorder,separation anxiety disorder, and generalized anxiety disorder.

[0228] Examples of depression include major depression, bipolardisorder, seasonal affective disorder, post-natal depression, manicdepression, and bipolar depression.

General Synthetic Methods

[0229] Representative compounds of the present invention can besynthesized in accordance with the general synthetic methodsdescribed below and illustrated in the schemes that follow. Sincethe schemes are an illustration, the invention should not beconstrued as being limited by the specific chemical reactions andspecific conditions described in the schemes and examples. Thevarious starting materials used in the schemes are commerciallyavailable or may be prepared by methods well within the skill ofpersons versed in the art. The variables are as defined herein andwithin the skill of persons versed in the art.

[0230] Abbreviations used in the instant specification,particularly the schemes and examples, are as follows:

TABLE-US-00002 Abbreviation Meaning AcOH acetic acid AIBNazobisisobutyronitrile aq aqueous atm atmosphere BOCtert-butyloxycarbonyl Cpd compound CSA camphorsulfonic acid DCCN,N-dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCMdichloromethane DIPEA diisopropylethylamine DMAN,N-dimethylacetamide DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dppf1,1'-bis-(diphenylphosphino)ferrocene EDCI1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride EtOAcethyl acetate EtOH ethanol h hour(s) HCl hydrochloric acid HOBt1-hydroxybenzotriazole MeOH methanol min minute(s) NCSN-chlorosuccinimide PHMS polymethylhydrosiloxane PyBroPbromotripyrrolidinophosphonium hexafluorophosphate rt roomtemperature S-Phos 2-dicyclohexylphosphino-2',6'- dimethoxybiphenylsatd saturated TBSC1 tert-butyldimethylsilyl chloride TEAtriethylamine THF tetrahydrofuran TLC thin layer chromatography

[0231] The following describes the general methodology that can beused to produce isoxazolinyl benzimidazoles of Formula (I).

##STR00069##

[0232] A suitably substituted compound of the Formula I-2 wherein Zis chloro, bromo, or iodo and R.sup.2 is other than chloro orbromo, can serve as a useful intermediate for the construction ofthe biaryl portion of the compounds of the present invention asshown in Scheme I. When not commercially available, a compound ofthe Formula I-2 wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH andW.sub.3 is C(R.sup.2) can be prepared by the halogenation of asuitably substituted corresponding compound of the Formula I-1using a variety of reagents. (For a review, see: Coombes, R. G."Organic Reaction Mechanisms (Electrophilic AromaticSubstitution)"; John Wiley & Sons, Ltd. (New York), 2003; p287-295.) A preferred reagent for bromination is bromine in asuitable solvent such as DCM, tetrachloromethane or preferablyacetic acid. A preferred reagent for chlorination is sulfurylchloride in a suitable solvent such as DCM or tetrachloromethane.Preferred reagents for iodination include iodine in a suitablesolvent such as DCM or tetrachloromethane or, more preferably,iodine and a silver salt such as silver sulfate in a suitablesolvent such as ethanol.

[0233] A compound of the Formula I-2 can then be coupled with asuitably substituted aryl boronic acid, trialkyltin reagent,trialkylsilane, and the like, of the Formula I-3 (wherein Y is thereactive coupling functionality) by a variety of coupling reactions(e.g. Suzuki, Stille, and Hiyama reactions) that are well known tothose versed in the art. (For a review of Suzuki reactions, see:Miyaura; N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. For a review ofStille reactions, see: Farina, V.; Krishnamurthy, V.; Scott, W. J."The Stille Reaction"; Organic Reactions 1997, 50, 1-652. Forreferences to Hiyama chemistry, see: Sahoo, A. K.; Oda, T.; Nakao,and Y. Hiyama Adv. Synth. Catal. 2004, 346, 1715-1727 and T. Nakao,Y, et al. J. Amer. Chem. Soc. 2005, 127, 6952-6953). A particularlyuseful method is the palladium-catalyzed Suzuki cross-couplingreaction (see also, Huff, B. et al. Org. Syn. 1997, 75, 53-60, andGoodson, F. E. et al. Org. Syn. 1997, 75, 61-68). Suitablepalladium catalysts for this reaction include palladium (II)acetate, palladium (II) chloride,bis(acetonitrile)-dichloro-palladium(II),dichloro-bis(di-tert-butylphenylphosphine)-palladium (II) and thelike; or preferably[1,1'-bis-(diphenylphosphino)-ferrocene]-palladium (II) dichloridedichloromethane adduct ((dppf)PdCl.sub.2.DCM) andtetrakis-(triphenylphosphine)-palladium(0) (Pd(PPh.sub.3).sub.4).The reactions also may be carried out in the presence or absence ofadded ligands for palladium which, when used, include one or morethan one of triphenylphosphine, tri-o-tolylphosphine,tri(tert-butyl)-phosphine, 1,1'-bis(diphenylphosphino)-ferrocene,bis[2-(diphenyl-phosphino)phenyl]ether,2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl,1-butyl-3-methylimidazolium hexafluorophosphate, and the like.Suitable bases for this transformation include cesium carbonate,potassium carbonate, sodium carbonate, cesium fluoride, potassiumfluoride, potassium tert-butoxide, sodium tert-butoxide, aqueoussodium hydroxide, aqueous sodium bicarbonate or preferablypotassium phosphate or aqueous sodium carbonate. Useful solventsinclude ethanol, THF, DMF, toluene, benzene or preferably DME ordioxane.

[0234] In this instance, a mixture of a compound of the Formula I-2and a compound of the Formula I-3 (wherein Y is a boronic acid orester) in a mixture of DME and water containing sodium carbonateand a catalytic amount of a preferred palladium catalyst can beheated to about 90.degree. C. to give the intermediate of theFormula I-4.

[0235] When R.sup.2 is fluoro, chloro, or bromo, R.sup.2 can beintroduced after the biaryl coupling as described herein bystarting with a suitably substituted compound of the Formula I-5 togive a biaryl intermediate of the Formula I-6, followed byhalogenation using the conditions described herein to produce acompound of the Formula I-4.

[0236] Alternatively when W.sub.1 is C(R.sup.2a), W.sub.2 is CH,and W.sub.3 is C(R.sup.2), the biaryl coupling partners can bereversed as shown in Scheme II such that a halo group is on thearyl ring in a compound of the Formula II-2 (Z=iodo, bromo, orchloro) and a boronic acid or ester moiety (Y=B(OH).sub.2 orB(OR).sub.2 where B(OR).sub.2 is, for example, pinacolatoboryl orneopentylglycolatoboryl) is on a compound of the Formula II-1,employing the catalysts, optional ligands, bases and solventsdescribed for Scheme I. In this instance, a mixture of a compoundof the Formula II-1 and a compound of the Formula II-2; in asolvent mixture of DME and water; in the presence of a base such assodium carbonate; and a catalytic amount of a preferred palladiumcatalyst; can be heated to 90.degree. C. to give the intermediateof the Formula I-4.

[0237] When not readily available, boronic esters of the FormulaII-1 can be synthesized from the corresponding halo derivatives ofthe Formula I-2, wherein W.sub.1 is C(R.sup.2a), W.sub.2 is CH, andW.sub.3 is C(R.sup.2), by a palladium-catalyzed boronation reaction(see, for example, Ishiyama, T. et al. J. Org. Chem. 1995, 60,7508-10 and Murata, M. et al. J. Org. Chem. 2000, 65, 164-8).Preferred conditions include treatment with a diboron reagent suchas bis(pinacolato)diboron, a palladium catalyst such as(dppf)PdCl.sub.2, and a base, preferably potassium acetate, in asuitable solvent such as DMSO, DMF or preferably dioxane.

##STR00070##

[0238] The nitro group of a compound of the Formula I-4 can bereduced to an amino group as shown in Scheme III to afford acompound of the Formula III-1 by a variety of standard methods(see: M. Hudlicky, "Reductions in Organic Chemistry"; EllisHorwood, Ltd.: Chichester, UK, 1984). These include, whereappropriate, catalytic hydrogenation using palladium metal as acatalyst in a suitable solvent such as methanol or ethanol, or,reduction with iron or zinc metal in the presence of a suitableacidic reagent or solvent such as hydrochloric acid or acetic acid,or by using iron and ammonium chloride in ethanol and water. Onepreferred method is with iron powder as the reducing agent in amixture of ethanol and acetic or hydrochloric acid and heating at50-80.degree. C.

##STR00071##

[0239] As illustrated in Scheme IV, an intermediate of the FormulaIV-3 (wherein V is C(R.sup.4) and Q is O) can be produced throughthe [3+2]cycloaddition reaction of an in situ-generated nitrileoxide and an appropriately substituted alkene of the Formula IV-2.(For a review of this chemistry, see: Jaeger, Volker; Colinas,Pedro A., Eds. "Chemistry of Heterocyclic Compounds (SyntheticApplications of 1,3-Dipolar Cycloaddition Chemistry towardHeterocycles and Natural Products)"; John Wiley & Sons, Ltd.(New York), 2002; Chapter 59, p 361-472.) Preferred conditions forthis reaction include generation of the nitrile oxide from ethylchlorohydroximinoacetate (Cpd IV-1) in an appropriate solvent,preferably DCM, in the presence of the alkene of the Formula IV-2with a trialkylamine, such as diisopropylethylamine, as a base.

##STR00072##

[0240] The resulting ester of the Formula IV-3 can be saponified bya number of common methods to produce the corresponding carboxylicacid; for example, by the action of lithium hydroxide in a waterand methanol solvent mixture to give the carboxylic acid of theFormula IV-4.

[0241] The acid chloride of a compound of the Formula IV-4 can beprepared using any of a number of standard known chlorinatingagents such as thionyl chloride or preferably oxalyl chloride asshown in Scheme V with DCM as the solvent and preferably with DMFadded as a catalyst. The acid chloride thus produced can be addedto a compound of the Formula III-1 in the presence of an acidscavenger and in an appropriate solvent, such as triethylamine inDCM, to give a mixture of the mono-acylated biphenyl intermediatesof the Formula V-1. A di-acylated biphenyl product may also begenerated during the course of the reaction and can be separatedfrom the mono-acylated mixture through conventional chromatographicmethods.

##STR00073##

[0242] The compound mixture of the Formula V-1 may be cyclized to abenzimidazole of the Formula VI-1 (Scheme VI) by the action of anacid catalyst while heating to about 100.degree. C. in anappropriate solvent. One preferred acid catalyst is(1S)-(+)-10-camphorsulfonic acid and a preferred solvent isdioxane. Other suitable acid catalysts include toluenesulfonic acidand acetic acid. Other suitable solvents include toluene and aceticacid.

##STR00074##

[0243] Scheme VII describes the general methodology that can beused to produce benzimidazoles of Formula (I) containing thecorresponding heterocyclic moieties of oxazoline (wherein V is Oand Q is CH.sub.2); and imidazoline (wherein V is NH and Q isCH.sub.2).

##STR00075##

[0244] In this approach, a compound of the Formula VII-2 may be auseful common precursor. A compound of the Formula VII-2 can beproduced by the reaction of a diamine of the Formula III-1 with anappropriately reactive trichloromethyl-substituted compound of theFormula VII-1 such as methyl 2,2,2-trichloroacetamidate, in thepresence of an acid catalyst such as acetic acid and in a suitablesolvent such as DCM or methanol; and more preferably in thepresence of acetic acid as both catalyst and solvent (Venable, J.D. et al. J. Med. Chem. 2005, 48, 8289-98).

[0245] Scheme VIII illustrates the reaction of variousdinucleophiles of the Formula VIII-1 with a compound of the FormulaVII-2, in a suitable solvent, and in the presence or absence of abase to afford heterocycles of the Formula VIII-2. Preferredconditions include the use of TEA or DIPEA as a base in DMF, DCM orpreferably THF as a solvent.

##STR00076##

[0246] Scheme IX illustrates a route for the preparation of variousderivatives of the Formula VIII-1, namely those of FormulaeVIII-1a, VIII-1b, and VIII-1c, that are useful for the preparationof compounds of the Formula (I).

##STR00077##

[0247] A diamine of the Formula VIII-1a (wherein V is NH, and Q isCH.sub.2) can be prepared by an initial Strecker-type reaction(see, for example, patent application WO 2006/028545) by reactingan appropriately substituted ketone of the Formula IX-1 with anamine and a cyanide derivative such as cyanotrimethylsilane, orsodium or potassium cyanide, in the presence of an acid such asacetic acid or hydrochloric acid, to give an aminonitrile of theFormula IX-2. Subsequent reduction of the cyano group of a compoundof the Formula IX-2 to give a compound of the Formula VIII-1a maybe effected by a number of methods. Reducing agents such as lithiumaluminum hydride, alane, lithium trimethoxyaluminum hydride orborane in a suitable solvent such as THF or diethyl ether may beused. (For a review and preferred conditions, see: Hudlicky, M."Reductions in Organic Chemistry"; Ellis Horwood, Ltd.: Chichester,UK, 1984.) An alternative reduction method is by hydrogenation overa metal catalyst in an alcoholic solvent such as methanol orethanol, at pressures of about 0 to about 100 psi, and, moreparticularly, at a pressure of about 30 to about 50 psi. Usefulcatalysts include Raney nickel, rhodium, palladium and platinum. Anacid catalyst such as acetic acid, perchloric acid, sulfuric acidor hydrochloric acid may be employed during the hydrogenationreaction. When an acid catalyst is not present, ammonia optionallymay be added to the reaction to suppress formation of possible sideproducts.

[0248] Cyanohydrin formation may be employed to give a compound ofthe Formula IX-3 by treatment of a ketone of the Formula IX-1 witha cyanide derivative in the presence of a catalyst (for a review,see: Gregory, R. J. Chem. Rev. 1999, 99, 3649). Reaction conditionsmay include the use of cyanotrimethylsilane (TMSCN), potassiumcyanide and 18-crown-6 in DCM (see: Greenlee, W. J.; Hangauer, D.G. Tetrahedron Lett. 1983, 24, 4559). Subsequent reduction of thenitrile using the methods described above for the formation of acompound of the Formula VIII-1a may then be employed to provide anamino alcohol of the Formula VIII-1b (wherein V is O and Q isCH.sub.2).

[0249] Hydrolysis of a compound of the Formula IX-3 may be used togive the corresponding hydroxy acid of the Formula IX-4 bytreatment with a strong acid such as concentrated sulfuric acid orconcentrated hydrochloric acid in a suitable solvent such as water,with or without an added co-solvent such as dioxane, ethanol oracetic acid. The coupling of ammonia in a suitable form such as anammonium salt, for example NH.sub.4Cl, with an acid of the FormulaIX-4 using conventional amide bond formation may afford a compoundof the Formula IX-5 (for a review, see: M. Bodansky and A.Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY(1984)). Preferred methods include the use ofbromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),N,N-dicyclohexylcarbodiimide (DCC) or more preferably1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)in the presence of 1-hydroxybenzotriazole (HOBt), with a base suchas DIPEA, TEA or preferably 4-methylmorpholine and in a solventsuch as DCM, THF, dioxane or preferably DMF. Amide reduction of acompound of the Formula IX-5 using reduction methods such as withborane, complexed with THF or dimethyl sulfide, in a suitablesolvent such as THF at reflux temperature, provides an alternativeroute to a compound of the Formula VIII-1b.

[0250] The conversion of a compound of the Formula IX-6 to thecorresponding amino ester of the Formula IX-7 (wherein R.sup.9 isC.sub.1-2alkyl) may be carried out by a number of standardprocedures used for ester formation on amino acids and peptides(for a review, see: Bodansky; M.; Bodansky, A. "The Practice ofPeptide Synthesis"; Springer-Verlag: NY, 1984) such as by theaction of thionyl chloride in methanol or ethanol at about0.degree. C., or by the action of trimethylsilyl-diazomethane (whenR.sup.9 is methyl) in a suitable solvent such as methanol orethanol. Subsequent reduction of the ester using standard methods(see: Hudlicky, M. "Reductions in Organic Chemistry"; EllisHorwood, Ltd.: Chichester, UK, 1984) may afford a compound of theFormula VIII-1c (wherein V is O and Q is CH.sub.2). When notcommercially available, a compound of the Formula IX-6 may bederived from the previously described aminonitrile of Formula IX-2by hydrolysis of the cyano group using concentrated sulfuric acidor preferably 6-12 M hydrochloric acid at temperatures of50-100.degree. C., with or without an added solvent such asdioxane.

[0251] Scheme X describes an alternate route to compounds ofFormula VI-1.

##STR00078##

[0252] The amino group of a compound of the Formula I-4 may beacylated by an acid chloride derivative of a carboxylic acid of theFormula IV-4. The acid chloride may be prepared from a compound ofFormula IV-4 using a conventional chlorinating agent as describedin Scheme V. One equivalent of acid chloride may be added to acompound of the Formula I-4, in the presence of a base, in anappropriate solvent, such as sodium hydride in THF, to give amono-acylated biphenyl intermediate of the Formula X-1. When morethan 1 equivalent of acid chloride is used, N,N-diacylatedcompounds may also be generated during the course of the reactionand may be separated from the mono-acylated compound X-1 throughconventional chromatographic methods. A compound of Formula X-1 maybe cyclized to a benzimidazole of the Formula VI-1 by the action ofan acid catalyst and an appropriate reducing agent while heating toabout 100.degree. C. in an appropriate solvent. A preferredreducing agent is iron powder, a preferred solvent is acetic acid,and a preferred acid catalyst is acetic acid. Other suitable acidcatalysts include (1S)-(+)-10-camphorsulfonic acid andtoluenesulfonic acid. Other suitable solvents include toluene.

[0253] Scheme XI illustrates an alternate synthesis of compounds ofthe Formula VI-1 utilizing intermediates of the Formula XI-3(wherein V is CH(R.sup.4), and Q is O).

##STR00079##

[0254] Compounds of the Formula XI-2 may be prepared by thereaction of dimethoxy-acetaldehyde with aqueous hydroxylamine in anappropriate solvent, such as DMF, and the in-situ generatedchlorooxime may then be added to a solution of an alkene of theFormula IV-2 and an acid scavenger in an appropriate solvent suchas DIPEA in DCM using a procedure similar to that of Liu, K., etal; J. Org. Chem. 1980 45, 3916-3918. Where compounds of FormulaXI-1 are not commercially available, they may be produced from thecorresponding ketone by a Wittig olefination reaction. (Forexample, see: March, J. "Advanced Organic Chemistry"; John Wileyand Sons, Inc.: NY, 1992 and Maryanoff; Reitz Chem. Rev. 1989, 89,863-927.) The resulting dimethylketal of compounds of Formula XI-2may be hydrolyzed by a number of common methods to produce thecorresponding aldehyde, for example, by the addition of a stronglyacidic cationic exchange resin such as Amberlyst-15 resin or Dowex50 resin in acetone (see, Coppola, G. M.; Synthesis 1984,1021-1023), to give aldehydes of the Formula XI-3. Reaction ofdiamines of Formula III-1 with aldehydes of the Formula XI-3 in thepresence of Na.sub.2S.sub.2O.sub.5 in an appropriate solvent suchas DMF provides compounds of the Formula VI-1.

[0255] One skilled in the art will recognize that protecting groupsmay be necessary at certain stages of the synthesis depending uponthe substituents and functional groups present on the reactants,and those skilled in the art will recognize where appropriategroups can be employed. (For lists of suitable protecting groups,conditions for protection and deprotection and a review of thechemistry, see: Greene, T. W.; G. M. Wuts, P. G. M. "ProtectiveGroups in Organic Synthesis"; John Wiley and Sons, Inc.: NY, 1999.)Microwave accelerated reactions also can be performed usingcommercial microwave units designed for this purpose, for examplethe Personal Chemistry Smith Synthesizer instrument.

[0256] The product of each process step may be separated from thereaction mixture and purified before use as a starting material ina subsequent step. Separation techniques typically includeevaporation, extraction, precipitation and filtration. Purificationtechniques typically include column chromatography (Still, W. C. etal. J. Org. Chem. 1978, 43, 2921), thin-layer chromatography,preparative HPLC, crystallization, trituration, anddistillation.

[0257] The starting materials and product of each process step areconfirmed by spectroscopic, spectrometric and analytical methodsincluding nuclear magnetic resonance (NMR), mass spectrometry (MS)and liquid chromatography (HPLC).

[0258] For preparing compounds of the present invention, commonsolvents known to those skilled in the art were used such as, butnot necessarily limited to, ethyl ether, THF, dioxane, methanol,ethanol, isopropanol, DMF, benzene, toluene, hexanes, cyclohexane,DCM, DME, and DCE. Compounds of the present invention may beisolated as the acid addition salt and may contain one or moreequivalents of the acid. The free base also may be obtained bytechniques known to those skilled in the art.

SPECIFIC EXAMPLES

[0259] Reagents were purchased from commercial sources.Microanalyses were performed at Quantitative Technologies, Inc.,Whitehouse, N.J. and are expressed in percentage by weight of eachelement per total molecular weight. Nuclear magnetic resonance(NMR) spectra for hydrogen atoms were measured in the indicatedsolvent with (TMS) as the internal standard on a Bruker Avance orVarian (300 or 400, or 500 MHz) spectrometer. The values areexpressed in parts per million downfield from TMS. The mass spectra(MS) were determined on an Agilent spectrometer as (ESI) m/z(M+H.sup.+) using an electrospray technique. Optical rotations wereobtained on a Perkin-Elmer polarimeter using the sodium D line aswavelength of light. Unless otherwise noted, the materials used inthe examples were obtained from readily available commercialsuppliers or synthesized by standard methods known to one skilledin the art of chemical synthesis. The substituent groups, whichvary between examples, are hydrogen unless otherwise noted.

Example 1

3-[7-Trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1--oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride (Cpd 27)JNJ41876666

##STR00080##

[0260] A. Ethyl 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylate

##STR00081##

[0262] To a 300 mL pressure vessel equipped with a magnetic stirbar was added methylenecyclohexane (5.83 g, 60.6 mmol) and EtOH(150 mL). Nitro-acetic acid ethyl ester (16.8 mL, 152 mmol) andDABCO (680 mg, 6.06 mmol) were then added. Additional EtOH (30 mL)was added to rinse the sides of the vessel, which was tightlycapped. The mixture was heated to 80.degree. C. for 42 h and thencooled to RT. The solvent was removed under reduced pressure, andthe residue was divided into three equal portions. Each portion waspurified by column chromatography using an 80-g SiO.sub.2pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over30 min, yielding 8.12 g (64%) of the desired ester. .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.: 4.34 (q, J=7.2 Hz, 2H), 2.91 (s,2H), 1.71-1.88 (m, 4H), 1.60-1.71 (m, 2H), 1.39-1.53 (m, 4H), 1.37(t, J=7.1 Hz, 3H).

B. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid

##STR00082##

[0264] Ethyl 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylate (8.12 g,38.5 mmol, as prepared in the previous step) was placed in a 200 mLround-bottom flask equipped with a magnetic stir bar, and MeOH (75mL) and water (25 mL) were added. Lithium hydroxide monohydrate(1.77 g, 42.3 mmol) was added as a solid. The reaction was stirredat RT for 20 h, and the solvents were removed under reducedpressure. The resulting solid was triturated with ether andcollected by filtration. The solid was then dissolved in water (200mL) and acidified to pH 2 with 3 M aq HCl. The precipitate wasisolated by filtration, washed well with water, air dried, anddried under vacuum. The filtrate was extracted three times with DCM(50 mL). The combined organic extracts were dried over anhydrousMgSO.sub.4, filtered, and the solvent was removed under reducedpressure. The initial precipitate and the material from theextraction were combined, giving 5.81 g (83%) of the titlecompound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 2.93 (s, 2H),1.72-1.89 (m, 4H), 1.60-1.72 (m, 2H), 1.37-1.54 (m, 4H).

C. 4-Bromo-2-nitro-6-trifluoromethyl-phenylamine

##STR00083##

[0266] 2-Nitro-6-trifluoromethyl-phenylamine (10.0 g, 48.5 mmol)was placed in a 200 mL round-bottom flask equipped with a magneticstir bar. Glacial acetic acid (100 mL) and bromine (3.24 mL, 63.1mmol) were added, and the mixture was stirred at RT for 18 h. Themixture was poured into ice (200 mL), and the excess bromine wasquenched with 10% aq Na.sub.2S.sub.2O.sub.3 (25 mL). Theprecipitate was isolated by filtration and washed with water. Thesolid was air-dried and then dried under vacuum to yield 13.8 g(100%) of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 8.49 (d, J=2.3 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H).

D. 5-Nitro-3,2'-bis-trifluoromethyl-biphenyl-4-ylamine

##STR00084##

[0268] 4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (10.0 g, 35.2mmol, as prepared in the previous step),2-trifluoromethylphenylboronic acid (8.70 g, 45.8 mmol), and(dppf)PdCl.sub.2 DCM (1.44 g, 1.76 mmol) were placed in a 500 mLround-bottom flask equipped with a magnetic stir bar and refluxcondenser. The flask was evacuated and backflushed with Ar. DME(150 mL) and 2M aq Na.sub.2 CO.sub.3 (50.0 mL, 100 mmol) were addedvia cannula. The mixture was stirred at 90.degree. C. for 18 h. Themixture was cooled to RT, diluted with EtOAc (100 mL), then washedwith water (100 mL) and brine (100 mL). The combined aqueous layerswere extracted twice with EtOAc (50 mL). The combined organicextracts were dried over MgSO.sub.4, filtered, and the solvent wasremoved under reduced pressure. The residue was purified on an 80-gpre-packed SiO.sub.2 column eluting with EtOAc/hexanes, 0:1 to 1:4,v/v over 30 min, yielding 11.3 g (92%) of the title compound..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.35 (d, J=2.0 Hz, 1H),7.78 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.53(t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.75 (br. s., 2H).

E. 5,2'-Bistrifluoromethyl-biphenyl-3,4-diamine

##STR00085##

[0270] 5-Nitro-3,2'-bis-trifluoromethyl-biphenyl-4-ylamine (11.3 g,32.5 mmol, as prepared in the previous step) was placed in a 500 mLround-bottom flask equipped with a magnetic stir bar. AnhydrousEtOH (150 mL) and 3M aq HCl (30 mL) were added via syringe. Ironpowder (9.07 g, 162 mmol) was added, and the mixture was stirred at80.degree. C. for 6 h. The reaction was cooled to RT and filteredthrough a pad of Celite. The filter cake was washed with MeOH (300mL). The solvent was removed under reduced pressure. The residuewas dissolved in EtOAc (150 mL) and washed with water (150 mL). Theaqueous layer was diluted with brine (100 mL) and extracted twicewith EtOAc (50 mL). The combined organic extracts were washed withsatd aq NaHCO.sub.3, dried over MgSO.sub.4, filtered, and thesolvent was removed under reduced pressure. The material was useddirectly in the next step without further purification.

F. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid(4-amino-5,2'-bis-trifluoromethyl-biphenyl-3-yl)-amide

##STR00086##

[0272] 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (4.17 g,22.8 mmol, as prepared in step B of this Example) was placed in a100 mL round-bottom flask equipped with a magnetic stir bar. DCM(45 mL) and DMF (50 .mu.L) were added via syringe. To the stirredsolution was added oxalyl chloride (2.60 mL, 29.6 mmol) dropwisevia syringe. After completion of the addition, the reaction wasstirred at RT for 2 h. The solvent was removed under reducedpressure, the resulting residue was dissolved in DCM (230 mL), andthis acid chloride solution was placed in a dropping funnel.

[0273] 5,2'-Bistrifluoromethyl-biphenyl-3,4-diamine (10.4 g, 32.5mmol, as prepared in step E of this Example) was placed in a 1000mL round-bottom flask equipped with a magnetic stir bar, and DCM(300 mL) and TEA (9.53 mL, 68.4 mmol) were added. Theabove-prepared acid chloride solution was added dropwise over aperiod of 4 h to the stirred reaction mixture. After completion ofthe addition, the solution was stirred at RT for 1 h, and thesolvent was removed under reduced pressure. The crude product waspurified by column chromatography using an 80-g SiO.sub.2pre-packed column eluting with EtOAc/hexanes 0:1 to 3:7, v/v over30 min, yielding 9.22 g (83%) of the title compound. Mass Spectrum(LCMS, APCI pos.): Calcd. forC.sub.23H.sub.21F.sub.6N.sub.3O.sub.2: 486.2 (M+H). found:486.1.

G.3-[7-Trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]--1-oxa-2-aza-spiro[4.5]dec-2-ene

##STR00087##

[0275] 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid(4-amino-5,2'-bis-trifluoromethyl-biphenyl-3-yl)-amide (9.22 g,19.0 mmol, as prepared in the previous step) was placed in a 250 mLround-bottom flask equipped with a magnetic stir bar. Dry dioxane(200 mL) and CSA (883 mg, 3.80 mmol) were added. The flask wasfitted with a reflux condenser, and the mixture was stirred at100.degree. C. for 7.5 h. The reaction was cooled to RT, and thesolvent was removed under reduced pressure. The residue wasdissolved in EtOAc (100 mL) and washed twice with satd aqNaHCO.sub.3 (50 mL). The organic extract was dried over MgSO.sub.4,filtered, and the solvent was removed under reduced pressure. Theresidue was dissolved in a minimum amount of MeOH (50 mL) andplaced in a freezer for 1 h. The resulting precipitate was isolatedby filtration and washed with MeOH. The precipitate was purified byrecrystallization from hot MeOH (30 mL), giving a pale yellowsolid, which was dried under high vacuum. The filtrate wasconcentrated under reduced pressure and purified by columnchromatography using an 80-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min. The solidprecipitate and column-purified material were combined, yielding8.12 g (91%) of the title compound. .sup.1H-NMR (400 MHz,CDCl.sub.3) 6: .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.89(d, J=7.6 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.68 (t, J=7.6 Hz, 2H),7.55 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 3.33 (s, 2H), 1.63-1.82 (m,6H), 1.35-1.58 (m, 4H).

H.3-[7-Trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]--1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride

[0276]3-[7-Trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2--yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene (524 mg, 1.12 mmol, asprepared in the previous step) was placed in an 8 mL vial, dry MeOH(2 mL) was added, and the mixture was warmed until the soliddissolved. This mixture was added to a mL vial containing ether (20mL) and 1 M HCl in ether (1.12 mL, 1.12 mmol), resulting in ahomogeneous solution. The solution was transferred to a 100 mLround-bottom flask, the solvent was removed under reduced pressure,and the solid was dried under vacuum, giving 469 mg (83%) of thedesired HCl salt. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.89(d, J=7.6 Hz, 1H), 7.73-7.81 (m, 1H), 7.71 (s, 1H), 7.63-7.70 (m,1H), 7.55 (d, J=7.3 Hz, 1H), 7.48 (s, 1H), 3.33 (s, 2H), 1.62-1.83(m, 6H), 1.33-1.59 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd.for C.sub.23H.sub.19F.sub.6N.sub.3O: 468.1 (M+H). found: 468.3.Elemental Analysis Calcd. for C.sub.23H.sub.19F.sub.6N.sub.3O: C,59.10; H, 4.10; F, 24.39; N, 8.99. Found C, 59.06; H, 4.04; F,24.30; N, 9.04 (% H.sub.2O 0.39, Pd <1 ppm).

[0277] Using the procedures described in Example 1, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00003 Cpd Data 13-[5-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.:7.79 (d, J = 7.8 Hz, 1H), 7.65 (td, J = 7.6, 0.8 Hz, 1H), 7.64 (brs, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.54 (br s, 1H), 7.43 (d, J = 7.6Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 3.29 (s, 2H), 1.71-1.91 (m, 6H),1.48-1.64 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.20F.sub.3N.sub.3O: 400.2 (M + H); found: 400.2. 73-[5-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.72 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H),7.57-7.63 (m, 1H), 7.47-7.56 (m, 3H), 7.42 (dd, J = 8.3, 1.3 Hz,1H), 3.31 (s, 2H), 1.62-1.80 (m, 6H), 1.34-1.57 (m, 4H). MassSpectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.20F.sub.3N.sub.3O.sub.2: 416.2 (M + H); found: 416.2.143-[7-Fluoro-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.86 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.6Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.26(s, 1H), 7.03 (d, J = 11.4 Hz, 1H), 3.31 (s, 2H), 1.60-1.81 (m,6H), 1.29-1.58 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.19F.sub.4N.sub.3O: 418.2 (M + H); found: 418.4. 154-Methyl-3-[5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.86 (d, J = 7.6 Hz, 1H), 7.72-7.78 (m, 1H),7.70 (d, J = 8.3 Hz, 1H), 7.59-7.68 (m, 1H), 7.56 (s, 1H), 7.47 (d,J = 7.6 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 3.51 (q, J = 7.2 Hz,1H), 1.33-1.90 (m, 10H), 1.27 (d, J = 7.3 Hz, 3H). Mass Spectrum(LCMS, ESI pos.): Calcd. for C.sub.23H.sub.22F.sub.3N.sub.3O: 414.2(M + H); found: 414.4. 233-[5-(2-Fluoro-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene trifluoroacetic acid salt .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.76 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.59(td, J = 8.0, 1.5 Hz, 1H), 7.47-7.51 (m, 1H), 7.38-7.47 (m, 1H),7.27-7.38 (m, 2H), 3.30 (s, 2H), 1.63-1.80 (m, 6H), 1.34-1.56 (m,4H).. 284-Methyl-3-[7-trifluormethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride.sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.89 (d, J = 7.6 Hz,1H), 7.73-7.81 (m, 1H), 7.70 (s, 1H), 7.63-7.70 (m, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.48 (s, 1H), 3.50 (q, J = 7.2 Hz, 1H), 1.76-1.87(m, 1H), 1.48-1.76 (m, 8H), 1.32-1.44 (m, 1H), 1.30 (d, J = 7.3 Hz,3H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.19F.sub.6N.sub.3O: 482.2 (M + H); found: 482.3. 513-[5-(2-Trifluoromethoxyphenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR(400 MHz, d.sub.6-DMSO) .delta.: 7.86 (s, 1H), 7.66-7.73 (m, 1H),7.64 (s, 1H), 7.50-7.62 (m, 3H), 3.33 (s, 2H), 1.62-1.83 (m, 6H),1.34-1.61 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.19F.sub.6N.sub.3O.sub.2: 484.1 (M + H); found: 484.2.53 3-[5-(2-Fluorophenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.92 (s, 1H), 7.71 (s, 1H), 7.62-7.70 (m,1H), 7.44-7.52 (m, 1H), 7.32-7.41 (m, 2H), 3.33 (s, 2H), 1.61-1.83(m, 6H), 1.35-1.59 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd.for C.sub.22H.sub.19F.sub.4N.sub.3O: 418.2 (M + H); found: 418.2.543-[4,7-Dimethyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.86 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.5Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.92(s, 1H), 3.37 (s, 2H), 2.53 (s, 3H), 2.18 (s, 3H), 1.62-1.85 (m,6H), 1.31-1.55 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.24H.sub.24F.sub.3N.sub.3O: 428.2 (M + H); found: 428.3.

Example 2

3-[5-(2-Trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro-[4.5]dec-2-ene (Cpd 9)

##STR00088##

[0278] A. Ethyl1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylate

##STR00089##

[0280] The method of Schlosser, M. et al. (Tetrahedron 1990, 46,2411-2424) was used. The methyltriphenylphosphonium bromide/sodiumamide "instant ylide" mixture (Aldrich) (1.2 eq., 2.5 g, 6.0 mmol)was placed in a 40 mL vial equipped with a magnetic stir bar, andthe vessel was evacuated and backflushed with Ar. Dry ether (10 mL)was added via syringe, and the reaction was stirred at RT for 2 h.Tetrahydropyran-4-one (0.46 mL, 5.0 mmol) was added dropwise viasyringe, and the reaction was stirred at RT for 16 h. The reactionwas quenched with water, and the aqueous layer was extracted twicewith ether (5 mL). The combined organic extracts were washed withbrine, dried over anhydrous MgSO.sub.4, and filtered.

[0281] The ether solution was transferred to a 100 mL round-bottomflask equipped with a magnetic stir bar, and DIPEA (1.1 eq., 0.96mL, 5.5 mmol) was added via syringe. Ethyl2-chloro-2-(hydroxyimino)acetate (1 eq., 758 mg, 5.00 mmol) wasdissolved in DCM (50 mL) and placed in a dropping funnel. The DCMsolution was added dropwise to the vigorously stirred etherreaction mixture over a period of 2 h. The resulting solution wasstirred at RT for 3 days. The solvent was removed under reducedpressure, and the residue was purified by column chromatographyusing a 24-g SiO.sub.2 pre-packed column eluting withEtOAc/hexanes, 0:1 to 2:3, v/v over 30 min, yielding 264 mg (25%)of the desired ester. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:4.35 (q, J=7.2 Hz, 2H), 3.89 (ddd, J=11.7, 8.6, 3.4 Hz, 2H),3.63-3.76 (m, 2H), 2.99 (s, 2H), 1.87-1.98 (m, 2H), 1.74-1.87 (m,2H), 1.37 (t, J=7.2 Hz, 3H).

B.3-[5-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-s-piro[4.5]dec-2-ene

##STR00090##

[0283] The title compound was prepared according to steps D throughH of Example 1. .sup.1H-NMR (400 MHz, d.sub.6-DMSO+d.sub.1-TFA).delta.: 7.86 (d, J=7.6 Hz, 1H), 7.71-7.78 (m, 1H), 7.68 (d, J=8.3Hz, 1H), 7.60-7.67 (m, 1H), 7.55 (s, 1H), 7.48 (d, J=7.3 Hz, 1H),7.26 (d, J=9.1 Hz, 1H), 3.75-3.87 (m, 2H), 3.54-3.68 (m, 2H), 3.42(s, 2H), 1.79-1.94 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd.for C.sub.22H.sub.18F.sub.5N.sub.3O: 402.1 (M+H). found: 402.2.

[0284] Using the procedures described in Example 2, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00004 Cpd Data 108,8,-Difluoro-3-[5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro [4.5]dec-2-ene JNJ41658110.sup.1H-NMR (400 MHz, d.sub.6-DMSO + d.sub.1-TFA) .delta.: 7.85 (d,J = 7.8 Hz, 1H), 7.71-7.78 (m, 1H), 7.69 (d, J = 8.3 Hz, 1H),7.59-7.67 (m, 1H), 7.56 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.27 (d,J = 8.3 Hz, 1H), 3.45 (s, 2H), 1.85-2.23 (m, 8H). Mass Spectrum(LCMS, ESI pos.): Calcd. for C.sub.22H.sub.18F.sub.5N.sub.3O: 436.1(M + H); found: 436.2.

Example 3

3-[4-Methyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene hydrochloride (Cpd 24)

##STR00091##

[0285] A. 1-Bromo-2-methyl-3,4-dinitro-benzene

##STR00092##

[0287] The title compound was prepared by an adaptation of theprocedure described by Mundla, S. R. (Tetrahedron Lett. 2000, 41,4277-4279). 2-Bromo-6-nitrotoluene (1.09 g, 5.05 mmol) was placedin a 50 mL round-bottom flask equipped with a magnetic stir bar.Conc. H.sub.2SO.sub.4 (10 mL) was added, and the solid was allowedto dissolve. The reaction was cooled in an ice bath, and fumingnitric acid (1.5 eq., 0.340 mL, 7.57 mmol) was added dropwise viasyringe at a rate such that the temperature of the mixture remainedbelow 10.degree. C. After completion of the addition, the reactionwas allowed to warm to RT and stir for 2 h. The reaction mixturewas poured into crushed ice, and the precipitate was isolated byfiltration. The solid was washed with water (30 mL) and allowed toair dry. The crude product was purified by column chromatographyusing a 40-g SiO.sub.2 pre-packed column eluting withEtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 879 mg (67%)of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 2.45 (s, 3H).

B.3-[4-Methyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2--aza-spiro[4.5]dec-2-ene hydrochloride

##STR00093##

[0289] The title compound was prepared according to steps D throughH of Example 1. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.87(d, J=7.6 Hz, 1H), 7.75 (t, J=7.3 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H),7.52 (d, J=8.3 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.16 (d, J=8.3 Hz,1H), 3.38 (s, 2H), 2.25 (s, 3H), 1.64-1.83 (m, 6H), 1.34-1.56 (m,4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.22F.sub.3N.sub.3O: 414.2 (M+H). found: 414.3.

Example 4

3-[5-(2-Fluoro-6-trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-az-a-spiro[4.5]dec-2-ene hydrochloride (Cpd 8)

##STR00094##

[0290] A.2'-Fluoro-3-nitro-6'-trifluoromethoxy-biphenyl-4-ylamine

##STR00095##

[0292] 2-Fluoro-1-iodo-6-trifluoromethoxybenzene (612 mg, 2.00mmol, prepared as described in WO2005/097136),4-amino-3-nitrophenylboronic acid pinacol ester (1.3 eq., 687 mg,2.60 mmol), and (dppf)PdCl.sub.2.DCM (0.05 eq., 81.6 mg, 0.100mmol) were placed in a 40 mL vial equipped with a magnetic stirbar. The vial was evacuated and backflushed with Ar, and DME (10mL) and 2M aq Na.sub.2 CO.sub.3 (4 mL) were added via syringe. Thevial was capped tightly and placed in a heating block where thereaction was stirred at 90.degree. C. for 24 h. The reaction wascooled to room temperature, diluted with EtOAc, and washedsequentially with water and brine. The organic extract was driedover anhydrous MgSO.sub.4, filtered, and the solvent was removedunder reduced pressure. The crude product was purified by columnchromatography using an 80-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 2:3, v/v over 30 min, yielding 548 mg(87%) of the desired compound. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 8.21 (s, 1H), 7.30-7.47 (m, 2H), 7.18 (d, J=8.1 Hz, 1H),7.14 (t, J=8.6 Hz, 1H), 6.91 (d, J=6.6 Hz, 1H), 5.37 (br. s.,2H).

B.3-[5-(2-Fluoro-6-trifluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1-oxa-2--aza-spiro[4.5]dec-2-ene hydrochloride

[0293] The title compound was prepared according to Example 1,steps E through H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.72 (d, J=8.3 Hz, 1H), 7.63 (s, 1H), 7.55-7.62 (m, 1H), 7.45 (t,J=8.8 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 3.31(s, 2H), 1.63-1.80 (m, 6H), 1.33-1.57 (m, 4H). Mass Spectrum (LCMS,ESI pos.): Calcd. for C.sub.22H.sub.19F.sub.4N.sub.3O.sub.2: 434.1(M+H). found: 434.2.

[0294] Using the procedures described in Example 4, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00005 Cpd Data 123-[5-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.95 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 8.6Hz, 1H), 7.67 (dd, J = 8.5, 1.6 Hz, 1H), 7.55 (dd, J = 8.0, 1.1 Hz,1H), 7.41 (dd, J = 8.1, 1.3 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H),1.63-1.82 (m, 6H), 1.37-1.55 (m, 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.22H.sub.19F.sub.2N.sub.3O.sub.3: 412.1 (M +H); found: 412.4. 133-[5-(2-Difluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.72 (d, J = 1.0 Hz, 1H), 7.71 (d, J = 5.3Hz, 1H), 7.48-7.55 (m, 1H), 7.47 (dd, J = 5.6, 1.8 Hz, 1H), 7.45(dd, J = 6.1, 1.5 Hz, 1H), 7.37-7.41 (m, 1H), 7.33 (d, J = 8.3 Hz,1H), 7.16 (t, J = 74 Hz, 1H), 3.32 (s, 2H), 1.63-1.83 (m, 6H),1.37-1.56 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.21F.sub.2N.sub.3O.sub.2: 398.2 (M + H); found: 398.4.26 3-[5-(2,6-Difluoro-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene trifluoroacetic acid salt .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.70 (d, J = 8.3 Hz, 1H), 7.66 (s, 1H),7.43-7.54 (m, 1H), 7.33 (dd, J = 8.6, 1.3 Hz, 1H), 7.19-7.29 (m,2H), 3.30 (s, 2H), 1.63-1.79 (m, 6H), 1.35-1.55 (m, 4H). MassSpectrum (LCMS, ESI pos.): Calcd. forC.sub.21H.sub.19F.sub.2N.sub.3O: 368.2 (M + H); found: 368.2.

Example 5

3-{5-[2-(2,2,2-Trifluoroethyl)-phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-aza-s-piro[4.5]dec-2-ene (Cpd 11)

##STR00096##

[0295] A. 1-(2-Bromo-phenyl)-2,2,2-trifluoro-ethanol

##STR00097##

[0297] The title compound was prepared by an adaptation of themethod described in Xue, Y. et al. (Bioorg. Med. Chem. 2007, 15,2156-2166). Tetrabutylammonium fluoride hydrate (0.05 eq., 131 mg,0.050 mmol) was placed in a 40 mL vial equipped with a magneticstir bar, and the vial was evacuated and backflushed with Ar. DryTHF (25 mL) was added via syringe, and 2-bromobenzaldehyde (1.16mL, 10.0 mmol) and trimethylsilyltrifluoromethane (1.3 eq., 1.90mL, 13.0 mmol) were sequentially added via syringe. The reactionwas stirred at RT for 16 h, and additional CF.sub.3 TMS (1 mL) wasadded. After stirring for 2 h, the reaction was poured into 3 M aqHCl (30 mL) and stirred at RT for 2 h. The reaction mixture wasextracted three times with DCM (30 mL), and the combined organicextracts were dried over anhydrous MgSO.sub.4, filtered, and thesolvent removed under reduced pressure, yielding 1.83 g (72%) ofthe title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.69(d, J=7.8 Hz, 1H), 7.60 (dd, J=8.1, 1.3 Hz, 1H), 7.40 (td, J=7.6,1.1 Hz, 1H), 7.27 (td, J=7.7, 1.8 Hz, 1H), 5.56-5.68 (m, 1H), 2.77(d, J=4.8 Hz, 1H).

B. Thiocarbonic acidO-[1-(2-bromo-phenyl)-2,2,2-trifluoro-ethyl]ester O-phenylester

##STR00098##

[0299] The title compound was prepared by an adaptation of themethod described in Robins, M. J. et al. (J. Am. Chem. Soc. 1983,105, 4059-4065). 1-(2-Bromo-phenyl)-2,2,2-trifluoro-ethanol (615mg, 2.41 mmol, as prepared in the previous step) was placed in an 8mL vial equipped with a magnetic stir bar. DCM (4 mL) and TEA (1.2eq., 0.403 mL, 2.89 mmol) were added via syringe. Phenylchlorothionoformate (1.1 eq., 0.367 mL, 2.65 mmol) was addeddropwise via syringe to the water-cooled solution. After completionof the addition, the reaction was stirred at RT for 16 h, pouredinto water, and extracted three times with DCM (10 mL). Thecombined organic extracts were dried over anhydrous MgSO.sub.4filtered, and the solvent was removed under reduced pressure. Thecrude product was purified by column chromatography using a 12-gSiO.sub.2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4,v/v over 30 min, yielding 695 mg (74%) of the title compound..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.58-7.68 (m, 2H),7.36-7.48 (m, 3H), 7.27-7.36 (m, 2H), 7.04-7.15 (m, 3H).

C. 1-Bromo-2-(2,2,2-trifluoro-ethyl)-benzene

##STR00099##

[0301] The method of Fu, G. C. et al. (J. Am. Chem. Soc. 1997, 119,6949-6950) was used. Thiocarbonic acidO-[1-(2-bromo-phenyl)-2,2,2-trifluoro-ethyl]ester O-phenyl ester(353 mg, 0.902 mmol, as prepared in the previous step) was placedin an 8 mL vial equipped with a magnetic stir bar.Polymethylhydrosiloxane (PMHS) (5 eq., 300 mg, 4.51 mmol) was addedvia pipette, and toluene (0.9 mL) and n-butanol (5.5 eq., 0.454 mL,4.96 mmol) were added via syringe. (Bu.sub.3Sn).sub.2O (0.038 eq.,17 .mu.L, 0.034 mmol) was added via microsyringe, and AIBN (0.15eq., 22.2 mg, 0.135 mmol) was added as a solid. The reaction wascapped tightly, placed in a heating block, and stirred at80.degree. C. for 14 h.

[0302] Additional (Bu.sub.3Sn).sub.2O (17 .mu.L) and AIBN (22 mg)were added, and the reaction was stirred an additional 14 h at80.degree. C. The reaction was cooled to RT, diluted with THF (4mL), and quenched with 2M aq NaOH (1 mL). The reaction was stirredat RT for 12 h and extracted three times with ether (10 mL). Thecombined organic extracts were washed with 1M HCl and brine, driedover anhydrous MgSO.sub.4, filtered, and the solvent was removedunder reduced pressure. The crude product was purified by columnchromatography using a 12 g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 3:17, v/v over 30 min, yielding 70 mg(34%) of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 7.61 (dd, J=8.0, 1.1 Hz, 1H), 7.35-7.40 (m, 1H), 7.31 (td,J=7.5, 1.1 Hz, 1H), 7.19 (td, J=7.7, 1.8 Hz, 1H), 3.63 (q, J=10.6Hz, 2H).

D.3-{5-[2-(2,2,2-Trifluoroethyl)-phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-az-a-spiro[4.5]dec-2-ene

##STR00100##

[0304] The procedures described in Example 4, steps A and B wereused to prepare the title compound. .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.64-7.82 (m, 1H), 7.52-7.64 (m, 1H),7.45-7.52 (m, 1H), 7.36-7.43 (m, 2H), 7.28-7.36 (m, 1H), 7.13-7.27(m, 1H), 3.48 (q, J=11.1 Hz, 1H), 3.29 (s, 2H), 1.69-1.91 (m, 6H),1.46-1.63 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.22F.sub.3N.sub.3O: 414.2 (M+H). found: 414.3.

Example 6

3-[7-Chloro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene hydrochloride (Cpd 16)

##STR00101##

[0305] A. 3-Nitro-2'-trifluoromethyl-biphenyl-4-ylamine

##STR00102##

[0307] 4-Bromo-2-nitroaniline (10.1 g, 46.7 mmol),2-trifluoromethylphenylboronic acid (1.3 eq., 11.5 g, 60.7 mmol),and (dppf)PdCl.sub.2.DCM (0.05 eq., 1.91 g, 2.34 mmol) were placedin a 500 mL round-bottom flask equipped with a magnetic stir bar.The vial was evacuated and backflushed with Ar, and DME (180 mL)and 2M aq Na.sub.2 CO.sub.3 (60 mL) were added via syringe. Theflask was capped tightly, and the reaction was stirred at90.degree. C. for 16 h. The reaction was cooled to RT, diluted withEtOAc, and washed sequentially with water and brine. The organicextract was dried over anhydrous MgSO.sub.4, filtered, and thesolvent was removed under reduced pressure. The crude product wasdry-loaded onto 25 g of SiO.sub.2 and purified by columnchromatography using an 80-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 3:7, v/v over 20 min, yielding 12.8 g(97%) of the desired compound. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 8.11 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.54-7.62(m, J=7.6 Hz, 1H), 7.44-7.53 (m, J=7.8 Hz, 1H), 7.36 (dd, J=8.6,1.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H).

B. 3-Chloro-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine

##STR00103##

[0309] The procedure of Nickson, T. E. et al. (Synthesis 1985,669-670) was used. 3-Nitro-2'-trifluoromethyl-biphenyl-4-ylamine(12.7 g, 45.0 mmol, as prepared in the previous step) was placed ina 250 mL round-bottom flask equipped with a magnetic stir bar and areflux condenser, and dry acetonitrile (150 mL) was added. Thesolid was allowed to dissolve, and NCS (1.5 eq., 9.02 g, 67.5 mmol)was added as a solid. The reaction was heated at 80.degree. C. for3 days. The reaction was cooled to RT, diluted with EtOAc, thenwashed twice with water (20 mL) and once with brine (30 mL). Thecombined organic extracts were dried over MgSO.sub.4, filtered, andthe solvent was removed under reduced pressure. The crude materialwas chromatographed on an 80-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding 6.96 g(49%) of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 8.10 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.57-7.62(m, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.44-7.54 (m, 1H), 7.32 (d, J=7.3Hz, 1H), 6.64 (br. s., 2H).

C.3-[7-Chloro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za-spiro[4.5]dec-2-ene

##STR00104##

[0311] 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (4.02 g,21.9 mmol, as prepared in Example 1, step B) was placed in around-bottom flask equipped with a magnetic stir bar. DCM (40 mL)and DMF (50 .mu.L) were added. Oxalyl chloride (2.5 mL, 28.5 mmol)was added dropwise via syringe, and the mixture was stirred at RTfor 1 h. The solvent was removed under reduced pressure.3-Chloro-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine (6.96 g.21.9 mmol) was placed in a round-bottom flask equipped with amagnetic stir bar. The flask was evacuated and backflushed withargon, and dry THF (50 mL) was added. The mixture was cooled to0.degree. C. in an ice bath, then NaH (2.64 g, 65.8 mmol, 60%dispersion in oil) was added in small portions. The above-preparedacid chloride was taken up in dry THF (20 mL) and added dropwise tothe 3-chloro-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine solutionat 0.degree. C. over 10 min. After the addition was complete, themixture was allowed to stir an additional 30 min at 0.degree. C.then warm to RT and stir at that temperature for 16 h. The mixturewas quenched with water, diluted with brine, and extracted threetimes with EtOAc. The combined organic extracts were dried overMgSO.sub.4, filtered, and the solvent was removed under reducedpressure. The residue was dissolved in AcOH and placed in around-bottom flask equipped with a magnetic stir bar. Fe powder(6.14 g, 110 mmol) was added. The flask was tightly capped, and themixture was heated to 80.degree. C. for 1 h. The mixture was cooledto RT and poured into ice. The resulting precipitate was filteredand washed with water. The filtrate was extracted with EtOAc. Thecombined organic extracts were dried over MgSO.sub.4, filtered, andthe solvent was removed under reduced pressure. The crude materialwas chromatographed on an 80-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min. The resultingmaterial was recrystallized from MeOH and isolated by filtration,yielding 5.12 g (54%) of the title compound. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta.: 13.52 (br. s., 1H), 7.86 (d, J=7.6 Hz, 1H),7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6 Hz,1H), 7.35 (s, 1H), 7.25 (s, 1H), 1.63-1.82 (m, 6H), 1.34-1.60 (m,4H).

D.3-[7-Chloro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za-spiro[4.5]dec-2-ene hydrochloride

[0312]3-[7-Chloro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa--2-aza-spiro[4.5]dec-2-ene (2.39 g, 5.52 mmol) was placed in a 100mL round-bottom flask. EtOAc (10 mL) was added, and the solid wasallowed to dissolve. HCl (5.52 mL, 5.52 mmol, 1 M in ether) wasadded dropwise via syringe with swirling to ensure sufficientmixing. The mixture was sonicated for 2 min, resulting in a whiteprecipitate, which was isolated by filtration and washed twice withEtOAc (10 mL) then once with ether (20 mL). The solid was driedunder high vacuum, yielding the title compound (2.43 g, 94%)..sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.86 (d, J=7.8 Hz,1H), 7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6Hz, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 3.33 (s, 2H), 1.63-1.81 (m,6H), 1.32-1.58 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.19ClF.sub.3N.sub.3O: 434.1 (M+H). found: 434.4.

Example 7

3-[7-Bromo-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-s-piro[4.5]dec-2-ene hydrochloride (Cpd 17)

##STR00105##

[0313] A. 3-Bromo-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine

##STR00106##

[0315] The method of Siegel, J. S. et al. (Org. Lett., 2006, 8,4989-4992) was used. 3-Nitro-2'-trifluoromethyl-biphenyl-4-ylamine(302 mg, 1.07 mmol, as prepared in Example 6, step A) was placed inan 8 mL vial equipped with a magnetic stir bar, and glacial aceticacid (2 mL) was added via pipette. The solid was allowed todissolve, and bromine (1.07 eq., 59.0 .mu.L, 1.14 mmol) was addeddropwise via microsyringe. The reaction was tightly capped andstirred at RT for 30 min, during which time a precipitate formed.The reaction was poured into crushed ice, and the precipitate wasisolated by filtration. The precipitate was washed with water (50mL), dissolved in DCM (40 mL), dried over anhydrous MgSO.sub.4,filtered, and the solvent removed under reduced pressure. The crudematerial was chromatographed on a 24-g SiO.sub.2 pre-packed columneluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 20 min, yielding341 mg (88%) of the title compound. .sup.1H-NMR (400 MHz,CDCl.sub.3) .delta.: 8.14 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.8 Hz,1H), 7.72 (d, J=2.0 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.7Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.70 (br. s., 2H).

B.3-[7-Bromo-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-az-a-spiro[4.5]dec-2-ene hydrochloride

[0316] The title compound was prepared according to Example 1,steps E through H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.86 (d, J=7.1 Hz, 1H), 7.75 (t, J=7.3 Hz, 1H), 7.65 (t, J=7.7 Hz,1H), 7.51 (d, J=7.6 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 3.33 (s,2H), 1.62-1.81 (m, 6H), 1.32-1.59 (m, 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.22H.sub.19BrF.sub.3N.sub.3O: 478.1 (M+H).found: 478.3.

Example 8

3-[5-(2-Difluoromethoxyphenyl)-7-methyl-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene hydrochloride (Cpd 20)

##STR00107##

[0317] A. 4-Amino-5-methyl-3-nitrophenylboronic acid pinacolester

##STR00108##

[0319] The title compound was prepared by an adaptation of themethod described by Lee, Y.-K. et al. (J. Med. Chem. 2008, 51,282-297). 4-Bromo-6-methyl-2-nitroaniline (1.16 g, 5.02 mmol),bis-(pinacolato)-diboron (3.0 eq., 3.81 g, 15.0 mmol),(dppf)PdCl.sub.2.DCM (0.1 eq., 420 mg, 0.514 mmol), and potassiumacetate (4.0 eq., 1.96 g, 20.0 mmol) were placed in a 100 mLround-bottom flask equipped with a magnetic stir bar. The flask wasfitted with a reflux condenser, and the apparatus was evacuated andbackflushed with Ar. Dry dioxane (50 mL) was added via syringe, andthe reaction was heated to reflux for 18 h. The reaction was cooledto RT, diluted with EtOAc (50 mL), and filtered. The filtrate wasconcentrated under reduced pressure and purified by columnchromatography on a 40-g SiO.sub.2 pre-packed column eluting withEtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding 1.09 g (78%)of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:8.48 (s, 1H), 7.65 (s, 1H), 6.33 (br. s., 2H), 2.23 (s, 3H), 1.34(s, 12H).

B.3-[5-(2-Difluoromethoxyphenyl)-7-methyl-1H-benzimidazol-2-yl]-1-oxa-2-a-za-spiro[4.5]dec-2-ene hydrochloride

##STR00109##

[0321] The title compound was prepared according to Example 4,steps A and B. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.55(s, 1H), 7.51 (dd, J=7.6, 1.8 Hz, 1H), 7.43-7.49 (m, 1H), 7.37 (dd,J=7.6, 1.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.16 (t,J=74 Hz, 1H), 3.37 (s, 2H), 2.63 (s, 3H), 1.65-1.83 (m, 6H),1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.23F.sub.2N.sub.3O.sub.2: 412.2 (M+H). found:412.3.

Example 9

2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-be-nzimidazole-4-carbonitrile hydrochloride (Cpd 21)

##STR00110##

[0322] A. 3-Iodo-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine

##STR00111##

[0324] The method of Koradin, C. et al. (Tetrahedron 2003, 59,1571-1587) was used. 3-Nitro-2'-trifluoromethyl-biphenyl-4-ylamine(752 mg, 2.66 mmol, as prepared in Example 6, step A) was placed ina 40 mL vial equipped with a magnetic stir bar, and anhydrous EtOH(27 mL) was added. Iodine (1.4 eq., 945 mg, 3.72 mmol) was added asa solid to the stirred solution. Silver sulfate (1.4 eq., 1.16 g,3.72 mmol) was added in one portion as a solid, and the reactionwas stirred at RT for 24 h. The reaction was filtered, and thesolvent was removed under reduced pressure. The residue wasdissolved in DCM (30 mL), washed with 10% aq Na.sub.2S.sub.2O.sub.3(10 mL), dried over anhydrous MgSO.sub.4, filtered, and the solventwas removed under reduced pressure. The crude product was purifiedby column chromatography using a 40-g SiO.sub.2 pre-packed columneluting with EtOAc/hexanes, 0:1 to 1:4, v/v, yielding 902 mg (83%)of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:8.17 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.76 (d, J=7.3 Hz,1H), 7.58 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.74 (br. s., 2H).

B. 3-Cyano-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine

##STR00112##

[0326] The title compound was prepared by an adaptation of themethod described by Youngblood, W. J. (J. Org. Chem. 2006, 71,3345-3356). 3-Iodo-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine(230 mg, 0.564 mmol, as prepared in the previous step) and Cu(I)CN(1.5 eq., 7.57 mg, 0.845 mmol) were placed in an 8 mL vial equippedwith a magnetic stir bar. Dry DMA (2.5 mL) was added via syringe,and the vial was tightly capped and placed in a heating block. Thereaction was stirred at 140.degree. C. for 14 h, cooled to RT, andpoured into water. The precipitate was isolated by filtration andwashed with water (10 mL). The precipitate was dissolved in EtOAc(25 mL), dried over anhydrous MgSO.sub.4, filtered, and the solventwas removed under reduced pressure. The crude product was purifiedby preparative TLC on a 2000 .mu.m SiO.sub.2 plate developed withEtOAc/hexanes, 1:9 v/v, yielding 86 mg (50%) of the title compound..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.37 (d, J=1.8 Hz, 1H),7.79 (d, J=7.8 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.62 (t, J=7.3 Hz,1H), 7.55 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.84 (br. s.,2H).

C.2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H--benzimidazole-4-carbonitrile hydrochloride

##STR00113##

[0328] The title compound was prepared according to Example 1,steps E through H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.88 (d, J=7.6 Hz, 1H), 7.74-7.81 (m, 1H), 7.71 (s, 2H), 7.64-7.70(m, 1H), 7.53 (d, J=7.6 Hz, 1H), 3.35 (s, 2H), 1.63-1.82 (m, 6H),1.31-1.59 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.19F.sub.3N.sub.4O: 425.2 (M+H). found: 425.2.

Example 10

3-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)-3H--benzimidazol-4-yl]-propan-1-ol hydrochloride (Cpd 22)

##STR00114##

[0329] A.3-(4-Amino-5-nitro-2'-trifluoromethyl-biphenyl-3-yl)-prop-2-yn-1--ol

##STR00115##

[0331] 3-Iodo-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine (466mg, 1.14 mmol, as prepared in Example 9, step A),(Ph.sub.3P).sub.2PdCl.sub.2 (0.05 eq., 40.1 mg, 0.057 mmol), andCuI (0.05 eq., 10.2 mg, 0.054 mmol) were placed in a 40 mL vialequipped with a magnetic stir bar. The vial was evacuated andbackflushed with Ar, and anhydrous THF (6 mL) and TEA (4.0 eq.,0.64 mL, 4.56 mmol) were added via syringe. Propargyl alcohol (4eq., 0.270 mL, 4.56 mmol) was added via syringe, and the reactionwas stirred at RT for 16 h. The solution was diluted with EtOAc (20mL) and filtered. The solvent was removed under reduced pressure,and the crude product was purified by column chromatography on a24-g SiO.sub.2 pre-packed column eluting with EtOAc/hexanes, 0:1 to3:2, v/v over 20 min, yielding 279 mg (73%) of the title compound..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.10 (d, J=2.0 Hz, 1H),7.73 (d, J=7.6 Hz, 1H), 7.53-7.59 (m, 1H), 7.53 (d, J=1.8 Hz, 1H),7.43-7.51 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.82 (br. s., 2H), 4.59(s, 2H).

B. 3-(4,5-Diamino-2'-trifluoromethyl-biphenyl-3-yl)-propan-1-ol

##STR00116##

[0333]3-(4-Amino-5-nitro-2'-trifluoromethyl-biphenyl-3-yl)-prop-2-yn-1-ol(148 mg, 0.440 mmol, as prepared in the previous step) was placedin an 8 mL vial equipped with a magnetic stir bar, and dry EtOH (2mL) was added via syringe. To the ethanol solution was added 10% Pdon activated carbon (27 mg), and the vial was capped with a rubberseptum. Hydrogen gas was bubbled through the stirred solution for 3min, and the reaction was stirred under an atmosphere of H.sub.2 at1 atm for 16 h. The vial was vented, the reaction was filtered, andthe filter was washed three times with MeOH (5 mL). The solvent wasremoved under reduced pressure to give 101 mg (73%) of the desiredcompound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.68 (d, J=7.6Hz, 1H), 7.48 (t, J=7.3 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.30 (d,J=7.6 Hz, 1H), 6.61 (s, 1H), 6.60 (s, 1H), 3.65 (t, J=5.9 Hz, 2H),3.48 (br. s., 4H), 2.66 (t, J=7.3 Hz, 2H), 1.86 (quin, J=6.6 Hz,2H).

C.5-[3-(tert-Butyl-dimethyl-silanoxy)-propyl]-2'-trifluoromethyl-biphenyl--3,4-diamine

##STR00117##

[0335] 3-(4,5-Diamino-2'-trifluoromethyl-biphenyl-3-yl)-propan-1-ol(101 mg, 0.324 mmol, as prepared in the previous step) was placedin an 8 mL vial equipped with a magnetic stir bar, and DCM (2 mL)was added via pipette. Imidazole (1.1 eq., 24.5 mg, 0.356 mmol) andTBSCl (1.1 eq., 53.7 mg, 0.356 mmol) were added sequentially assolids, and the reaction was stirred at RT for 2 h. The reactionwas filtered, the precipitate was washed once with DCM (5 mL), andthe filtrate was concentrated under reduced pressure. The crudeproduct was purified by column chromatography on a 24-g SiO.sub.2pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:1, v/v over30 min, yielding 93.2 mg (68%) of the title compound. .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.: 7.69 (d, J=7.8 Hz, 1H), 7.49 (t,J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.61(s, 1H), 6.59 (s, 1H), 3.66 (t, J=5.9 Hz, 2H), 3.52 (br. s., 4H),2.65 (t, J=7.3 Hz, 2H), 1.75-1.87 (m, 2H), 0.91 (s, 9H), 0.07 (s,6H).

D.3-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)--3H-benzimidazol-4-yl]-propan-1-ol hydrochloride

##STR00118##

[0337] The title compound was prepared according to Example 1,steps F through H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.85 (d, J=7.6 Hz, 1H), 7.73 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.6 Hz,1H), 7.48 (d, J=7.3 Hz, 1H), 7.37 (s, 1H), 7.08 (s, 1H), 3.45 (t,J=6.6 Hz, 2H), 3.33 (s, 2H), 3.01 (t, J=7.5 Hz, 2H), 1.79-1.90 (m,2H), 1.61-1.79 (m, 6H), 1.31-1.57 (m, 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.25H.sub.26F.sub.3N.sub.3O.sub.2: 458.2(M+H). found: 458.3.

Example 11

3-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)-3H--benzimidazol-4-yl]-prop-2-en-1-ol (Cpd 25)

##STR00119##

[0338] A.3-(4,5-Diamino-2'-trifluoromethyl-biphenyl-3-yl)-prop-2-en-1-ol

##STR00120##

[0340]3-(4-Amino-5-nitro-2'-trifluoromethyl-biphenyl-3-yl)-prop-2-yn-1-ol(131 mg, 0.390 mmol, as prepared in Example 10, step A) was placedin an 8 mL vial equipped with a magnetic stir bar, and EtOH (4 mL)was added via syringe followed by water (1 mL). Ammonium chloride(10 eq., 209 mg, 3.90 mmol) and Fe powder (5 eq., 109 mg, 1.95mmol) were added as solids. The vial was tightly capped, placed ina heated block, and stirred at 80.degree. C. for 16 h. The reactionwas cooled to RT, filtered, and the solids were washed three timeswith MeOH (5 mL). The filtrate was concentrated under reducedpressure, the residue was dissolved in EtOAc (20 mL) and washedwith water (20 mL), and the aqueous layer was extracted three timeswith EtOAc (10 mL). The combined organic extracts were washed withbrine (20 mL), dried over anhydrous MgSO.sub.4, filtered, and thesolvent was removed under reduced pressure, yielding 95 mg of thetitle compound as a 1:1 mixture with3-(4,5-diamino-2'-trifluoromethylbiphenyl-3-yl)-prop-2-yn-1-ol. Themixture was carried through to the next step.

B.5-[3-(tert-Butyldimethylsilanoxy)-propenyl]-2'-trifluoromethylbiphenyl--3,4-diamine

##STR00121##

[0342] The procedure described in Example 10, step C was used withthe crude mixture of3-(4,5-diamino-2'-trifluoromethyl-biphenyl-3-yl)-prop-2-en-1-ol and3-(4,5-diamino-2'-trifluoromethylbiphenyl-3-yl)-prop-2-yn-1-ol. Thecrude product was purified by preparative TLC on a 2000 .mu.mSiO.sub.2 plate developed with EtOAc/hexanes, 1:4 v/v, yielding55.6 mg (43% over two steps) of the title compound. .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.: 7.72 (d, J=7.8 Hz, 1H), 7.51 (t,J=7.6 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.65(s, 1H), 6.52 (s, 1H), 6.45 (d, J=11.4 Hz, 1H), 5.95 (dt, J=11.6,6.1 Hz, 1H), 4.31 (dd, J=6.3, 1.0 Hz, 2H), 0.87 (s, 9H), 0.02 (s,6H).

C.3-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)--3H-benzimidazol-4-yl]-prop-2-en-1-ol

##STR00122##

[0344] The title compound was prepared according to Example 1,steps F and G. .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.: 7.80(d, J=7.8 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H),7.44 (d, J=7.6 Hz, 1H), 7.58-7.35 (br. m, 1H), 6.77-7.16 (m, 2H),6.08 (dt, J=11.7, 6.7 Hz, 1H), 4.32 (d, J=6.6 Hz, 2H), 1.67-1.91(m, 6H), 1.43-1.65 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd.for C.sub.25H.sub.24F.sub.3N.sub.3O.sub.2: 456.2 (M+H). found:456.1.

Example 12

3-[5-(2-Fluoro-6-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene (Cpd 6)

##STR00123##

[0345] A.2'-Fluoro-3-nitro-6'-trifluoromethyl-biphenyl-4-ylamine

##STR00124##

[0347] Using the procedure for step A in Example 4, the titlecompound was prepared from1-bromo-2-fluoro-6-trifluoromethylbenzene (0.850 mL, 6.09 mmol) and4-amino-3-nitrophenylboronic acid pinacol ester (1.3 eq., 2.09 g,7.92 mmol) in 89% yield (1.62 g). .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 8.10 (s, 1H), 7.53-7.61 (m, 1H), 7.43-7.53 (m, 1H), 7.35(t, J=8.5 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H),5.47 (br. s., 2H).

B. 2'-Fluoro-6'-trifluoromethyl-biphenyl-3,4-diamine

##STR00125##

[0349] 2'-Fluoro-3-nitro-6'-trifluoromethyl-biphenyl-4-ylamine (754mg, 2.51 mmol, as prepared in the previous step) was placed in a 40mL vial equipped with a magnetic stir bar, then EtOH (20 mL) andwater (5 mL) were added. Ammonium chloride (10 eq., 1.34 g, 25.1mmol) was added as a solid, and then iron powder (5 eq., 701 mg,12.6 mmol) was added. The vial was tightly capped and placed in aheating block where the reaction was stirred at 80.degree. C. for14 h. The reaction was cooled to rt, poured into water, andextracted three times with EtOAc (40 mL). The combined organicextracts were dried over anhydrous MgSO.sub.4, filtered, and thesolvent was removed under reduced pressure to give 662 mg (98%) ofthe title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.52(d, J=7.8 Hz, 1H), 7.39 (td, J=7.9, 5.7 Hz, 1H), 7.25-7.32 (m, 1H),6.71-6.77 (m, 1H), 6.60-6.67 (m, 2H), 3.45 (br. s., 4H).

C.3-[5-(2-Fluoro-6-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2--aza-spiro[4.5]dec-2-ene

##STR00126##

[0351] The procedures described in Example 1, steps F and G wereused to prepare the title compound. .sup.1H-NMR (400 MHz,d.sub.6-DMSO+d.sub.1-TFA) .delta.: 7.63-7.77 (m, 4H), 7.57 (s, 1H),7.23 (d, J=8.3 Hz, 1H), 3.31 (s, 2H), 1.63-1.85 (m, 6H), 1.34-1.59(m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.19F.sub.4N.sub.3O: 418.2 (M+H). found: 418.2.

Example 13

2-{2-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-1H-benzimidazol-5-yl]-phenyl-}-propan-2-ol (Cpd 18)

##STR00127##

[0352] A.3-(5-Bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene

##STR00128##

[0354] The title compound was prepared from1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (283 mg, 1.55mmol, as prepared in Example 1, step B) and4-bromobenzene-1,2-diamine (1.3 eq., 377 mg, 2.02 mmol) in 68%overall yield (299 mg) according to the procedures described inExample 1, steps F and G. .sup.1H-NMR (400 MHz, d.sub.4-MeOH).delta.: 7.74 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.8Hz, 1H), 3.25 (s, 2H), 1.69-1.88 (m, 6H), 1.43-1.63 (m, 4H).

B.2-{2-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-1H-benzimidazol-5-yl]-phe-nyl}-propan-2-ol

##STR00129##

[0356] Using the procedure for step D in Example 1, the titlecompound was prepared from3-(5-bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene(150 mg, 0.449 mmol, as prepared in the previous step) and3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (2.0 eq., 145 mg, 0.898mmol, prepared as described in US2007/259936) and(dppf)PdCl.sub.2.DCM (0.10 eq., 36.6 mg, 0.045 mmol) in 9% yield(16.4 mg). .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.: 7.82 (dd,J=8.1, 1.3 Hz, 1H), 7.53-7.68 (m, 1H), 7.47 (br. s., 1H), 7.35 (td,J=7.6, 1.6 Hz, 1H), 7.19-7.24 (m, 2H), 7.05 (dd, J=7.6, 1.3 Hz,1H), 3.28 (s, 2H), 1.69-1.90 (m, 6H), 1.46-1.65 (m, 4H), 1.33 (s,6H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.24H.sub.27N.sub.3O.sub.2: 390.2 (M+H). found: 390.4.

Example 14

2-[5-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-3-oxa-1-aza-spiro[4-.5]dec-1-ene (Cpd 2)

##STR00130##

[0357] A. (4-Bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acidtert-butyl ester

##STR00131##

[0359] 4-Bromo-benzene-1,2-diamine (1.87 g, 10.0 mmol) was placedin a 100 mL round-bottom flask equipped with a magnetic stir bar.DCM (50 mL), solid BOC-anhydride (5.46 g, 25.0 mmol) and 2.5 Maqueous NaOH (10 mL) were added. The mixture was stirred at rt for3 d. The mixture was diluted with water and extracted three timeswith DCM (20 mL). The combined organic extracts were dried overMgSO.sub.4, filtered, and the solvent was removed under reducedpressure. The residue was chromatographed on a 50-g pre-packedSiO.sub.2 column, eluting with EtOAc/hexanes, 1:9, v/v to afford3.40 g (88%) of the title compound.

B.(3-tert-Butoxycarbonylamino-2'-trifluoromethoxy-biphenyl-4-yl)-carbamicacid tert-butyl ester

##STR00132##

[0361] The title compound was prepared from(4-bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acidtert-butyl ester (as prepared in the previous step) and2-trifluoromethoxyphenylboronic acid according to the proceduredescribed in Example 1, step D. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 7.59 (br. s., 2H), 7.37-7.42 (m, 1H), 7.26-7.34 (m, 3H),7.24 (dd, J=8.3, 2.0 Hz, 1H), 7.00 (br. s., 1H), 6.94 (br. s., 1H),1.52 (s, 9H), 1.50 (s, 9H).

C.2-Trichloromethyl-5-(2-trifluoromethoxy-phenyl)-1H-benzimidazole

##STR00133##

[0363](3-tert-Butoxycarbonylamino-2'-trifluoromethoxy-biphenyl-4-yl)-carb-amic acid tert-butyl ester (573 mg, 1.22 mmol, as prepared in theprevious step) was placed in a mL vial equipped with a magneticstir bar. DCM (10 mL) and TFA (5 mL) were added, and the mixturestirred at rt for 12 h. The solvent was removed under reducedpressure, and the residue was dissolved in DCM and washed with 2Maq NaOH. The organic extract was dried over MgSO.sub.4 andconcentrated in vacuo. The residue was dissolved in AcOH (5 mL) andplaced in an 8 mL vial equipped with a magnetic stir bar. Themixture was cooled to 0.degree. C., treated withmethyl-2,2,2-trichloroacetimidate (0.167 mL, 1.35 mmol) viasyringe, and stirred at rt for 3 days. The solvent was removedunder reduced pressure. The crude product was purified by columnchromatography using a 12-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min, yielding 409 mg(85%) of the desired compound. .sup.1H-NMR (400 MHz, d.sub.4-MeOH).delta.: 7.71-7.77 (m, 2H), 7.52-7.57 (m, 1H), 7.39-7.51 (m,4H).

D. (1-Amino-cyclohexyl)-methanol

##STR00134##

[0365] LiAlH.sub.4 powder (2.28 g, 60.0 mmol) was placed in a 200mL round-bottom flask equipped with a magnetic stir bar. The flaskwas evacuated and backflushed with Ar, cooled to 0.degree. C., andcharged with dry THF (10 mL) via cannula.1-Amino-cyclohexylcarboxylic acid (2.86 g, 20.0 mmol) was added insmall portions as a solid. Upon completion of the addition, themixture was heated to reflux for 12 h. The mixture was cooled to0.degree. C., treated slowly with satd aq Na.sub.2 CO.sub.3 (50mL), warmed to rt, and stirred for 2 h. A white precipitate formed,which was separated by filtration, washed with THF (75 mL), andwashed twice with EtOAc (100 mL). The filtrate was concentrated invacuo. The residue was dissolved in DCM (50 mL), dried overNa.sub.2 SO.sub.4, and concentrated in vacuo to afford 2.80 g (97%)of the title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:3.33 (s, 2H), 1.45-1.56 (m, 6H), 1.31-1.45 (m, 4H).

E.2-[5-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-3-oxa-1-aza-spir-o[4.5]dec-1-ene

[0366]2-Trichloromethyl-5-(2-trifluoromethoxy-phenyl)-1H-benzimidazole(241 mg, 0.610 mmol, as prepared in step B of this Example) and(1-amino-cyclohexyl)-methanol (315 mg, 2.44 mmol, as prepared inthe previous step) were placed in a 40 mL vial equipped with amagnetic stir bar. Water (8 mL) was added, and the mixture wascooled to 0.degree. C. and stirred at that temperature for 1 h.Complete dissolution of starting materials did not occur, so themixture was warmed to rt, treated with dioxane (8 mL), and stirredat rt for 14 h. The mixture was extracted three times with EtOAc(20 mL). The combined organic extracts were dried over MgSO.sub.4and concentrated in vacuo. The crude product was purified by columnchromatography using a 12-g SiO.sub.2 pre-packed column elutingwith EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min. The column wasrepeated under these conditions, yielding 24.6 mg (10%) of thedesired compound. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.78(br. s., 1H), 7.46-7.64 (m, 5H), 7.27-7.46 (m, 1H), 4.27 (s, 2H),1.60-1.82 (m, 6H), 1.47-1.58 (m, 1H), 1.33-1.46 (m, 3H).

[0367] Using the procedures described in Example 14, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00006 Cpd Data 32-[5-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-3-aza-spiro[4.5]dec-2-ene .sup.1H-NMR (400 MHz, d.sub.4-MeOH).delta.: 7.74 (br. s., 2H), 7.50-7.56 (m, 1H), 7.37-7.48 (m, 4H),3.82 (s, 2H), 1.78-1.96 (m, 4H), 1.66-1.77 (m, 2H), 1.47-1.62 (m,4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.20F.sub.3N.sub.3O.sub.2: 416.2 (M + H); found: 416.1.4 2-[5-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-3-aza-spiro[4.5]dec-2-ene .sup.1H-NMR (400 MHz, d.sub.4-MeOH).delta.: 7.79 (d, J = 7.8 Hz, 1H), 7.73 (br. s, 1H), 7.65 (t, J =7.2 Hz, 1H), 7.60 (br. s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (d, J= 7.6 Hz, 1H), 7.29 (br. d, J = 6.8 Hz, 1H), 3.84 (s, 2H),1.80-1.98 (m, 4H), 1.69-1.79 (m, 2H), 1.43-1.65 (m, 4H). MassSpectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.20F.sub.3N.sub.3O: 400.2 (M + H); found: 400.1. 52-[5-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-3-oxa-1-aza-spiro[4.5]dec-1-ene .sup.1H-NMR (400 MHz, d.sub.4-MeOH).delta.: 7.79 (d, J = 7.8 Hz, 1H), 7.71 (br. s, 1H), 7.65 (t, J =7.2 Hz, 1H), 7.62 (br. s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 7.29 (d, J = 6.6 Hz, 1H), 4.32 (s, 2H), 1.75-1.94(m, 4H), 1.65-1.75 (m, 2H), 1.41-1.65 (m, 4H). Mass Spectrum (LCMS,ESI pos.): Calcd. for C.sub.22H.sub.20F.sub.3N.sub.3O: 400.2 (M +H); found: 400.2. 192-(1,3-Diaza-spiro[4.5]dec-2-en-2-yl)-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta. (ppm):7.80-7.84 (m, 2H), 7.71 (s, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.60 (t,J = 7.8 Hz, 1H), 7.39-7.47 (m, 2H), 3.99 (s, 2H), 1.76-2.03 (m,6H), 1.45-1.69 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. forC.sub.22H.sub.21F.sub.3N.sub.4: 399.2 (M + H), Found 399.2. 292-[5-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-3,8-dioxa-1-aza-spiro[4.5]dec-1-ene .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.(ppm): 7.79 (d, J = 7.8 Hz, 1H), 7.48-7.79 (m, 4H), 7.42 (d, J =7.6 Hz, 1H), 7.23-7.35 (m, 1H), 4.36 (s, 2H), 3.97-4.09 (m, 2H),3.65-3.78 (m, 2H), 1.78-1.94 (m, 4H). Mass Spectrum (LCMS, ESIpos.) Calcd. for C.sub.21H.sub.18F.sub.3N.sub.3O.sub.2: 402.1 (M +H), Found 402.1.

Example 15

3-[5-(2-Chloro-phenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene hydrochloride (Cpd 30)

##STR00135##

[0368] A.2'-Chloro-5-nitro-3-trifluoromethyl-biphenyl-4-ylamine

##STR00136##

[0370] 4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (1.01 g, 3.55mmol), 2-chlorophenylboronic acid (1.5 eq., 833 mg, 5.33 mmol), and(dppf)PdCl.sub.2.DCM (0.05 eq., 145 mg, 0.178 mmol) were placed ina 40 mL vial equipped with a magnetic stir bar. The vial wasevacuated and backflushed with Ar, and DME (15 mL) and 2M aqNa.sub.2 CO.sub.3 (5 mL) were added via syringe. The vial wascapped tightly and placed in a heating block where the reaction wasstirred at 90.degree. C. for 18 h. The mixture was cooled to rt,diluted with EtOAc, and washed with water. The aqueous layers werecombined and extracted with EtOAc. The combined organic extractswere dried over anhydrous MgSO.sub.4, filtered, and the solvent wasremoved under reduced pressure. The crude product was purified bycolumn chromatography using a 24-g SiO.sub.2 pre-packed columneluting with EtOAc/hexanes, 0 to 1:4, v/v over 20 min, yielding1.05 g (94%) of the desired compound. .sup.1H-NMR (400 MHz,CDCl.sub.3) .delta.: 8.47 (d, J=2.0 Hz, 1H), 7.89 (d, J=2.0 Hz,1H), 7.47-7.53 (m, 1H), 7.30-7.37 (m, 3H), 6.76 (br. s., 2H).

B.3-[5-(2-Chloro-phenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2--aza-spiro[4.5]dec-2-ene

##STR00137##

[0372] 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (611 mg,3.33 mmol, as prepared in Example 1, step B) was placed in a 40 mLvial equipped with a magnetic stir bar. DCM (6 mL) and DMF (1 drop)were added via syringe. To the stirred solution was added oxalylchloride (1.3 eq., 0.367 mL, 4.33 mmol) dropwise via syringe. Aftercompletion of the addition, the reaction was stirred at rt for 1 h.The solvent was removed under reduced pressure, and the resultingresidue was dissolved in dry THF (7 mL).

[0373] 2'-Chloro-5-nitro-3-trifluoromethyl-biphenyl-4-ylamine (1eq., 1.06 g, 3.33 mmol, as prepared in the previous step) wasplaced in a 40 mL vial equipped with a magnetic stir bar. The vialwas evacuated and backflushed with Ar, and dry THF (10 mL) wasadded. The mixture was cooled to 0.degree. C. in an ice bath, andNaH (3 eq., 400 mg, 9.99 mmol, 60% dispersion in oil) was added insmall portions. The above-prepared acid chloride solution was addeddropwise over a period of 10 min to the stirred reaction mixture.The resulting solution was stirred at 0.degree. C. for 30 min thenwarmed to rt and stirred for 16 h. The mixture was quenched withwater and brine, and extracted three times with EtOAc (20 mL). Thecombined organic extracts were dried over anhydrous MgSO.sub.4 andconcentrated under reduced pressure. The residue was dissolved inglacial acetic acid (20 mL) and placed in a 40 mL vial equippedwith a stir bar. Fe powder (5 eq., 930 mg, 16.7 mmol) was added,the vial was capped, and the mixture was stirred at 80.degree. C.for 1 h. The mixture was cooled to rt and poured into ice (100 mL).The precipitate was filtered, and the solid was washed with water,dissolved in EtOAc, dried over anhydrous MgSO.sub.4, andconcentrated under reduced pressure. The crude product was purifiedby column chromatography using a 40-g SiO.sub.2 pre-packed columneluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding1.14 g (79%) of the desired compound. .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 13.52 (br. s., 1H), 7.86 (d, J=7.6 Hz, 1H),7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6 Hz,1H), 7.35 (s, 1H), 7.25 (s, 1H), 3.33 (s, 2H), 1.63-1.82 (m, 6H),1.33-1.59 (m, 4H).

C.3-[5-(2-Chloro-phenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2--aza-spiro[4.5]dec-2-ene hydrochloride

[0374]3-[5-(2-Chloro-phenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-ox-a-2-aza-spiro[4.5]dec-2-ene (1.14 g, 2.63 mmol, as prepared in theprevious step) was placed in a 100 mL round-bottom flask, and EtOAc(10 mL) was added. HCl (1 eq., 2.60 mL, 2.63 mmol, 1 M solution inether) was added via syringe. The solvent was removed under reducedpressure, and the solid was dried under high vacuum for 3 days,yielding 1.12 g (90%) of the desired compound. .sup.1H-NMR (400MHz, d.sub.6-DMSO) .delta.: 7.80 (s, 1H), 7.60-7.66 (m, 1H), 7.59(s, 1H), 7.52-7.58 (m, 1H), 7.43-7.51 (m, 2H), 1.61-1.82 (m, 6H),1.32-1.59 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.19ClF.sub.3N.sub.3O: 434.1 (M+H). found: 434.2.

Example 16

3-[5-(2-Fluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec--2-ene

##STR00138##

[0375] A. 2'-Fluoro-3-nitro-biphenyl-4-ylamine

##STR00139##

[0377] A solution of 4-bromo-2-nitro-phenylamine (2.17 g, 10.0mmol) in dioxane (40 mL) was treated with 2-fluorophenylboronicacid (1.40 g, 10.0 mmol) and NaHCO.sub.3 (40.0 mL, 80.0 mmol, 2Maqueous). The mixture was degassed via sonication and flushed withAr. Pd(PPh.sub.3).sub.4 (116 mg, 0.100 mmol) was added, and themixture was heated to 80.degree. C. for 12 h. The mixture wasdiluted with water (40 mL) and extracted twice with EtOAc (40 mL).The combined organic layers were dried over MgSO.sub.4 andconcentrated in vacuo. The residue was purified on silica(EtOAc/hexanes, 0:1 to 1:1, v/v) to obtain 1.80 g (78%) of thetitle compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.36 (d,J=1.8 Hz, 1H), 7.64 (dt, J=8.6, 2.0 Hz, 1H), 7.45 (td, J=7.8, 1.8Hz, 1H), 7.30-7.38 (m, 1H), 7.13-7.27 (m, 2H), 6.91 (d, J=8.6 Hz,1H), 6.18 (br. s., 2H).

B. 1,8-Dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid ethylester

##STR00140##

[0379] To a well-vented 500 mL three-necked round-bottom flask wasadded methyl triphenylphosphonium bromide/sodium amide mixture("instant ylide", 22.9 g, 5.49 mmol) and dry ether (100 mL). Themixture was stirred at rt for 1 h and filtered through aglass-fritted funnel directly into a solution oftetrahydro-pyran-4-one (5.00 g, 4.99 mmol) in ether (20 mL). Thismixture was stirred at rt for 4 h.Ethyl-2-chloro-2-(hydroxyamino)acetate (8.32 g, 5.49 mmol) in DCM(100 mL) was added dropwise via addition funnel over 3 h, and themixture was stirred for 2.5 days. Water (100 mL) was added, and themixture was extracted three times with DCM (200 mL, 100 mL, 100mL). The combined organic extracts were dried over MgSO.sub.4 andconcentrated in vacuo. The residue was purified on a 200-g Sepra Si50 SPE column (Isco system: Flow rate=30 mL/min;Eluent=EtOAc/heptane, 1:9 v/v for 10 min, then 1:9 to 2:3 v/v over40 min) to afford the title compound (3.00 g, 28%) as a tan oil..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 4.35 (q, J=7.2 Hz, 2H),3.89 (ddd, J=11.8, 8.7, 3.3 Hz, 2H), 3.65-3.75 (m, 2H), 2.99 (s,2H), 1.89-1.97 (m, 2H), 1.76-1.86 (m, 2H), 1.37 (t, J=7.2 Hz,3H).

C. 1,8-Dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid

##STR00141##

[0381] A solution of1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester(3.00 g, 1.41 mmol, as prepared in the previous step) in MeOH (60mL) and water (20 mL) was treated with LiOH (649 mg, 1.55 mmol) atrt for 2.5 h. MeOH was removed in vacuo. The resulting aqueoussolution was acidified with 1 N aq HCl and extracted three timeswith EtOAc (100 mL, 100 mL, 50 mL). The combined organic extractswere dried over MgSO.sub.4 and concentrated in vacuo to afford thetitle compound (2.50 g, 96%) as a white solid. .sup.1H-NMR (400MHz, CDCl.sub.3) .delta.: 3.86-3.95 (m, 2H), 3.74 (dt, J=11.8, 4.7Hz, 2H), 3.01 (s, 2H), 1.91-1.99 (m, 2H), 1.80-1.89 (m, 2H).

D. 1,8-Dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid(2'-fluoro-3-nitro-biphenyl-4-yl)-amide

##STR00142##

[0383] A solution of1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (87.7 mg,0.474 mmol, as prepared in the previous step) in CH.sub.2 Cl.sub.2(10 mL) was treated with oxalyl chloride (41.3 .mu.L, 0.474 mmol)and DMF (1 drop) at rt for 1 h. Simultaneously, a solution of2'-fluoro-3-nitro-biphenyl-4-ylamine (100 mg, 0.431 mmol, asprepared in step A of this Example) in dry THF (10 mL) was treatedwith NaH (51.7 mg, 1.29 mmol, 60% dispersion in oil) at rt for 1 h.The acid chloride solution was concentrated in vacuo, taken up indry THF (10 mL), and slowly added to the2'-fluoro-3-nitro-biphenyl-4-ylamine solution. The mixture wasallowed to stir for 20 min at rt, quenched with satd aq NH.sub.4Cl,diluted with water, and extracted with EtOAc. The combined organicextracts were dried over MgSO.sub.4 and concentrated in vacuo. Theresidue was purified on a 40-g Sepra Si 50 SPE column (Isco system:Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:9 v/v for 10 min, then1:9 to 2:3 v/v over 40 min) to afford the title compound (131 mg,76%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:11.58 (s, 1H), 8.87 (d, J=8.8 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.89(dt, J=8.8, 1.6 Hz, 1H), 7.47 (td, J=7.7, 1.8 Hz, 1H), 7.35-7.44(m, 1H), 7.24-7.31 (m, 1H), 7.20 (ddd, J=10.9, 8.3, 1.0 Hz, 1H),3.92 (ddd, J=11.8, 8.8, 3.2 Hz, 2H), 3.71-3.82 (m, 2H), 3.10 (s,2H), 1.94-2.03 (m, 2H), 1.83-1.93 (m, 2H). Mass Spectrum (LCMS,APCI pos.): Calcd. for C.sub.20H.sub.18FN.sub.3O.sub.5: 400.1(M+H). found: 400.1.

E.3-[5-(2-Fluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]-dec-2-ene

##STR00143##

[0385] A solution of1,8-dioxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid(2'-fluoro-3-nitro-biphenyl-4-yl)-amide (131 mg, 0.327 mmol, asprepared in the previous step) in glacial acetic acid (10 mL) wastreated with Fe powder (91.2 mg, 1.36 mmol) and heated to100.degree. C. under a reflux condenser for 4 h. The pH of themixture was adjusted to 7 with 6M aq NaOH. The resulting aqueousmixture was extracted three times with EtOAc (50 mL), and thecombined organic layers were dried over MgSO.sub.4 and concentratedin vacuo. The residue was purified on a 40-g Sepra Si 50 SPE column(Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:9 v/vfor 10 min, then 1:9 to 2:3 v/v over 40 min) to afford the titlecompound (98.8 mg, 86%) as an off-white solid. .sup.1H-NMR (400MHz, CDCl.sub.3) .delta.: 7.78-7.90 (m, 1H), 7.55-7.68 (m, 1H),7.46-7.54 (m, 2H), 7.29-7.39 (m, 1H), 7.14-7.26 (m, 2H), 3.97 (ddd,J=11.7, 8.1, 3.4 Hz, 2H), 3.70-3.81 (m, 2H), 3.47 (s, 2H),1.99-2.08 (m, 3H), 1.87-1.98 (m, 2H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.20H.sub.18FN.sub.3O.sub.2: 352.1 (M+H).found: 352.2.

F.3-[5-(2-Fluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]-dec-2-ene hydrochloride

[0386] A solution of3-[5-(2-fluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]de-c-2-ene (98.8 mg, 0.281 mmol, as prepared in the previous step) inEtOH (5 mL) was treated with HCl (56.2 .mu.L, 0.281 mmol, 5 M inisopropanol) at rt for 2 h. The mixture was concentrated in vacuoand the residue was dissolved in a minimum amount of EtOH (2.5 mL)with sonication and heating. The solution was cooled to rt, andhexanes were added dropwise until the solution became cloudy. Thesolution was allowed to sit for 2 min then was treated withadditional hexanes. The resulting precipitate was filtered, washedwith hexanes, and air-dried to afford the title compound (63.7 mg,58%) as a white solid. .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.:7.85 (s, 1H), 7.77-7.83 (m, 1H), 7.70-7.77 (m, 1H), 7.46-7.53 (m,1H), 7.32-7.41 (m, 1H), 7.21-7.27 (m, 1H), 7.13-7.21 (m, 1H),3.78-3.88 (m, 2H), 3.63-3.73 (m, 2H), 3.32-3.36 (m, 2H), 1.85-1.98(m, 4H). Mass Spectrum (LCMS, APCI pos.): Calcd. forC.sub.20H.sub.18FN.sub.3O.sub.2: 352.1 (M+H). found: 352.3.

[0387] Using the procedures described in Example 16, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00007 Cpd Data 323-[7-Methyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.74 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.6Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 7.6Hz, 1H), 7.30 (s, 1H), 3.83 (ddd, J = 11.8, 7.3, 4.7 Hz, 2H), 3.68(dt, J = 11.8, 4.8 Hz, 2H), 3.36 (s, 2H), 2.63 (s, 3H), 1.86-1.96(m, 4H). 333-[7-Bromo-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride Ex 7, step A butbrominated with NBS) .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.:7.75 (d, J = 7.8 Hz, 1H), 7.59-7.65 (m, 1H), 7.50-7.59 (m, 3H),7.37 (d, J = 7.6 Hz, 1H), 3.77-3.88 (m, 2H), 3.62-3.72 (m, 2H),3.36 (s, 2H), 1.84-1.93 (m, 4H). Mass Spectrum (LCMS, APCI pos.):Calcd. for C.sub.21H.sub.17BrF.sub.3N.sub.3O.sub.2: 480.1 (M + H);found: 480.2. 343-[7-Chloro-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.74 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.3Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.47 (br. s., 1H), 7.37 (d, J =6.8 Hz, 2H), 3.78-3.87 (m, 2H), 3.67 (dt, J = 11.8, 4.8 Hz, 2H),3.35 (s, 2H), 1.83-1.93 (m, 4H). Mass Spectrum (LCMS, APCI pos.):Calcd. for C.sub.21H.sub.17ClF.sub.3N.sub.3O.sub.2: 436.1 (M + H);found: 436.3. 352-(1,8-Dioxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl-)- 3H-benzimidazole-4-carbonitrile hydrochloride .sup.1H-NMR (400MHz, d.sub.4-MeOH) .delta.: 7.74 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H),7.57-7.65 (m, 1H), 7.49-7.56 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H),3.81 (dt, J = 11.8, 5.8 Hz, 2H), 3.63-3.72 (m, 2H), 3.36 (s, 2H),1.85 (t, J = 5.4 Hz, 4H). Mass Spectrum (LCMS, APCI pos.): Calcd.for C.sub.22H.sub.17F.sub.3N.sub.4O.sub.2: 427.1 (M + H); found:427.2. 368,8-Dimethyl-3-[5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.71-7.77 (m, 2H), 7.58-7.65 (m, 2H),7.50-7.57 (m, 1H), 7.46 (dd, J = 8.6, 1.0 Hz, 1H), 7.36 (d, J = 7.6Hz, 1H), 3.24 (s, 2H), 1.82-1.93 (m, 2H), 1.71-1.81 (m, 2H), 1.55(ddd, J = 13.5, 9.1, 4.2 Hz, 2H), 1.26-1.36 (m, 2H), 0.93 (d, J =3.5 Hz, 6H). Mass Spectrum (LCMS, APCI pos.): Calcd. forC.sub.24H.sub.24F.sub.3N.sub.3O: 428.2 (M + H); found: 428.3. 373-[5-(Chloro-phenyl)-1H-benzimidazol-2-yl]-8,8-dimethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.78 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 7.60(d, J = 8.6 Hz, 1H), 7.45-7.49 (m, 1H), 7.30-7.39 (m, 3H), 3.25 (s,2H), 1.84-1.92 (m, 2H), 1.72-1.81 (m, 2H), 1.56 (ddd, J = 13.5,9.1, 4.2 Hz, 2H), 1.26-1.35 (m, 2H), 0.93 (d, J = 3.5 Hz, 6H). MassSpectrum (LCMS, ESI pos.): Calcd. for C.sub.23H.sub.24ClN.sub.3O:393.2 (M + H); found: 393.3. 383-[5-(2,6-Difluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.82 (dd, J = 8.6, 0.8 Hz, 1H), 7.79 (s,1H), 7.63 (dd, J = 8.6, 1.5 Hz, 1H), 7.39 (tt, J = 8.5, 6.4 Hz,1H), 7.06 (t, J = 8.2 Hz, 2H), 3.78-3.88 (m, 2H), 3.64-3.73 (m,2H), 3.34 (s, 2H), 1.86-1.95 (m, 4H). 398,8-Dimethyl-3-[7-trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride.sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.: 7.74 (d, J = 7.6 Hz,1H), 7.65 (s, 1H), 7.57-7.64 (m, 1H), 7.49-7.55 (m, 1H), 7.41 (s,1H), 7.37 (d, J = 7.6 Hz, 1H), 3.27 (s, 2H), 1.76-1.86 (m, 2H),1.66-1.76 (m, 2H), 1.53 (ddd, J = 13.3, 8.9, 4.3 Hz, 2H), 1.25-1.35(m, 2H), 0.92 (d, J = 2.5 Hz, 6H). Mass Spectrum (LCMS, APCI pos.):Calcd. for C.sub.25H.sub.23F.sub.6N.sub.3O: 496.2 (M + H); found:496.3. 403-[5-(2-Chloro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.76-7.82 (m, 1H), 7.72-7.75 (m, 1H), 7.61(dd, J = 8.6, 1.5 Hz, 1H), 7.44-7.50 (m, 1H), 7.29-7.40 (m, 3H),3.78-3.88 (m, 2H), 3.63-3.73 (m, 2H), 3.35 (s, 2H), 1.87-1.95 (m,4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.20H.sub.18ClN.sub.3O: 368.1 (M + H); found: 368.2. 413-[7-Chloro-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-8,8-dimethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR(400 MHz, d.sub.4-MeOH) .delta.: 7.69-7.83 (m, 2H), 7.44-7.67 (m,2H), 7.25-7.42 (m, 2H), 3.26 (s, 2H), 1.61-1.86 (m, 4H), 1.44-1.58(m, 2H), 1.21-1.35 (m, 2H), 0.85-0.95 (m, 6H). Mass Spectrum (LCMS,ESI pos.): Calcd. for C.sub.24H.sub.23ClF.sub.3N.sub.3O: 462.2 (M +H); found: 462.3. 423-[7-Trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride .sup.1H-NMR(400 MHz, d.sub.4-MeOH) .delta.: 7.76 (d, J = 7.6 Hz, 1H), 7.72 (s,1H), 7.59-7.65 (m, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H),7.39 (d, J = 7.6 Hz, 1H), 3.78-3.86 (m, 2H), 3.63-3.72 (m, 2H),3.37 (s, 2H), 1.82-1.91 (m, 4H). Mass Spectrum (LCMS, ESI pos.):Calcd. for C.sub.22H.sub.17F.sub.6N.sub.3O.sub.2: 470.1 (M + H);found: 470.2.

Example 17

2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-5-(2-trifluoromethyl-phenyl)-1H-im-idazo[4,5-b]pyridine hydrochloride (Cpd 56)

##STR00144##

[0388] A.3-Nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine

##STR00145##

[0390] To a solution of 6-chloro-2-nitro-pyridin-3-ylamine (143 mg,1.00 mmol), 2-trifluoromethylphenylboronic acid (285 mg, 1.50 mmol)and K.sub.3PO.sub.4 (424 mg, 2.00 mmol) in toluene (5 mL) wereadded S-Phos (16.4 mg, 0.040 mmol) and Pd(OAc).sub.2 (4.49 mg,0.020 mmol). The resulting mixture was stirred at 90.degree. C.under Ar for 4 h. The reaction mixture was allowed to cool to rt,diluted with EtOAc (20 mL) and filtered through a pad of Celite.The filtrate was concentrated, and the resulting residue waspurified on silica (EtOAc/hexanes, 0:1 to 1:1 v/v) to obtain thetitle compound (130 mg, 46%). .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 8.39 (d, J=8.3 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.46-7.62(m, 2H), 7.39 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H).

B. 6-(2-Trifluoromethyl-phenyl)-pyridine-2,3-diamine

##STR00146##

[0392] To a solution of2-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-ylamine (130 mg,0.460 mmol, as prepared in the previous step) in EtOH (10 mL), 10%Pd/C (60 mg) was added. The resulting mixture was hydrogenated at50 psi for 3 h. The reaction mixture was filtered through a pad ofCelite, and the filtrate was concentrated in vacuo to obtain thetitle compound, which was directly used in the next step withoutfurther purification. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:7.62 (d, J=7.8 Hz, 1H), 7.41-7.49 (m, 1H), 7.29-7.41 (m, 2H), 6.81(d, J=7.8 Hz, 1H), 6.64 (d, J=7.8 Hz, 1H), 4.31 (br. s., 2H), 3.34(br. s., 2H).

C. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid[2-amino-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide

##STR00147##

[0394] The title compound was prepared from6-(2-trifluoromethyl-phenyl)-pyridine-2,3-diamine (as prepared inthe previous step) according to the procedure described in Example16, step D. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.26 (s,1H), 7.70-7.76 (m, 2H), 7.55-7.61 (m, 1H), 7.45-7.52 (m, 2H), 6.87(d, J=7.8 Hz, 1H), 4.72 (s, 2H), 3.03 (s, 2H), 1.75-1.88 (m, 5H),1.66-1.75 (m, 2H), 1.48 (br. s., 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.21H.sub.21F.sub.3N.sub.4O.sub.2: 419.2(M+H). found: 419.2.

D.2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-5-(2-trifluoromethyl-phenyl)-1H--imidazo[4,5-b]pyridine hydrochloride

[0395] The title compound was prepared from1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid[2-amino-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide (asprepared in the previous step) according to the proceduresdescribed in Example 16, steps E and F, except that the iron powderin step E was omitted. .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.:8.08 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.69-7.76 (m, 1H),7.61-7.68 (m, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H),3.32 (s, 2H), 1.72-1.90 (m, 6H), 1.47-1.65 (m, 4H). Mass Spectrum(LCMS, ESI pos.): Calcd. for C.sub.21H.sub.19F.sub.3N.sub.4O: 401.2(M+H). found: 401.2.

Example 18

2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-im-idazo[4,5-c]pyridine hydrochloride (Cpd 57)

##STR00148##

[0396] A.4-Nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-ylamine

##STR00149##

[0398] The title compound was prepared from5-bromo-3-nitro-pyridin-2-ylamine (patent application WO2005037197) and 2-trifluoromethylphenylboronic acid according tothe procedure described in Example 17, step A. .sup.1H-NMR (400MHz, CDCl.sub.3) .delta.: 9.26 (s, 1H), 7.77 (d, J=7.8 Hz, 1H),7.59-7.66 (m, 1H), 7.52-7.59 (m, 1H), 7.48 (d, J=7.6 Hz, 1H), 6.79(s, 1H).

B. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid[4-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide

##STR00150##

[0400] The title compound was prepared from4-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-ylamine (as preparedin the previous step) and1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared inExample 1, step B) according to the procedure described in Example16, step D. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 9.45 (s,1H), 8.93 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.1 Hz, 1H),7.59 (t, J=7.5 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 2.97 (s, 2H),1.73-1.90 (m, 5H), 1.62-1.73 (m, 3H), 1.40-1.54 (m, 2H). MassSpectrum (LCMS, ESI pos.): Calcd. forC.sub.21H.sub.19F.sub.3N.sub.4O.sub.4: 449.1 (M+H). found:449.2.

C.2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H--imidazo[4,5-c]pyridine hydrochloride

[0401] The title compound was prepared from1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid[4-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide (asprepared in the previous step) according to the proceduresdescribed in Example 16, steps E and F. .sup.1H-NMR (400 MHz,CDCl.sub.3) .delta.: 8.94 (s, 1H), 7.84 (d, J=7.6 Hz, 1H),7.69-7.76 (m, 1H), 7.60-7.68 (m, 2H), 7.56 (d, J=7.3 Hz, 1H), 4.56(s, 2H), 1.73-1.90 (m, 6H), 1.48-1.66 (m, 4H). Mass Spectrum (LCMS,ESI pos.): Calcd. for C.sub.21H.sub.19F.sub.3N.sub.4O: 401.2 (M+H).found: 401.2.

[0402] Using the procedures described in Example 18, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00008 Cpd Data 582-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-b]pyridine hydrochloride .sup.1H-NMR (400MHz, d.sub.4-MeOH/CDCl.sub.3) .delta.: 8.28 (br. s., 1H), 7.73 (d,J = 7.6 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz,1H), 7.39 (s, 1H), 7.33 (d, J = 7.6 Hz, 1H), 3.23 (s, 2H),1.64-1.83 (m, 7H), 1.40-1.52 (m, 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.21H.sub.19F.sub.3N.sub.4O: 401.2 (M + H);found: 401.3.

Example 19

3-[7-Methyl-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro-[4.5]dec-2-ene hydrochloride (Cpd 48)

##STR00151##

[0403] A. 3-Dimethoxymethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene

##STR00152##

[0405] To a 40 mL vial equipped with a magnetic stir bar was addedDMF (10 mL) and dimethoxy-acetaldehyde (1.50 mL, 10.0 mmol).Aqueous hydroxylamine (0.640 mL, 10.5 mmol) was added via syringe,and the mixture was stirred for 2 h at rt. NCS (1.40 g, 10.5 mmol)was added in small portions as a solid. The mixture was stirred anadditional 1 h at rt, diluted with DCM (40 mL), dried overMgSO.sub.4, and filtered. The solid was washed with DCM. Thefiltrate was diluted to a volume of 100 mL and transferred to two60 mL syringes. Methylene-cyclohexane (2.40 mL, 20.0 mmol), DIPEA(1.92 mL, 11.0 mmol), and DCM (10 mL) were placed in a 200 mLround-bottom flask equipped with a magnetic stir bar. Theabove-prepared chlorooxime solution was added dropwise with asyringe pump at a rate of 0.0774 mL/min until the addition wascomplete. The mixture stirred at rt for 3 days, and the solvent wasremoved under reduced pressure. The residue was dissolved in water(50 mL) and extracted three times with hexanes (25 mL). Thecombined organic extracts were dried over MgSO.sub.4 andconcentrated in vacuo. The material was used in the next stepwithout purification.

B. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde

##STR00153##

[0407] 3-Dimethoxymethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene (1.06 g,4.97 mmol, as prepared in the previous step) was placed in a 50 mLround-bottom flask equipped with a stir bar. Acetone (20 mL), water(0.3 mL), and Amberlyst-15 resin (200 mg) were added. The mixturewas stirred at rt for 24 h. The solids were removed by filtrationand rinsed with acetone (20 mL), and the solvent was removed underreduced pressure. The residue was purified by column chromatographyusing a 40-g SiO.sub.2 pre-packed column eluting withEtOAc/heptane, 0:1 to 3:2, v/v over 30 min, yielding 451 mg (54%)of the desired compound. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:9.90 (s, 1H), 2.81 (s, 2H), 1.72-1.87 (m, 4H), 1.58-1.69 (m, 2H),1.40-1.53 (m, 4H).

C. 2',6'-Difluoro-5-methyl-biphenyl-3,4-diamine

##STR00154##

[0409] The title compound was prepared from2-methyl-6-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyla-mine (as prepared in Example 8, step A) and2-bromo-1,3-difluoro-benzene according to the procedures describedin Example 4, step A and Example 1, step E. .sup.1H-NMR (400 MHz,CDCl.sub.3) .delta.: 7.17 (tt, J=8.3, 6.3 Hz, 1H), 6.87-6.97 (m,2H), 6.76 (s, 1H), 6.72 (s, 1H), 3.44 (br. s., 4H), 2.21 (s,3H).

D.3-[7-Methyl-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-sp-iro[4.5]dec-2-ene

##STR00155##

[0411] 2',6'-Difluoro-5-methyl-biphenyl-3,4-diamine (186 mg, 0.792mmol, as prepared in the previous step) was placed in an 8 mL vialequipped with a stir bar, and dry DMF (2 mL) was added.1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (122 mg, 0.730 mmol,as prepared in step B of this Example) was added as a solution inDMF (2 mL). Solid Na.sub.2S.sub.2O.sub.5 (153 mg, 0.803 mmol) wasadded, and the mixture was heated to 100.degree. C. for 4 h. Thecooled mixture was poured into water (100 mL) and extracted threetimes with EtOAc (50 mL). The combined organic extracts were driedover MgSO.sub.4, filtered, and the solvents were removed underreduced pressure. The residue was purified by column chromatographyusing a 4-g SiO.sub.2 pre-packed column eluting with EtOAc/hexanes,0:1 to 3:17, v/v over 30 min, yielding 105 mg (38%) of the titlecompound. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.: 7.43-7.55(m, 2H), 7.15-7.30 (m, 3H), 3.35 (s, 2H), 2.61 (s, 3H), 1.63-1.83(m, 6H), 1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd.for C.sub.22H.sub.21F.sub.2N.sub.3O: 382.2 (M+H). found: 382.2.

E.3-[7-Methyl-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-sp-iro[4.5]dec-2-ene hydrochloride

[0412] The title compound was prepared from3-[7-methyl-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spir-o[4.5]dec-2-ene (as prepared in the previous step) according to theprocedure described in Example 1, step H. .sup.1H-NMR (400 MHz,CDCl.sub.3) 6: .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.43-7.55 (m, 2H), 7.15-7.30 (m, 3H), 3.35 (s, 2H), 2.61 (s, 3H),1.63-1.83 (m, 6H), 1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.22H.sub.21F.sub.2N.sub.3O: 382.2 (M+H).found: 382.2.

Example 20

3-[7-Methyl-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5-]dec-2-ene hydrochloride (Cpd 47)

##STR00156##

[0413] A. 2'-Fluoro-5-methyl-biphenyl-3,4-diamine

##STR00157##

[0415] The title compound was prepared from4-bromo-2-methyl-6-nitro-phenylamine and2-(2-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane usingthe procedures described in Example 1, steps D and E. .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.: 7.36 (td, J=7.8, 1.9 Hz, 1H),7.16-7.23 (m, 1H), 7.03-7.15 (m, 2H), 6.84 (s, 1H), 6.79-6.82 (m,1H), 3.47 (br. s., 4H), 2.20 (s, 3H).

B.3-[7-Methyl-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[-4.5]dec-2-ene

##STR00158##

[0417] 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (167 mg, 1.00mmol, as prepared in Example 19, step B) was placed in a 25 mLround-bottom flask equipped with a magnetic stir bar.2'-Fluoro-5-methyl-biphenyl-3,4-diamine (218 mg, 1.01 mmol, asprepared in the previous step) was added as a solution in EtOH (10mL). The flask was fitted with a reflux condenser (top open toair), and the mixture was heated to 80.degree. C. for 6 h. Thecooled mixture was concentrated under reduced pressure. The residuewas purified by column chromatography using a 40-g SiO.sub.2pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over30 min, yielding 159 mg (44%) of the title compound. .sup.1H-NMR(400 MHz, CDCl.sub.3) .delta.: 7.57 (br. s., 1H), 7.50 (td, J=7.8,1.9 Hz, 1H), 7.31-7.37 (m, 1H), 7.08-7.28 (m, 4H), 2.64 (s, 3H),2.31 (s, 2H), 1.69-1.89 (m, 6H), 1.47-1.64 (m, 4H).

C.3-[7-Methyl-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[-4.5]dec-2-ene hydrochloride

[0418] The title compound was prepared from3-[7-methyl-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.-5]dec-2-ene (as prepared in the previous step) according to theprocedure described in Example 1, step H. .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.54-7.65 (m, 2H), 7.39-7.49 (m, 1H),7.28-7.38 (m, 3H), 3.36 (s, 2H), 2.63 (s, 3H), 1.65-1.82 (m, 6H),1.32-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.22H.sub.22FN.sub.3O: 364.2 (M+H). found: 364.2.

Example 21

3-[7-Methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene hydrochloride (Cpd 46)

##STR00159##

[0419] A. 5-Methyl-2'-trifluoromethyl-biphenyl-3,4-diamine

##STR00160##

[0421] The title compound was prepared from4-bromo-2-methyl-6-nitro-phenylamine and4,4,5,5-tetramethyl-2-(2-trifluoromethyl-phenyl)-[1,3,2]dioxaborolaneaccording to the procedures described in Example 1, steps D and E..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.68 (d, J=7.8 Hz, 1H),7.47 (t, J=7.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz,1H), 6.59 (s, 1H), 6.61 (s, 1H), 3.41 (br. s., 4H), 2.19 (s,3H).

B.3-[7-Methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za-spiro[4.5]dec-2-ene

##STR00161##

[0423] 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (135 mg,0.807 mmol, as prepared in Example 19, step B) was placed in a 4 mLvial equipped with a magnetic stir bar. 40% Aqueous NaHSO.sub.3(0.8 mL) was added via syringe, and the mixture stirred at rt for 2h. 5-Methyl-2'-trifluoromethyl-biphenyl-3,4-diamine (246 mg, 0.923mmol, as prepared in the previous step) was placed in an 8 mL vialequipped with a magnetic stir bar. EtOH (2 mL) was added. The1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde solution was addedto the 5-methyl-2'-trifluoromethyl-biphenyl-3,4-diamine solution.The flask which had contained the1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde solution was rinsedwith EtOH (0.5 mL) and water (0.25 mL), and this was also added tothe 5-methyl-2'-trifluoromethyl-biphenyl-3,4-diamine solution. Themixture was heated to 90.degree. C. for 2 h. The mixture was pouredinto water, and the precipitate was isolated by filtration. Thesolid was washed with water, dissolved in EtOAc, dried overMgSO.sub.4, filtered, and the solvent was removed under reducedpressure. The residue was purified by column chromatography using a40-g SiO.sub.2 pre-packed column eluting with EtOAc/heptane, 0:1 to3:7, v/v over 30 min, yielding 136 mg (41%) of the title compound..sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.: 7.76 (d, J=7.8 Hz,1H), 7.61 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.26-7.49 (m,2H), 7.03 (br. s., 1H), 2.63 (br. s., 3H), 1.69-1.88 (m, 6H),1.45-1.63 (m, 4H).

C.3-[7-Methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za-spiro[4.5]dec-2-ene hydrochloride

[0424] The title compound was prepared from3-[7-methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene (as prepared in the previous step) accordingto the procedure described in Example 1, step H. .sup.1H-NMR (400MHz, d.sub.6-DMSO) .delta.: 7.85 (d, J=7.8 Hz, 1H), 7.73 (t, J=7.3Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.36 (s,1H), 7.10 (s, 1H), 3.34 (s, 2H), 2.60 (s, 3H), 1.64-1.84 (m, 6H),1.33-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.23H.sub.22F.sub.3N.sub.3O: 414.2 (M+H). found: 414.2.

Example 22

3-[5-(2-Chlorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-en-e hydrochloride (Cpd 45)

##STR00162##

[0425] A.3-(5-Bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene

##STR00163##

[0427] The title compound was prepared from4-bromo-benzene-1,2-diamine and1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared inExample 1, step B) according to the procedures described in Example1, steps F and G. .sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.: 7.74(s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.8 Hz, 1H), 3.25(s, 2H), 1.69-1.87 (m, 6H), 1.45-1.63 (m, 4H).

B.3-[5-(2-Chlorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2--ene

##STR00164##

[0429] The title compound was prepared from3-(5-bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene(as prepared in the previous step) and 2-chloro-benzene-boronicacid according to the procedure described in Example 1, step D..sup.1H-NMR (400 MHz, d.sub.4-MeOH) .delta.: 7.46-7.76 (m, 3H),7.29-7.42 (m, 4H), 3.27 (s, 2H), 1.69-1.87 (m, 6H), 1.46-1.62 (m,4H).

C.3-[5-(2-Chlorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2--ene hydrochloride

[0430] The title compound was prepared from3-[5-(2-chlorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-e-ne (as prepared in the previous step) according to the proceduredescribed in Example 1, step H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO).delta.: 7.71 (d, J=8.6 Hz, 1H), 7.66 (s, 1H), 7.56-7.62 (m, 1H),7.35-7.52 (m, 4H), 3.31 (s, 2H), 1.63-1.81 (m, 6H), 1.35-1.55 (m,4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.21H.sub.20ClN.sub.3O: 366.1 (M+H). found: 366.2.

Example 23

3-[7-(3-Methoxy-propyl)-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]--1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride (Cpd 52)

##STR00165##

[0431] A.5-(3-Methoxy-propyl)-2'-trifluoromethyl-biphenyl-3,4-diamine

##STR00166##

[0433] The title compound was prepared from3-iodo-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine (as preparedin Example 9, step A) and 3-methoxy-propyne according to theprocedures described in Example 10, steps A and B.

B.3-[7-(3-Methoxy-propyl)-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-y-l]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride

[0434] The title compound was prepared from5-(3-methoxy-propyl)-2'-trifluoromethyl-biphenyl-3,4-diamine (asprepared in the previous step) and1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared inExample 1, step B) according to the procedures described in Example1, steps F through H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.86 (d, J=7.6 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.6 Hz,1H), 7.48 (d, J=7.6 Hz, 1H), 7.41 (s, 1H), 7.11 (s, 1H), 3.31-3.41(m, 2H), 3.36 (s, 2H), 3.22 (s, 3H), 3.03 (t, J=7.5 Hz, 2H),1.86-1.98 (m, 2H), 1.63-1.83 (m, 6H), 1.32-1.59 (m, 4H). MassSpectrum (LCMS, ESI pos.): Calcd. forC.sub.26H.sub.28F.sub.3N.sub.3O.sub.2: 472.2 (M+H). found:472.3.

Example 24

3-[7-Chloro-4-methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-o-xa-2-aza-spiro[4.5]dec-2-ene hydrochloride (Cpd 55)

##STR00167##

[0435] A.5-Chloro-2-methyl-2'-trifluoromethyl-biphenyl-4-ylamine

##STR00168##

[0437] The title compound was prepared from1-bromo-5-chloro-2-methyl-4-nitro-benzene and2-trifluorophenylboronic acid according to the procedures describedin Example 1, steps D and E. .sup.1H-NMR (400 MHz, CDCl.sub.3).delta.: 7.72 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.43 (t,J=7.6 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.03 (s, 1H), 6.64 (s, 1H),4.01 (br. s., 2H), 1.90 (s, 3H).

B.N-(5-Chloro-2-methyl-3-nitro-2'-trifluoromethyl-biphenyl-4-yl)-acetamid-e

##STR00169##

[0439] 5-Chloro-2-methyl-2'-trifluoromethyl-biphenyl-4-ylamine (384mg, 1.34 mmol, as prepared in the previous step) was placed in a 50mL round-bottom flask equipped with a magnetic stir bar. Aceticanhydride (1.5 mL) was added. The mixture was stirred at rt for 1 hand then cooled to 0.degree. C. To a 4 mL vial cooled at 0.degree.C. was added AcOH (0.27 mL), acetic anhydride (0.31 mL), and nitricacid (0.45 mL). The nitrating mixture was added dropwise viapipette to the above-prepared solution, maintaining the temperaturebelow 10.degree. C. Upon completion of the addition, the mixturewas stirred at 0.degree. C. for 1 hour and poured onto ice. Theresulting precipitate was isolated by filtration, washed withwater, and dissolved in EtOAc. The solution was dried overMgSO.sub.4 and filtered, and the solvent was removed under reducedpressure. The residue was purified by column chromatography using a40-g SiO.sub.2 pre-packed column eluting with EtOAc/hexanes, 0:1 to3:7, v/v over 30 min, yielding 301 mg (60%) of the title compound..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.80 (d, J=7.8 Hz, 1H),7.54-7.68 (m, 2H), 7.50 (s, 1H), 7.43 (s, 1H), 7.25 (d, J=7.6 Hz,1H), 2.21 (s, 3H), 1.98 (s, 3H).

C.3-[7-Chloro-4-methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]--1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride

[0440] The title compound was prepared fromN-(5-chloro-2-methyl-3-nitro-2'-trifluoromethyl-biphenyl-4-yl)-acetamide(as prepared in the previous step) and1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared inExample 1, step B) according to the procedures described in Example1, steps E through H. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.87 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.3 Hz, 1H), 7.66 (t, J=7.7 Hz,1H), 7.40 (d, J=7.3 Hz, 1H), 7.07 (s, 1H), 3.34 (s, 2H), 2.16 (s,3H), 1.62-1.83 (m, 6H), 1.31-1.61 (m, 4H). Mass Spectrum (LCMS, ESIpos.): Calcd. for C.sub.23H.sub.21ClF.sub.3N.sub.3O: 448.1 (M+H).found: 448.3.

Example 25

3-[7-Chloro-5-(2-trifluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza--spiro[4.5]dec-2-ene methanesulfonate (Cpd 50)

##STR00170##

[0441] A.3-[7-Chloro-5-(2-trifluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1--oxa-2-aza-spiro[4.5]dec-2-ene

##STR00171##

[0443] The title compound was prepared from4-bromo-2-nitro-phenylamine, 2-trifluoromethoxyphenylboronic acid,and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as preparedin Example 1, step B) according to the procedures described inExample 6, steps A through C. .sup.1H-NMR (400 MHz, d.sub.4-MeOH).delta.: 7.51-7.65 (m, 2H), 7.36-7.50 (m, 4H), 3.31 (br. s., 3H),1.68-1.90 (m, 6H), 1.45-1.64 (m, 4H).

B.3-[7-Chloro-5-(2-trifluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1-oxa-2--aza-spiro[4.5]dec-2-ene methanesulfonate

[0444]3-[7-Chloro-5-(2-trifluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1-ox-a-2-aza-spiro[4.5]dec-2-ene (64.0 mg, 0.142 mmol, as prepared inthe previous step) was placed in an 8 mL vial, and EtOAc (1 mL) wasadded. Methanesulfonic acid (9.22 .mu.L, 0.142 mmol) was added viamicrosyringe. The solvent was removed under reduced pressure. Theresidue was triturated with ether (4 mL), and the solvent wasremoved via pipette. Trituration and solvent removal were repeated.The solid was dried under high vacuum to yield 72.3 mg (93%) of thetitle compound. .sup.1H-NMR (400 MHz, d.sub.6-DMSO) .delta.:7.59-7.66 (m, 1H), 7.45-7.59 (m, 4H), 7.40 (s, 1H), 3.32 (s, 2H),2.33 (s, 3H), 1.59-1.82 (m, 6H), 1.30-1.59 (m, 4H). Mass Spectrum(LCMS, ESI pos.): Calcd. forC.sub.23H.sub.19ClF.sub.3N.sub.3O.sub.2: 450.1 (M+H). found:450.2.

Example 26

3-[7-Chloro-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5-]dec-2-ene methanesulfonate (Cpd 49)

##STR00172##

[0445] A. 3-Chloro-2'-fluoro-5-nitro-biphenyl-4-ylamine

##STR00173##

[0447] The title compound was prepared from4-bromo-2-nitro-phenylamine and 2-fluorophenylboronic acidaccording to the procedures described in Example 6, steps A and B..sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.32 (d, J=1.8 Hz, 1H),7.81 (t, J=1.8 Hz, 1H), 7.42 (td, J=7.8, 1.8 Hz, 1H), 7.30-7.38 (m,1H), 7.23 (dd, J=7.6, 1.3 Hz, 1H), 7.13-7.22 (m, 1H), 6.64 (br. s.,2H).

B.3-[7-Chloro-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[-4.5]dec-2-ene

##STR00174##

[0449] The title compound was prepared from3-chloro-2'-fluoro-5-nitro-biphenyl-4-ylamine (as prepared in theprevious step) and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylicacid (as prepared in Example 1, step B) according to the proceduresdescribed in Example 16, steps B and C. .sup.1H-NMR (400 MHz,d.sub.4-MeOH) .delta.: 7.64 (br. s., 1H), 7.52 (td, J=7.8, 1.8 Hz,1H), 7.48 (s, 1H), 7.35-7.43 (m, 1H), 7.27 (td, J=7.5, 1.3 Hz, 1H),7.21 (ddd, J=11.1, 8.2, 1.1 Hz, 1H), 1.71-1.88 (m, 6H), 1.48-1.66(m, 4H).

C.3-[7-Chloro-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[-4.5]dec-2-ene methanesulfonate

[0450] The title compound was prepared from3-[7-chloro-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.-5]dec-2-ene (as prepared in the previous step) according to theprocedure described in Example 25, step B. .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.57-7.66 (m, 2H), 7.49 (s, 1H), 7.41-7.48(m, 1H), 7.33-7.38 (m, 1H), 7.28-7.33 (m, 1H), 3.33 (s, 2H), 2.32(s, 3H), 1.62-1.83 (m, 6H), 1.33-1.58 (m, 4H). Mass Spectrum (LCMS,ESI pos.): Calcd. for C.sub.21H.sub.19ClFN.sub.3O: 384.1 (M+H).found: 384.3.

[0451] Using the procedures described in Example 26, and reagents,starting materials and conditions known to those skilled in theart, the following compounds representative of the presentinvention were prepared:

TABLE-US-00009 Cpd Data 443-[7-Chloro-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene methanesulfonate .sup.1H-NMR (400 MHz,d.sub.6-DMSO) .delta.: 7.46-7.57 (m, 1H), 7.55 (s, 1H), 7.41 (s,1H), 7.20-7.31 (m, 2H), 3.34 (s, 2H), 2.37 (s, 3H), 1.62-1.81 (m,6H), 1.30-1.58 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.21H.sub.18ClF.sub.2N.sub.3O: 402.1 (M + H); found: 402.2.

Example 27

2-Methyl-4-[2-(1-oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylph-enyl)-3H-benzimidazol-4-yl]-butan-2-ol (Cpd 43)

##STR00175##

[0452] A.4-(4,5-Diamino-2'-trifluoromethyl-biphenyl-3-yl)-2-methyl-butan--2-ol

##STR00176##

[0454] The title compound was prepared from3-iodo-5-nitro-2'-trifluoromethyl-biphenyl-4-ylamine (as preparedin Example 9, step A) and 2-methyl-but-3-yn-2-ol according to theprocedures described in Example 10, steps A and B.

B. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid[4-amino-5-(3-hydroxy-3-methyl-butyl)-2'-trifluoromethyl-biphenyl-3-yl]-a-mide

##STR00177##

[0456]4-(4,5-Diamino-2'-trifluoromethyl-biphenyl-3-yl)-2-methyl-butan-2-o-l (57.5 mg, 0.170 mmol, as prepared in the previous step) wasplaced in a 50 mL round-bottom flask equipped with a magnetic stirbar. DCM (15 mL), PyBrOP (95.0 mg, 0.204 mmol), and DIPEA (36.0.mu.L, 0.204 mmol) were added via syringe.1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (31.0 mg, 0.170mmol, as prepared in Example 1, step B) in DCM (10 mL) was placedin an addition funnel and added dropwise over 2 h. After completionof the addition, the mixture was stirred at rt for 2 h. The solventwas removed under reduced pressure. The residue was chromatographedon a 40-g pre-packed SiO.sub.2 column eluting with EtOAc/heptane,0:1 to 3:7, v/v over 20 min, yielding 34.4 mg (40%) of the titlecompound. Mass Spectrum (LCMS, ESI pos.) Calcd. forC.sub.27H.sub.32F.sub.3N.sub.3O.sub.3: 504.2 (M+H). Found504.1.

C.2-Methyl-4-[2-(1-oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethy-lphenyl)-3H-benzimidazol-4-yl]-butan-2-ol

[0457] The title compound was prepared from1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid{4-amino-5-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyl]-2'-trifluo-romethyl-biphenyl-3-yl}-amide (as prepared in the previous step)according to the procedure described in Example 1, step G..sup.1H-NMR (400 MHz, d.sub.6-DMSO+d.sub.1-TFA) .delta.: 7.85 (d,J=7.8 Hz, 1H), 7.73 (t, J=7.3 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.48(d, J=7.6 Hz, 1H), 7.37 (s, 1H), 7.08 (s, 1H), 3.33 (s, 2H),2.97-3.10 (m, 2H), 1.63-1.83 (m, 8H), 1.35-1.57 (m, 4H), 1.18 (s,6H). Mass Spectrum (LCMS, ESI pos.): Calcd. forC.sub.27H.sub.30F.sub.3N.sub.3O.sub.2: 486.2 (M+H). found:486.1.

[0458] The following compounds of Formula (I) were prepared by theschemes and examples described herein.

TABLE-US-00010 Cpd No. Cpd Name 13-[6-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene; 22-[6-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-3-oxa-1-aza-spiro[4.5]dec-1-ene; 32-[6-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-3-aza-spiro[4.5]dec-2-ene; 42-[6-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-3-aza-spiro[4.5]dec-2-ene; 52-[6-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-3-oxa-1-aza-spiro[4.5]dec-1-ene; 63-[5-(2-Fluoro-6-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za- spiro[4.5]dec-2-ene; 73-[5-(2-Trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene; 83-[5-(2-Fluoro-6-trifluoromethoxy-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2--aza- spiro[4.5]dec-2-ene; 93-[5-(2-Trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene; 108,8-Difluoro-3-[5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa--2- aza-spiro[4.5]dec-2-ene; 113-{5-[2-(2,2,2-Trifluoroethyl)-phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-az-a- spiro[4.5]dec-2-ene; 123-[5-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-1H-benzimidazol-2-yl]-1-oxa-2-- aza-spiro[4.5]dec-2-ene hydrochloride; 133-[5-(2-Difluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 143-[7-Fluoro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za- spiro[4.5]dec-2-ene hydrochloride; 154-Methyl-3-[5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za- spiro[4.5]dec-2-ene hydrochloride; 163-[7-Chloro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za- spiro[4.5]dec-2-ene hydrochloride; 173-[7-Bromo-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-az-a- spiro[4.5]dec-2-ene hydrochloride; 182-{2-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-1H-benzimidazol-5-yl]-phenyl}-propan-2-ol; 192-(1,3-Diaza-spiro[4.5]dec-2-en-2-yl)-5-(2-trifluoromethyl-phenyl)-1H-benzimidazole hydrochloride; 203-[5-(2-Difluoromethoxyphenyl)-7-methyl-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 212-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-- benzimidazole-4-carbonitrile hydrochloride; 223-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)--3H- benzimidazol-4-yl]-propan-1-ol hydrochloride; 233-[5-(2-Fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-- ene, trifluoroacetic acid salt; 243-[4-Methyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2--aza- spiro[4.5]dec-2-ene hydrochloride; 253-[2-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)--3H- benzimidazol-4-yl]-prop-2-en-1-ol; 263-[5-(2,6-Difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]d-ec- 2-ene, trifluoroacetic acid salt; 273-[7-Trifluoromethyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]--1- oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 284-Methyl-3-[7-trifluoromethyl-5-(2-trifluoromethylphenyl)-1H-benzimidaz-ol-2-yl]-1- oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 292-[5-(2-Trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-3,8-dioxa-1-aza-spiro[4.5]dec-1-ene; 303-[5-(2-Chloro-phenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2--aza- spiro[4.5]dec-2-ene hydrochloride; 313-[5-(2-Fluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]-dec- 2-ene hydrochloride; 323-[7-Methyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-diox-a-2- aza-spiro[4.5]dec-2-ene hydrochloride; 333-[7-Bromo-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa--2- aza-spiro[4.5]dec-2-ene hydrochloride; 343-[7-Chloro-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1,8-diox-a-2- aza-spiro[4.5]dec-2-ene hydrochloride; 352-(1,8-Dioxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl-)-3H- benzimidazole-4-carbonitrile hydrochloride; 368,8-Dimethyl-3-[5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-ox-a-2-aza- spiro[4.5]dec-2-ene hydrochloride; 373-[5-(Chloro-phenyl)-1H-benzimidazol-2-yl]-8,8-dimethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 383-[5-(2,6-Difluoro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 398,8-Dimethyl-3-[7-trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride;403-[5-(2-Chloro-phenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-aza-spiro[4.5]-dec- 2-ene hydrochloride; 413-[7-Chloro-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]-8,8-dimethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 423-[7-Trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-benzimidazol-2-yl]--1,8- dioxa-2-aza-spiro[4.5]dec-2-ene 432-Methyl-4-[2-(1-oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethylphenyl)-3H-benzimidazol-4-yl]-butan-2-ol; 443-[7-Chloro-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene methanesulfonate; 453-[5-(2-Chlorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-- ene hydrochloride; 463-[7-Methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-a-za- spiro[4.5]dec-2-ene hydrochloride; 473-[7-Methyl-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 483-[7-Methyl-5-(2,6-difluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 493-[7-Chloro-5-(2-fluorophenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene methanesulfonate; 503-[7-Chloro-5-(2-trifluoromethoxyphenyl)-1H-benzimidazol-2-yl]-1-oxa-2-aza-spiro[4.5]dec-2-ene methanesulfonate; 513-[5-(2-Trifluoromethoxyphenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]--1- oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 523-[7-(3-Methoxy-propyl)-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-y-l]- 1-oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 533-[5-(2-Fluorophenyl)-7-trifluoromethyl-1H-benzimidazol-2-yl]-1-oxa-2-a-za- spiro[4.5]dec-2-ene hydrochloride; 543-[4,7-Dimethyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1-oxa--2- aza-spiro[4.5]dec-2-ene hydrochloride; 553-[7-Chloro-4-methyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]--1- oxa-2-aza-spiro[4.5]dec-2-ene hydrochloride; 562-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-5-(2-trifluoromethyl-phenyl)-1H-- imidazo[4,5-b]pyridine hydrochloride; 572-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-- imidazo[4,5-c]pyridine hydrochloride; and 582-(1-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-- imidazo[4,5-b]pyridine hydrochloride;

and pharmaceutically acceptable salts thereof.

BIOLOGICAL EXAMPLES

In Vitro Models

Example 1a

In Vitro Canine TRPM8 Functional Assay

[0459] The functional activity of compounds of the Formula (I) wasdetermined by measuring changes in intracellular calciumconcentration using a Ca.sup.2+-sensitive fluorescent dye. Thechanges in fluorescent signal were monitored by a fluorescenceplate reader, either a FLIPR.TM. (Molecular Devices) or FDSS(Hamamatsu). Increases in intracellular Ca.sup.2+ concentrationwere readily detected upon activation with icilin.

[0460] At 24 hrs prior to assay, HEK293 cells stably expressingcanine TRPM8 were seeded in culture medium in black wall,clear-base poly-D-lysine coated 384-well plates (BD Biosciences,NJ, USA) and grown overnight in 5% CO.sub.2 at 37.degree. C. Onassay day, growth media was removed and cells were loaded withCalcium 3 Dye (Molecular Devices) for 35 min at 37.degree. C.,under 5% CO.sub.2 and then for 25 min at room temperature andatmosphere. Subsequently, cells were tested for agonist-inducedincreases in intracellular Ca.sup.2+ levels using FLIPR.TM. orFDSS. Cells were challenged with a compound of the Formula (I) (atvarying concentrations) and intracellular Ca.sup.2+ was measuredfor 5 min prior to the addition of icilin to all wells to achieve afinal concentration that produces approximately an 80% maximalresponse. EC.sub.50 or IC.sub.50 values for compounds of thepresent invention were determined from eight-point dose-responsestudies. Curves were generated using the average of quadruplicatewells for each data point. The resultant data are displayed inTable 2.

TABLE-US-00011 TABLE 2 % Inh. Cpd @ 0.200 .mu.M IC.sub.50 (nM) 199.5 3.1 2 106 7.0 3 60 n.d. 4 84 61 5 94 6.0 6 102 0.6 7 102 1.1 8102 0.8 9 101 6.7 10 102 0.9 11 102 1.5 12 87 91 13 102 2.5 14 1022.2 15 102 3.9 16 102 3.3 17 102 2.7 18 102 7.9 19 50 n.d. 20 1031.8 21 103 0.7 22 103 0.2 23 103 2.9 24 103 5.6 25 100 0.8 26 1002.3 27 100 0.8 28 101 1.1 29 71 100 30 97 1.0 31 99 13.4 32 100 4.933 100 1.7 34 100 4.0 35 100 5.2 36 99 12.5 37 99 5.2 38 99 8.3 3999 6.3 40 98 11.0 41 92 50.2 42 100 1.4 43 99 1.7 44 100 2.1 45 972.4 46 97 1.8 47 97 6.9 48 97 3.9 49 101 6.1 50 101 1.9 51 97 1.252 97 1.0 53 97 1.7 54 97 5.8 55 97 4.7 56 101 4.6 57 102 2.7 58101 2.0

Example 1b

In Vitro Rat and Human TRPM8 Functional Assay

[0461] HEK293 cells are routinely grown as monolayer in Dulbecco'sminimum essential medium supplemented with 10% FBS, 1 mML-glutamine, 100 units/mL penicillin and 100 ug/mL streptomycin.Cells are maintained in 5% CO2 at 37.degree. C.

[0462] For functional expression of TRPM8, the full-length cDNAencoding human and rat TRPM8 are subcloned into pCI-NEO mammalianexpression vectors. The expression constructs are transientlytransfected into HEK293 cells according to the FuGENE 6Transfection Reagent.RTM. (ROCHE) instructions. Within twenty-fourhours, transiently transfected cells are harvested and eitherseeded directly into assay plate or cryopreserved for futureusage.

[0463] Transfected cells may be either cryopreserved or freshlytransfected and plated into clearbase poly-D-lysine coated 384-wellplates (BD Biosciences, NJ, USA) at a density of 10,000 cells perwell in culture medium and grown overnight. The following day, allmedium is removed and the cells are incubated with 52 L of0.5.times. calcium 3 dye (Molecular Devices) prepared in completeassay buffer containing 20 mM HEPES, 0.1% BSA, and 2.5 mMprobenecid at 37.degree. C. for thirty five minutes. The cells arethen incubated for an additional fifteen minutes at roomtemperature before initiating experiments. Following incubation,plates are inserted into a FDSS instrument, where cells werechallenged with compounds of the Formula (I) (at varyingconcentrations) and intracellular Ca.sup.2+ are measured for 5 minprior to the addition of icilin at the EC.sub.80 concentration.IC50 values for compounds of the Formula (I) are determined fromeight point dose-response studies.

[0464] Maximal fluorescence intensity (FI) achieved upon additionof icilin is exported from the FDSS and further analyzed usingGraphPad Prism 3.02 (Graph Pad Software Inc., CA, U.S.A.) wheredata is normalized to percent of maximal response. The doseresponse curves from the average of quadruplicate wells for eachdata point are analyzed by using nonlinear regression of eithersigmoidal dose response or sigmoidal dose response (variableslope). Finally, the IC.sub.50 values are calculated with thebest-fit dose curve determined by Prism.

Example 2

TRPM8 Patch Clamp Assays

[0465] For patch clamp experiments, HEK293 cells are stablytransfected with canine TRPM8 and cultured in DMEM supplementedwith 10% fetal bovine serum, 100 units/ml penicillin, 100 .mu.g/mlstreptomycin and 1 mg/ml G418. Cells are maintained at 37.degree.C. and in 5% CO.sub.2.

[0466] The extracellular solution contains (in mM): NaCl, 132;EGTA, 1; KCl, 5.4; MgCl.sub.2, 0.8; HEPES, 10; glucose, 10; pH=7.4.Recordings are performed using the conventional whole-cell patchclamp technique, 1-2 days after plating cells onto glass coverslipsat densities appropriate for single cell recording. Currents areamplified by a patch clamp amplifier and filtered at 2 kHz(Axopatch 200B, Molecular Devices, Union City, Calif.). Menthol(100 .mu.M) is applied to the cell at 0.5 ml/min via a gravity-fedperfusion system. Recordings involving menthol activation areperformed at 22.degree. C.

[0467] In experiments where temperatures are varied, temperatureramps are generated by cooling the perfusate in an in-line cooler(Model SC-20, Warner Instruments, Hamden, Conn.) controlled by atemperature controller (Model CL-100, Warner Instruments). Thetemperature in the vicinity of the recorded cell is measured with acustom-made miniature thermo-microprobe connected to a monitoringthermometer (Model TH-8, Physitemp, Clifton, N.J.), and sampledusing Digidata 1322A and pClamp 9.0 (Molecular Devices), as are thecurrents concurrently measured in the whole-cell patch clamp mode.The current is continuously sampled (at 100 Hz) at a holdingpotential of -60 mV.

[0468] Compounds of the Formula (I) are diluted from 10 mM DMSOstocks (stored at -20.degree. C.) into an extracellular solutioneither containing 100 M menthol or subjected to cooling. Increasingconcentrations of a compound are applied to a cell in a cumulativemanner and concentration-dependent responses are measured aftersteady-state activation is achieved by either 100 .mu.M menthol orcooling to 10.degree. C. A saturating concentration of a referenceantagonist is applied at the end of an experiment (either in thepresence of 100 .mu.M menthol or 10.degree. C. temperature) toestablish the baseline from which all the other measurements aresubtracted.

[0469] Percentage inhibition by a compound is calculated asfollows: 100.times.(1-I.sub.comp/I.sub.0); where I.sub.comp andI.sub.0 are steady-state current amplitudes in either the presenceor absence of a concentration of compounds of the Formula (I).Concentration-response data are fitted to a logistic function asfollows: R=100/(1+c/IC.sub.50).sup.p; where, R is the percentageinhibition, p is the Hill coefficient and c is the concentration ofcompounds of the Formula (I).

In Vivo Models

Example 3

Inhibition of Icilin-Induced Behaviors in Rodents

[0470] Icilin was initially developed as a "super-cooling" compoundby Delmar Chemicals Ltd. Subsequently it was shown to be one of themost potent known agonists of TRPM8 (McKemy, D. D. et al. Nature2002, 416(6876), 52-8), having an EC.sub.50=0.2 .mu.M instimulating calcium ion influx into TRPM8 transfected cells(Behrendt, H. J. et al. Brit. J. Pharmacol. 2004, 141(4), 737-45).Initial in vivo testing of icilin showed it to cause "wet-dog"shakes in rats. Similar shaking or jumping behavior was alsoevident in mice, rabbits, cats, dogs and monkeys. In humans, icilinproduced a sensation of coolness on contact with mucous membranes,cold prickling when 0.1 mg was dropped on the tongue and coldnessin the mouth, pharynx and chest lasting 30-60 minutes when 5-10 mgwas ingested orally (Wei, E. T.; Seid, D. A. J. Pharm. Pharmacol.1983, 35, 110). The inhibition or reversal of icilin-inducedshaking behaviors in rodents provides evidence for the utility ofTRPM8 antagonists of the Formula (I) in treating or preventing adisease, syndrome, disorder, or condition in a subject in which thedisease, syndrome, disorder or condition is affected by themodulation of TRPM8 receptors.

Example 3a

Inhibition of Icilin-Induced "Wet-Dog" Shakes in Rats

[0471] Male Sprague Dawley rats (220-450 g, Charles River Labs,n=6-9/treatment) were used to evaluate the ability of selectedcompounds of the Formula (I) to block icilin-induced "wet-dog"shakes (WDS). Compounds of the Formula (I) were administered in anappropriate vehicle, such as hydroxypropyl-.beta.-cyclodextrin(HP.beta.CD), methocellulose, 10% Solutol, or H.sub.2O, or thelike, by the appropriate route, i.p. or p.o., 30-120 minutes beforeicilin. Icilin was administered in PEG-400 or 10% solutol/H.sub.2O,at 1.0 or 3.0 mg/kg, i.p. and spontaneous "wet-dog" shakes werecounted 10-20 minutes post-icilin. Results are presented as apercent inhibition of shakes, which was calculated as [1-(testcompound WDS count/vehicle WDS count)].times.100.

Example 3b

Reversal of Icilin-Induced Behaviors in Rats

[0472] Male Sprague Dawley rats (225-450 g, Charles River Labs,n=4-6/treatment) were used to evaluate the ability of selectedcompounds of the Formula (I) to reverse icilin-induced "wet-dog"shakes. Icilin was administered in PEG-400 or 10% solutol/H.sub.2O,at 1.0 or 3.0 mg/kg, i.p. and spontaneous "wet-dog" shakes (WDS)were counted 10-20 minutes post-icilin. Animals that exhibited 10or more shakes were randomized into treatment groups andimmediately administered compounds of the Formula (I) in anappropriate vehicle, such as hydroxypropyl-.beta.-cyclodextrin (HP.beta. CD), methocellulose, 10% Solutol, or H.sub.2O, or the like,and by the appropriate route, such as i.p. or p.o. Spontaneous"wet-dog" shakes were counted 60-70 minutes after compoundadministration. Results are presented as a percent inhibition ofshakes, which was calculated as [1-(test compound WDS count/vehicleWDS count)].times.100. Resultant data is shown in Table 3.

TABLE-US-00012 TABLE 3 Cpd No. Dose (mg/kg) Route Post-icilin %Inhibition 1 30 p.o. 1 h 100 7 10 p.o. 1 h >96 8 10 p.o. 1 h>96 16 10 p.o. 1 h >99 27 10 p.o. 1 h >99 28 10 p.o. 1 h30 30 10 p.o. 1 h >98 51 10 p.o. 1 h >98 53 10 p.o. 1 h>98

Example 3c

Rightward Shift of Icilin Dose Effect Curve in Rats

[0473] Male Sprague Dawley rats (200-400 g, Charles River Labs,n=6-9/treatment) were administered icilin in a suitable vehicle(e.g. PEG-400, 10% Solutol) at 0.1-30 mg/kg, i.p. Spontaneous"wet-dog" shakes were counted 10-20 minutes post-icilin in order togenerate an icilin dose-effect curve. A compound of the presentinvention was administered orally inhydroxypropyl-.beta.-cyclodextrin 60 minutes before icilinchallenge to assess the compound's ability to inhibit spontaneous"wet-dog" shakes (WDS) produced by a range of icilin doses. TheED.sub.50 of the icilin dose-effect curve generated in the presenceof TRPM8 antagonist may be compared to that generated in thepresence of vehicle to determine the magnitude of rightwardshift.

Example 4

In Vivo Model of Subacute Inflammatory Pain

Carrageenan-Induced Hyperalgesia

[0474] Intraplantar injection of carrageenan into the hind paw ofrats causes a robust acute inflammatory response characterized byreddening, swelling and hypersensitivity of the paw to thermal andmechanical stimuli typically peaking 3-6 hours followingapplication and subsiding over the 12-24 hours.

Example 4a

Rat Carrageenan-Induced Radiant Heat Hypersensitivity

[0475] To assess the effect of test compounds of the Formula (I) oninflammatory hyperalgesia radiant heat response latencies wereevaluated 3 hours following intraplantar carrageenan (Lambda, TypeIV, 200 uL) injection into a single hind paw in male Sprague-Dawleyrats. The test compound was administered either 2 hours prior to or1 hour following carrageenan injection. The intent was to determinewhether the compound would prevent or retard the hypersensitivityassociated with this inflammogen. Baseline thermal responselatencies were determined prior to any treatment and again 3 hoursafter carrageenan injection. Percent reversal of hyperalgesiarelative to vehicle treatment (% R) was calculated for bothcompound treatment paradigms according to the followingformula.

% R=(Post compound latency-Post vehicle latency)/((Baselinelatency-Post vehicle latency).times.100%

Example 5

In Vivo Model for of Chronic Inflammatory Pain

Complete Freund's Adjuvant (CFA)-Induced Hyperalgesia

[0476] Intraplantar injection of complete Freund's adjuvant (CFA)in rodents results in a long-lasting inflammatory reaction,characterized by a pronounced hypersensitivity to both thermal andmechanical stimuli. This hypersensitivity peaks between 24-72 hoursfollowing injection and can last for several weeks. To assesswhether test compounds of the Formula (I) reverse establishedhypersensitivity, a 100 .mu.L intraplantar injection of CFA(suspended in a 1:1 emulsion of saline and heat-killedMycobacterium tuberculosis in mineral oil) can be injected into asingle hind paw of Sprague-Dawley rats (typically males rangingfrom 150-350 g). This paradigm also may be conducted with amultiple dosing or a prophylactic dosing regime designed to alterthe course of hyperalgesia development. This test predicts theanalgesic, anti-allodynic and antihyperalgesic effect of numerouseffective clinical agents, including acetaminophen, NSAIDS such asaspirin and ibuprofen, and opioids, such as morphine.

Example 5a

CFA-Induced Paw Radiant Heat Hypersensitivity

[0477] Each rat is placed in a test chamber on a warm glass surfaceand allowed to acclimate for approximately 10 minutes. A radiantthermal stimulus (beam of light) is then focused through the glassonto the plantar surface of each hind paw in turn. The thermalstimulus is automatically shut off by a photoelectric relay whenthe paw is moved or when the cut-off time is reached (20 secondsfor radiant heat at .about.5 Amps). An initial (baseline) responselatency to the thermal stimulus is recorded for each animal priorto the injection of CFA. Twenty-four hours following intraplantarCFA injection, the response latency of the animal to the thermalstimulus is then re-evaluated and compared to the animal's baselineresponse time. Only rats that exhibit at least a 25% reduction inresponse latency (i.e. hyperalgesia) are included in furtheranalysis. Immediately following the post-CFA latency assessment,test compound or vehicle (usually Solutol, hydroxypropylmethylcellulose, hydroxypropyl beta-cyclodextrin or PEG-400) isadministered i.p. or p.o. to rats. Post-compound treatmentwithdrawal latencies are assessed at fixed time intervals,typically 30, 60 and 120 minutes. The percent reversal (% R) ofhypersensitivity is calculated according to the followingformula:

% Reversal=(Treatment Response-CFA Response)/(Baseline Response-CFAResponse).times.100.

Example 5b

CFA-Induced Paw Cold Hypersensitivity

[0478] Prior to intraplantar CFA injection, mice or rats are placedindividually in elevated observation chambers having wire meshfloors. Through the mesh floor a series of three applications ofacetone (0.04-0.10 mL/application) is sprayed onto the bottom ofthe paw using a multidose syringe device. A positive response takesthe form of an abrupt withdrawal and licking of the paw. Thecumulative duration of licking is recorded for each of the threetrials, which are then averaged to give the individual's response.Twenty-four hours following CFA injection, acetone lickingdurations are markedly elevated, implying a hypersensitivity tocooling. Test compounds of the Formula (I) can be assessed fortheir ability to return acetone-evoked paw licking durations topre-CFA levels (typically near zero) following systemicadministration. Percent inhibition is calculated as follows

% Inhibition=[1-(treatment licking duration/vehicle lickingduration)].times.100.

Example 6

Chemically-Induced Abdominal Irritant Models of Visceral Pain

[0479] A chemical irritant (such as acetic acid, kaolin,bradykinin, phenyl-p-(benzo) quinine, bromo-acetylcholine, orzymosan) is injected in mice intraperitoneally, causing acontraction of the abdominal musculature, which is characterized byan elongation of the body extending through to the hind limbs. Thenumber of such responses is quantitated and is reduced bypretreatment of analgesic agents, thus forming the basis for ascreening test (Collier, H. O. et al. Brit. J. Pharmacol.Chemother. 1968, 32(2): 295-310). This type of abdominal irritanttest has been used to predict the analgesic effect of numerousclinically effective agents, the potency of which in the abdominalirritant test parallels the magnitude of the dose needed in therelief of clinical pain. Such agents include acetaminophen, NSAIDSsuch as aspirin and ibuprofen, opioids, such as morphine andcodeine, and other centrally acting analgesics, such astramadol.

[0480] One modification of the chemically-induced abdominalirritant model of visceral pain is to pretreat animals with agentsknown to induce inflammatory responses following intraperitonealinjection (such as LPS, zymosan, or thioglycolate). A smallintraperitoneal dose of such an inflammogen, administered hours ordays before the acute chemical irritant challenge, has been shownto increase the number of abdominal contractions observed (Ribeiro,R. A. et al. Eur. J. Pharmacol. 2000, 387(1), 111-8). While someanalgesic agents are effective at mitigating acute viscerochemicalnociception, others, particularly those dependent upon receptorinduction, are more effective at preventing or reversing theenhancement of behavioral responses caused by a preconditioninginflammatory stimulus. Because of the up-regulation of the TRPM8receptor in inflammation, TRPM8 antagonists that are effective atreducing the mean number of contractions are predicted to provideanalgesic action in human clinical use.

[0481] The ability of compounds of the Formula (I) to mitigatechemical irritant-induced abdominal contractions following apre-conditioning inflammatory stimulus can be studied as follows.Thioglycolate (3%, w/v, 2-3 mL i.p.) is injected into male CD1 mice(20-40 g, Charles River Labs), at a maximum dosage volume of 80mL/kg, to induce peritoneal inflammation. Following a twenty-fourhour pre-inflammation period these mice are dosed orally withcompounds of the Formula (I) (30 mg/kg; n=10) or vehicle (HPMC with2% Tween80; n=9) and then one hour later subjected to an abdominalirritant challenge of acetic acid (1%, 10 mL/kg, i.p.). Immediatelyfollowing injection of acetic acid, mice are placed individually inglass bell jars (approximately 15 cm in diameter) for counting ofabdominal contractions over the next 15 minutes. The total numberof abdominal contractions is summed for each treatment group andemployed in the following formula to calculate Percent Inhibition(% I):

% I=[1-(test compound contractions/vehiclecontractions)].times.100.

Example 7

In Vivo Models of Neuropathic Pain

[0482] The sciatic nerve is the major sensorimotor innervation ofthe (hind) leg and foot. Injury to the sciatic nerve or itsconstituent spinal nerves often results in pain-related behaviors.In rats and mice, tight ligation of the L5 spinal nerve with silksuture, partial tight ligation of the sciatic nerve with silksuture or loose ligation of the sciatic nerve with chromic gutsuture each result in behaviors reminiscent of neuropathic pain inhumans. These lesions (one per animal) are performed surgically inanesthetized rodents. Both the spinal nerve and sciatic nervelesions result in allodynia, a painful response to normallyinnocuous stimuli, and hyperalgesia, an exaggerated response tonormally noxious stimuli. It is important to note that both ofthese pain-related behaviors are evoked by the testing proceduresand that normal use of the paw (e.g., walking) is relativelyuncompromised, apart from occasional "guarding" of the paw.Subsequent to the surgery, the subjects' behaviors, such asgrooming, feeding, and weight gain, are normal, except forhypersensitivity (as defined above) of the affected paw.

[0483] In addition to induction by nerve damage resulting fromaccidental trauma or surgical procedures, neuropathic pain can alsobe induced by diabetes (Fox, A. et al. Pain 1999, 81, 307-316) orby treatment with chemotherapeutic agents, such as paclitaxel orvincristine (Yaksh, T. L. et al. Pain 2001, 93, 69-76).

[0484] Agents that attenuate neuropathic pain in the clinic alsoare effective in rodent neuropathic pain models. These agentsinclude the recently approved Cymbalta (Duloxetine, Iyengar, S. etal. J. Pharmacol. Exp. Ther. 2004, 311, 576-584), morphine (Suzuki,R. et al. Pain 1999, 80, 215-228), and gabapentin (Hunter, J. C. etal. Eur. J. Pharmacol. 1997, 324, 153-160). The dual TRPV1/TRPM8receptor antagonist BCTC reduced mechanical hyperalgesia andtactile allodynia in the chronic constriction injury rodentneuropathic pain model (Pomonis, J. D. et al. Pharmacol. Exp. Ther.2003, 306, 387-393; Behrendt, H. et al. Brit. J. Pharm. 2004, 141,737). Cold allodynia is a particularly debilitating symptom ofneuropathic pain conditions (Jorum, E. et al. Pain 2003, 101,229-235). The antiallodynic effect of compounds of the Formula (I)in this rodent model is predictive of clinical effect for thesenovel agents.

Example 7a

Chronic Constriction Injury (CCI)-Induced Model of NeuropathicPain

Acetone-Induced Hypersensitivity

[0485] Male Sprague Dawley rats (225-450 g; n=5-8/treatment) wereused to evaluate the ability of selected compounds of the Formula(I) to reverse CCI-induced cold hypersensitivity. Four looseligatures of 4-0 chromic gut were surgically placed around the leftsciatic nerve under inhalation anesthesia as described by Bennettet al. (Bennett, G. J.; Xie, Y. K. Pain 1988, 33(1), 87-107).Fourteen to 35 days following CCI surgery, subjects were placed inelevated observation chambers containing wire mesh floors and fiveapplications of acetone (0.05 mL/application separated byapproximately 5 minutes) were spritzed onto the plantar surface ofthe paw using a multidose syringe. An abrupt withdrawal or liftingof the paw was considered a positive response. The number ofpositive responses was recorded for each rat over the five trials.Following baseline withdrawal determinations, compounds of Formula(I) are administered in an appropriate vehicle, such ashydroxypropyl-.beta.-cyclodextrin (HP .alpha. CD), methylcellulose,Methocel, 10% Solutol, or H.sub.2O, or the like, by the appropriateroute, i.p. or p.o. The number of withdrawals were redetermined 1to 3 h after compound administration. Results are presented as apercent inhibition of shakes, which was calculated for each subjectas [1-(test compound withdrawals/pre-test withdrawals)].times.100and then averaged by treatment. Resultant data is shown in Table4.

TABLE-US-00013 TABLE 4 Dose % Cpd No. (mg/kg) Route Post-doseInhibition 1 10 p.o. 3 h 65 7 10 p.o. 3 h 83 16 10 p.o. 3 h 82.5 1710 p.o. 3 h 97 27 10 p.o. 3 h 83 30 10 p.o. 3 h 62.9 51 10 p.o. 3 h57.1 53 10 p.o. 3 h 42.9

Example 7b

Chronic Constriction Injury (CCI)-Induced Model of NeuropathicPain

Cold Plate-Induced Hypersensitivity

[0486] In male SD rats (175-325 g), four loose ligatures of 4-0chromic gut are surgically placed around the left sciatic nerveunder inhalation anesthesia as described by Bennet et al. (Bennett,G. J.; Xie, Y. K. Pain 1988, 33(1), 87-107). Seven to 21 daysfollowing sciatic chronic constriction injury (CCI) surgery, thesubjects can be placed onto a commercial cold plate device cooledby peltier elements such that the surface temperature is held at1.degree. C. Each subject can undergo a 6 minute conditioningperiod followed by a 3 minute assessment period during which thetotal duration of hind paw lifting is recorded. This procedure isrepeated at several intervals prior to and following systemic drugadministration. Compounds of the Formula (I) can be assessed fortheir ability to return duration of paw lifting back to pre-lesionlevels. The duration of paw lifting during the 3 minute test periodfollowing administration of test compound is taken as a percentageof the duration of paw lifting during the 3 minute test periodprior to test compound treatment.

Example 7c

Chronic Constriction Injury (CCI)-Induced Model of NeuropathicPain

Mechanical Allodynia (von Frey Test)

[0487] In male SD rats (175-325 g), four loose ligatures of 4-0chromic gut are surgically placed around the left sciatic nerveunder inhalation anesthesia as described by Bennet et al. (Bennett,G. J.; Xie, Y. K. Pain 1988, 33(1), 87-107). Seven to 21 daysfollowing sciatic chronic constriction injury (CCI) surgery, thesubjects can be placed onto an elevated rack of plexigas chambershaving wire mesh or another type of perforated flooring. Themeasurement of mechanical allodynia can be performed using the vonFrey hairs (Semmes-Weinstein Monofilaments, Stoelting Co., IL)wherein the rats can be habituated to the wire mesh bottom cagesbefore the start of the experiment. Static allodynia can be testedin the unrestrained rats by touching the plantar surface of thehind paw with von Frey hairs in ascending order of force (1.2, 1.5,2.0, 3.6, 5.5, 8.5, 12, 15, 29, and 76 g) for up to 6 s or until apaw withdrawal response can be elicited. The lowest amount of forcerequired to elicit a response can be recorded as the withdrawalthreshold in log g. This procedure is repeated at several intervalsprior to and following systemic drug administration. Compounds ofthe Formula (I) can be assessed for their ability to return thethreshold force, which elicits paw lifting back to pre-lesionlevels.

Example 8

Inflammatory Agent-Induced Models of Pyresis/Antipyresis

[0488] Compounds of the Formula (I) can be tested in animal modelsof pyresis, according to previously documented and validatedmethods, such as those described by Kozak et al. (Kozak, W.;Fraifeld, V. Front. Biosci. 2004, 9, 3339-55). Fever is a frequentaccompaniment of inflammatory disease. Animal models make use ofthe pyretic properties of yeast and other inflammatory agents,injecting a yeast suspension or other agent subcutaneously(Tomazetti, J. et al. J. Neurosci. Methods 2005, 147(1), 29-35);Van Miert, A. S.; Van Duin, C. T. Eur. J. Pharmacol. 1977, 44(3),197-204). For example, Male Wistar rats (75-100 g) can be housed ingroups of four to a cage at controlled temperature (23.+-.1.degree.C.) with a 12 h light: 12 h dark cycle (lights on at 07:00 h) andwith standard lab chow and tap water ad libitum. All measuredtemperatures can be taken between 08:00 and 19:00 h. Each animalcan be used in only one study. Rectal temperature (TR) can bemeasured by inserting a lubricated thermistor probe (externaldiameter: 3 mm) 2.8 cm into the rectum of the animal. The probe canbe linked to a digital device, which displayed the temperature atthe tip of the probe with a 0.1.degree. C. precision and logs thevalues over time. Immediately after measuring the initial basalrectal temperature, the animals can be injected with commerciallyavailable dried baker yeast (Saccharomyces cerevisiae) suspended inpyrogen-free 0.9% NaCl (0.05-0.25 g/kg, i.p.) or 0.9% NaCl (10ml/kg). TR changes can be recorded every hour up to 12 h, andexpressed as the difference from the basal value. Since it has beenpreviously reported that handling and temperature measuring-relatedstress alter rectal temperature, these animals can be habituated tothe injection and measuring procedure for 2 days before experimentsare carried out. In these sessions, the animals can be subjected tothe same temperature measuring procedure described above, and canbe injected intraperitoneally (i.p.) with 0.9% NaCl (10 ml/kg).

[0489] To assess the effect of potential antipyretic compounds onbasal rectal temperature study animals can have their TR measuredfor 4 h, and after the fourth TR measurement they can besubcutaneously (s.c.) injected with vehicle (such as 10% Solutol insterile water 5 ml/kg) or compounds of the Formula (I) prepared invehicle. TR can then be recorded every hour up to 8 h after thecompound injections. To assess the effect of compounds of theFormula (I) on baker yeast-induced hyperthermia, study animals canhave their basal TR measured and then be injected with a pyrogenicdose of baker yeast (for example, 0.135 g/kg). TR changes can berecorded every hour up to 4 h, when potential antipyretics agentssuch as those compounds of the Formula (I) are administered. Rectaltemperature can then be monitored over the following 8 h. Basalrectal temperature and changes in rectal temperature can beexpressed as means.+-.S.E.M. of the differences from TR at 07:00 h.Data can be analyzed by two-way analysis of variance (ANOVA), withtime of measures treated as within subject factor, depending on theexperimental design. Post hoc analysis can be carried out by theF-test for simple effect and the Student-Newman-Keuls test, whenappropriate. A value of P<0.05 would be considered statisticallysignificant.

[0490] The modification of the subsequent pyretic response bytherapeutic agents can also be monitored by rectal telemetry orother measurements of body temperature. Several clinically relevantagents such as acetaminophen, aspirin and ibuprofen, reduce feverin these models. The antipyretic effect of TRPM8 antagonists, suchas compounds of the Formula (I), in these tests would also bepredictive of their clinical effect.

Example 9

CFA-Induced Model of Rheumatoid Arthritis

[0491] Compounds of the Formula (I) can be tested in animal modelsof rheumatoid arthritis, according to previously documented andvalidated methods, such as those described by Nagakura et al(Nagakura, Y. et al. J. Pharmacol. Exp. Ther. 2003, 306(2), 490-7).For example, arthritis can be induced by the CFA inoculation in therats (Male Lewis rats 150-225 g; Charles River). Briefly, 100 mg ofMycobacterium Butyricum (Difco, Detroit, Mich.) can be thoroughlymixed with 20 mL of paraffin oil. Then mixture can be autoclavedfor 20 min at 120.degree. C. Each rat can be injected in the rightfootpad (hind paw) with the mixture in a 0.1-mL volume underinhalation anesthesia. The rats serving as controls can be injectedwith 0.1 mL of saline. Pain and other disease developmentparameters can be measured in the CFA- or saline-treated rats justbefore inoculation and up to 28 days post-inoculation. Themeasurement for pain parameters can be conducted for bothmechanical and thermal (hot or cold) endpoints. The measurement ofmechanical allodynia can be performed using the von Frey hairs(Semmes-Weinstein Monofilaments, Stoelting Co., IL) wherein therats can be habituated to wire mesh bottom cages before the startof the experiment. Static allodynia can be tested in theunrestrained rats by touching the plantar surface of the hind pawwith von Frey hairs in ascending order of force (1.2, 1.5, 2.0,3.6, 5.5, 8.5, 12, 15, 29, and 76 g) for up to 6 s or until a pawwithdrawal response can be elicited. The lowest amount of forcerequired to elicit a response can be recorded as the withdrawalthreshold in log g. Thermal hyperalgesia can be assessed using theradiant heat test wherein a mobile radiant heat source can belocated under a glass surface upon which the rat is placed. Thebeam of light can be focused on the hind paw, and the pawwithdrawal latencies are defined as the time taken by the rat toremove its hind paw from the heat source. The measurement of jointhyperalgesia can be performed by a modification of the previouslyreported method (Rupniak, N. M. J. et al. Pain 1997, 71, 89-97).The torso of each rat can be held from the back with the left palm,and the bending and extension (one after the other and five timesin each direction) of the ankle within its limits of range ofmotion can be performed with the right fingers. The total number ofvocalizations emitted after the manipulation (the bending andextension, five times in each direction) can be recorded for eachpaw (the maximum score is 10 for each paw).

[0492] The scoring of mobility can be performed by modifying theevaluation scale reported by Butler et al. (Butler, S. H. et al.Pain 1992, 48, 73-81): score 6, walks normally; score 5, walksbeing protective toward the ipsilateral hind paw (touches theipsilateral hind paw fully on the floor); score 4, walks beingprotective toward the ipsilateral hind paw (touches only the toe ofthe ipsilateral hind paw on the floor); score 3, walks beingprotective toward both hind paws (touches the contralateral hindpaw fully on the floor); score 2, walks being protective towardboth hind paws (touches only the toe of the contralateral hind pawon the floor); score 1, crawls only using the fore paws; and score0, does not move. Paw volumes can be measured by volumedisplacement of electrolyte solution in a commercially availableplethysmometer device. The hind paw can be immersed to the junctionof the hairy skin, and the volumes can be read on a digitaldisplay. The scoring of joint stiffness can be performed asfollows: the body of rats can be held from the back with the leftpalm, and the bending and extension (once in each direction) of theankle within its limits of range of motion can be performed withthe right fingers. It can be confirmed beforehand that there is norestriction of ankle joint movement in the bending and extensionmanipulations in naive rats, and the scoring can be performedaccording to the evaluation scale reported by Butler (Butler, S. H.et al. Pain 1992, 48, 73-81): score 2, there are restrictions offull range of movement of the ankle in both bending and extension;score 1, there is a restriction of full range of movement of theankle in bending or extension; and score 0, no restriction. Themeasurements for paw volume and joint stiffness can be conductedfor both hind paws.

[0493] Compounds of the Formula (I) can be assessed forantihyperalgesic efficacy as follows: thirty-two rats (8 rats perdose and four doses per compound) that are to be treated with theCFA and another eight rats as naive controls can be used for eachdrug evaluation. The analgesic effects can be evaluated onpost-inoculation day 9, when mechanical allodynia, thermalhyperalgesia, joint hyperalgesia, and joint stiffness in theipsilateral paw reached almost the maximum, although thoseparameters in the contralateral paw changed only slightly and thesystemic disturbance shown by the change of mobility score issmall. On the day before evaluation, body weight, mechanicalallodynia, thermal hyperalgesia, and joint hyperalgesia can bemeasured for the 32 rats that are to be used for compoundevaluation. The rats are allocated to four groups (eight rats pergroup) such that the differences in the averages of thoseparameters among the groups became small. All the analgesic effectevaluations and behavioral observations can be carried out by theobserver who is blind to the drug treatment.

[0494] Data can be expressed as the mean+/-S.E.M. The time-coursecurves for mechanical allodynia, thermal hyperalgesia, jointhyperalgesia, body weight, and paw volume can be subjected totwo-way repeated measures analysis of variance with post hoc ttest. In experiments for evaluation of compounds of Formula (I),the difference in scores between the vehicle-treated and naivecontrol groups can be analyzed by Student's t test to confirmsignificant changes in the pain parameters in the ipsilateral paw.The analgesic effects can be analyzed by Dunnett's t test, and ineach case the drug-treated groups can be compared with thevehicle-treated group. In each statistical analysis, the comparisoncan be conducted for paws on the corresponding side. P<0.05 isconsidered statistically significant. In this model, the centrallyacting analgesics morphine and tramadol fully relieved pain,whereas the NSAIDs, indomethacin and diclofenac are partiallyeffective, evidencing the model's clinical predictability. Theanalgesic effect of compounds of the Formula (I) in this test wouldpredict their clinical usefulness in treating arthritis.

Example 10

In Vivo Model for Arthritis

Inflammogen-Induced Hyperalgesia of the Knee Joint

[0495] Compounds of the Formula (I) can be tested in animal modelsof osteoarthritis, according to previously documented and validatedmethods, such as those described by Sluka et al. (Sluka, K. A.;Westlund, K. N. Pain 1993, 55(3), 367-77). For example, maleSprague-Dawley rats (Harlan, Indianapolis, Ind.) weighing 225 to350 g can be briefly anesthetized with vaporized halothane and theninjected with a mixture of 3% carrageenan and 3% kaolin (100 .mu.Lin 0.9% sterile saline) into the joint cavity of one knee. Afterthe injection, the animals can be returned to their cages until thetime of testing. For behavioral testing, animals can be placed inindividual clear plastic cages on top of an elevated wire meshsurface that restricted movement. The animals should be allowed toacclimate for approximately 1 hour before testing. Von Freyfilaments, as described above, can then be used to test forenhanced responses to mechanical stimuli. The filaments can besuccessively applied through the wire mesh perpendicularly to theplantar surface in between the pads of the third and fourthphalanges. The response threshold to mechanical stimuli can bedetermined before inflammation of the knee joint; 4 hours afterinflammation to confirm the development of hyperalgesia;immediately after the administration of test compound such as thoseof Formula (I) i.e. 5 hours after inflammation; and at 8, 12, and24 hours after inflammation.

[0496] The Kruskal-Wallis test, a nonparametric test, can be usedto analyze the effects for frequency, intensity, and group forresponse to mechanical stimuli at baseline, 4 hours afterinflammation, and after compound treatment (5 hours, 8 hours, 12hours, and 24 hours after inflammation). Further post hoc testingbetween groups can be executed by using the Mann-Whitney signedrank test. The data can be presented as median with 25th and 75thpercentiles. Significance is P.ltoreq.0.05.

[0497] Additionally, the gait of the animal or other pain-relatedbehavior can be scored as the dependent measure of the painfuleffect of the arthritis on the animal's activity (Hallas, B.;Lehman, S.; Bosak, A. et al. J. Am. Osteopath. Assoc. 1997, 97(4),207-14). The effect of test drug on the animal's normal behaviorcan be quantified from zero, meaning no response, to three forincapacitating impairment. Effective analgesic treatment includesthe clinically used indomethacin (Motta, A. F. et al. Life Sci.2003, 73(15), 1995-2004). Thus the benefit of compounds of theFormula (I) in this model would predict their clinicalrelevance.

Example 11

Sarcoma Cell-Induced Models of Bone Cancer Pain

[0498] Compounds of the Formula (I) can be tested in animal modelsof bone cancer pain, according to previously documented andvalidated methods, such as those described in the scientificliterature (El Mouedden, M.; Meert, T. F. Pharmacol. Biochem.Behav. 2005, 82(1), 109-19; Ghilardi, J. R. et al. J. Neurosci.2005, 25(12), 3126-31). In preparation for cell inoculation andtumor induction, osteolytic murine sarcoma cells (NCTC 2472,American Type Culture Collection (ATCC), Rockville, Md., USA) canbe cultured in NCTC 135 medium (Invitrogen) containing 10% horseserum (Gibco) and passaged 2 times weekly according to ATCCguidelines. For their administration, cells can be detached byscraping and then centrifuged at 1000.times.g. The pellet can besuspended in fresh NCTC 135 medium (2.5.times.10.sup.6 cells/20.mu.L) and then used for intramedullary femur inoculation. MaleC3H/HeNCrl mice (25-30 g, Charles River Labs) can be used in suchexperiments. After induction of general anesthesia with xylazine(10 mg/kg i.p.) and ketamine (100 mg/kg i.p.) the left hind paw canbe shaved and disinfected with povidone-iodine followed by 70%ethanol. A superficial incision of 1 cm can then be made over theknee overlaying the patella. The patellar ligament can then be cut,exposing the condyles of the distal femur. A 23-gauge needle can beinserted at the level of the intercondylar notch and theintramedullary canal of the femur to create a cavity for injectionof the cells. Twenty microliters of media (sham animals) or mediacontaining tumor cells (approximately 2.5.times.10.sup.6 cells) canthen be injected into the bone cavity using a syringe. To preventleakage of cells outside the bone, the injection site can be sealedwith dental acrylic and the wound closed with skin stitches.

[0499] Pain behaviors can be evaluated in separate groups (n=6) ofsham and bone tumor mice with confirmed hyperalgesia as assessed byspontaneous lifting behavior. Animals can be behaviorally testedduring a 3-week period prior to and after tumor inoculation. Bodyweight of the mice can be recorded throughout the experimentalperiod to help monitor general health status. To measure thespontaneous lifting, the animals can be habituated in a transparentacrylic cylinder of 20 cm diameter put on an horizontal surface andthereafter observed during 4 min for spontaneous lifting behaviorof the left hind paw. After spontaneous lifting behaviorassessment, animals can be immediately placed on a mouse rotarod(e.g. ENV-575M\, Med Associates Inc., GA, USA) at a speed of 16 rpmfor 2 min wherein limb-use during forced ambulation is scored:4=normal; 3=limping; 2=partial non-use of left hind paw;1=substantial non-use of left hind paw; 0=non-use of left hind paw.Assessment of cold allodynia may be made by exposing theipsilateral hind paw of the mouse to 5 repeated applications ofacetone (20 .mu.L) and quantifying the lift/licking frequencyand/or duration. Post-mortem evaluation of bone destruction can beassessed by ACT processing followed by scanning using a system suchas the Skyscan 1076 microtomograph system for small animal imaging(Skyscan 1076\, Skyscan, Aartselaar, Belgium). Measuredhistomorphometry parameters of bone destruction can be subsequentlycorrelated with behavioral endpoints.

[0500] The antihyperalgesic, antiallodynic and disease modifyingeffects of compounds of the Formula (I) can be tested in thismurine model of bone cancer pain in separate groups (n=6 per dosegroup). Animals with confirmed hyperalgesia, as assessed byspontaneous or acetone-evoked lifting, can be behaviorally tested,for example, on days and 22 after distal femur tumor inoculationbefore and 1 h after systemic administration of vehicle (e.g. 20%HPbCD in sterile water) or compounds of the Formula (I). Thestatistical analysis can be performed by one-way ANOVA to comparebehavioral measurements and bone parameters among the experimentalgroups. To compare behavioral measurements and bone parametersbetween sham and tumor-bearing animals, a Mann-Whitney U test canbe used. Results are considered statistically significant atP<0.05 (two-tailed). Data are expressed as mean+/-S.E.M.

[0501] Bone cancer causes intense pain in humans, mimicked inanimal models of bone cancer pain in rodents such as that describedabove. Analgesic treatments that are effective in this modelinclude COX-2 inhibitors (Sabino, M. A.; Ghilardi, J. R.; Jongen,J. L. et al. Cancer Res. 2002, 62(24), 7343-9) and high doses ofmorphine (Luger, N. M. et al. Pain 2002, 99(3), 397-406), agentsused clinically for pain relief in patients experiencing bonecancer pain. Because this model so closely mimics the human diseasestate, the finding that cold allodynia is a prominent symptom (Lee,Seong et al. Yonsei Med. J. 2005, 46(2), 252-9) strongly supportsthe concept that TRPM8 antagonists of the present invention willprovide relief of pain associated with human bone cancer.

Example 12

Respiratory Irritant-Induced Models of Cough

[0502] Compounds of the Formula (I) can be tested in animal modelsof antitussive activity, according to previously documented andvalidated methods, such as those described by: Tanaka, M. andMaruyama, K. J. Pharmacol. Sci. 2005, 99(1), 77-82; Trevisani, M.et al. Throax 2004, 59(9), 769-72; and Hall, E. et al. J. Med.Microbiol. 1999, 48, 95-98. Testing is conducted in transparentventilated chambers with a constant airflow of 400 mL/min. Thetussive agent (citric acid 0.25 M or capsaicin 30 mM) can benebulized via a miniultrasonic nebulizer with an output of 0.4mL/min. The appearance of cough can be detected by means of a tieclip microphone and confirmed by the characteristic posture of theanimal. The cough sounds can be recorded and digitally stored. Ablinded observer subsequently counts the number of elicited coughefforts. In some cases, animals can be sensitized by pre-exposureto certain agents such as ovalbumin. A test compound can beadministered to at the peak of irritant-induced cough to evaluatethe antitussive effects of the compound. In addition, prophylacticor multiple dosing regimes can be utilized to evaluate the testcompound for modulation of the onset and duration ofirritant-induced cough. Variations of these tests predict theantitussive effects of effective clinical agents, including NMDAantagonists such as dextrorphan and dextromethorphan, opioids suchas codeine, beta 2 agonists such as salbutamol and antimuscarinicssuch as ipratropium (Bolser, D. C. et al. Eur. J. Pharmacol. 1995,277(2-3), 159-64; Braga, P. C. Drugs Exper. Clin. Res. 1994, 20,199-203). The antitussive action of menthol in both guinea pig andhumans (Eccles, R. Curr. Allergy Asthma Rep. 2003, 3(3), 210-4;Laude, E. A. et al. Pulm. Pharmacol. 1994, 7(3), 179-84; Morice, A.H. et al. Thorax 1994, 49(10), 1024-6) is predictive of theclinical utility of compounds of the Formula (I) as antitussiveagents.

Example 13

Chemical Irritant-Induced Models of Itch, Contact Dermatitis,Eczema and Other Manifestations of Dermal Allergy, Hypersensitivityand/or Inflammation

[0503] Compounds of the Formula (I) can be tested in animal modelsof contact dermatitis or itch, according to previously documentedand validated methods, such as those described in the scientificliterature (Saint-Mezard, P. et al. Eur. J. Dermatol. 2004, 14(5),284-95; Thomsen, J. S. et al. J. Exp. Dermatol. 2002, 11(4), 370-5;Weisshaar, E. et al. Arch. Dermatol. Res. 1998, 290(6), 306-11;Wille, J. J. et al. Skin Pharmacol. Appl. Skin Physiol. 1999,12(1-2), 18-27). Mice (or species such as guinea pig or rat) can besensitized with 25 mL of 0.5% dinitrofluorobenzene solution (DNFBdiluted 4:1 in acetone:olive oil immediately before application orother haptens, such as 12-myristate-13 acetate, picryl chloride,oxazolone, capsaicin, arachidonic acid, lactic acid, trans-retinoicacid or sodium lauryl sulfate) painted to the shaved dorsal skin oruntreated (controls). Five days later, 10 mL of 0.2% DNFB anonirritant dose) can be applied onto both sides of the right earand the same amount of solvent alone onto the left ear. Earthickness can be monitored daily using a caliper. Compounds of theFormula (I) can be administered at the peak of inflammation toevaluate the anti-allergy activity of compounds. In addition,prophylactic or multiple dosing regimes can be utilized to evaluatethe test compound for modulation of the onset and duration ofanti-allergy activity. Variations of these tests can predict theanti-allergy and itch activity of effective clinical agents. Theability of these models to predict the therapeutic effect ofcompounds in human dermal conditions is supported by thecross-species ability of serotonin to induce itch (Weisshaar, E.;Gollnick, H. Skin Therapy Lett. 2000, 5(5), 1-2, 5). Additionally,the contact sensitizing property of commercially important drugsand the ability of ion channel modulators to prevent and treat skinsensitization in these models (Kydonieus, A. et al. Proceedings ofthe International Symposium on Controlled Release of BioactiveMaterials 24th: 23-24, 1997) demonstrate the therapeutic utility ofcompounds of the Formula (I) in dermal sensitization.

Example 14

Chemical Irritant-Induced Models of Rhinitis and OtherManifestations of Nasal Hypersensitivity and/or Inflammation

[0504] Compounds of the Formula (I) can be tested in animal modelsof rhinitis, according to previously documented and validatedmethods, such as those described in the scientific literature(Hirayama, Y. et al. Eur. J. Pharmacol. 2003, 467(1-3), 197-203;Magyar, T. et al. Vaccine 2002, 20(13-14), 1797-802; Tiniakov, R.L. et al. J. Appl. Physiol. 2003, 94(5), 1821-8). Testing can beconducted in mouse, guinea pig, dog or human in response tointranasal challenge with one or more irritants such as cold air,capsaicin, bradykinin, histamine, pollens, dextran sulfate,2,4-tolylene diisocyanate, Bordetella bronchiseptica, Pasteurellamultodica or acetic acid. In some cases, animals can be sensitizedby pre-exposure to certain agents including, but not limited to,ragweed or ovalbumin. Prior to or following irritantadministration, the test subject can receive, respectively, theprophylactic or therapeutic administration one or more times ofcompounds of the Formula (I), or vehicle control, by the enteral orparenteral route. Significant differences indicative of nasalrhinitis or sensitization for the test compound-treated subjectscompared with vehicle-treated subjects can be taken as evidence ofanti-rhinitis activity. Independent variables include dose,frequency and route of administration, time interval betweenprophylactic or therapeutic test compound administration andirritant challenge as well as sex and non-sex genotype of the testsubject. The intimate role of neurogenic inflammation in thesehypersensitivity states demonstrates that compounds of the Formula(I) desensitize or block the sensitization underlying these diseasestates.

Example 15

Conflict-Induced Models of Anxiety, Panic Disorder and OtherNon-Adaptive Stressful or Phobic Responses

[0505] Compounds of the Formula (I) can be tested in animal modelsof anxiety, panic disorders and other non-adaptive responses,according to previously documented and validated methods, such asthose described by Cryan and Holmes (Cryan, J. F.; Holmes, A. Nat.Rev. Drug Discov. 2005, 4(9), 775-90) or Braw et al. (Braw, Y. etal. Behav. Brain Res. 2006, 167, 261-269). Specifically, forstudies in rats, the following apparati may be utilized: anopen-field arena (62 cm.times.62 cm) enclosed by opaque walls (30cm high) and plus-maze consists of two open arms, 50 cm.times.10cm, and two enclosed arms, 50 cm.times.10 cm.times.40 cm with anopen roof, arranged such that the two arms of each type areopposite each other. The maze is elevated to a height of 70 cm. Thewalls of the enclosed arms are made from black Plexiglas, while thefloors from white Plexiglas. Videotape recordings can be analyzedusing the `Observer` system (Noldus Information Technology). Asubject rat can be removed from its home cage, weighed and placedgently in the center of the open-field arena. The rat can beallowed to explore the open-field freely while its behavior isvideotaped for 5 min. Afterwards, it can be transferred to theplus-maze and placed at the center, facing a closed arm. The rat'sbehavior can again be videotaped for 5 min, after which it can bereturned to its home cage. The apparatus can be cleaned using a 70%ethanol solution between rats.

[0506] Open-field and plus-maze measures can be grouped into twobehavioral classes, namely `anxiety-like behaviors` and `activity`.Open-field behavioral measures may include 1) Anxiety measures: %time in center square, % number of entries to center square (fromtotal squares entered), % time freezing, latency to first freezing(freezing is scored when the subject is in an immobile state for atleast 3 seconds; and 2) Activity measures: Total squares entered,number of rearings (standing on two hind legs), latency for firstrearing. Plus-maze measures may include 1) Anxiety: % time in openarms, % number of entries to open arms (from total entries), numberof unprotected head dips, latency to enter open arm; and 2)Activity: Total entries to all arms. Anxiety-like behaviors andactivity can be analyzed by one-way ANOVA's on each of themeasures, for each the between-subject comparisons. Plus-mazeanalyses can be conducted in a similar fashion.

[0507] Testing may also be conducted in mouse or rat in thisfashion in order to measure avoidance of other aversiveenvironmental stimuli such as Geller or Vogel anticonflict tests,the light/dark test and the hole-board test (see Cryan, J. F.;Holmes, A. Nat. Rev. Drug Discov. 2005, 4(9), 775-90). Prior toenvironmental exposure, the test subject can receive theprophylactic administration one or more times of compounds of theFormula (I), or vehicle control (e.g. 10% Solutol in sterilewater), by the enteral or parenteral route. The cumulative time ornumber of times spent engaged in the aversive behavior can bemeasured. Significant differences in one or more of these measuresfor the test compound-treated subjects compared withvehicle-treated subjects can be taken as evidence of anxiolyticactivity. Because these models are pharmacologically validated bythe effectiveness of clinically useful anxiolytics (Cryan, J. F.;Holmes, A. Nat. Rev. Drug Discov. 2005, 4(9), 775-90), they will beuseful for the detection of anxiolytic compounds of the Formula(I).

Example 16

Bladder Pressure- and Hypertrophy-Induced Models of UrinaryIncontinence

[0508] Compounds of the Formula (I) can be tested in animal modelsof urinary incontinence according to previously documented andvalidated methods, such as those described by in the scientificliterature (Kaiser, S.; Plath, T. (Metagen Pharmaceuticals GmbH,Germany DE Patent 10215321); McMurray, G. et al. Brit. J.Pharmacol. 2006, 147 Suppl 2, S62-79). TRPM8 is expressed in humanprostate, testicle, seminiferous tubules, scrotal skin and inflamedbladder (Stein, R. J. et al. J. Urol. 2004, 172(3), 1175-8; Stein,R. J. et al. J. Urol. 2004, 172(3), 1175-8; Mukerji et al. BMCUrology 2006, 6, 6). Excitation of TRPM8 receptors through coolingor application of menthol causes contraction in the bladder and adecrease in micturation threshold volume (Tsukimi, Y.; Mizuyachi,K. et al. Urology 2005, 65(2), 406-10). To assess compounds of theFormula (I) for potential urinary incontinence activity,Sprague-Dawley rats are surgically implanted with bladder cathetersallowing for the delivery of fluid (typically saline) and themonitoring of pressure (using a pressure transducer). Cystometryrecordings can be monitored with a polygraph to evaluate voidinginterval, threshold pressure, bladder capacity, bladder compliance,and the number of spontaneous bladder contractions. For example,the bladder catheter can be connected to a Harvard infusion pump,and bladders perfused overnight with saline at 2 mL/h. The nextmorning the bladder catheter can be attached (using a "T"connector) to a Statham pressure transducer (Model P23 Db) and to aHarvard infusion pump. A plastic beaker attached to a forcedisplacement transducer (Grass FTO3) can be placed under the rat'scage to collect and record urine volume. The cystometric evaluationof bladder function can be started by infusing saline (20 mL/h) andafter the first micturition the infusion is maintained for 20 min.Two hours after the first cystometry period, the rats can be dosedorally with compounds of the Formula (I) and a second cystometry isperformed between 30 min and 4 h after administration of testcompound. The appropriate vehicle (e.g. 10% Solutol in sterilewater) can be similarly administered to groups of rats that servedas controls and the cystometry can be performed at the samerespective time points.

[0509] Compounds of the Formula (I) can also be evaluated underconditions of bladder hypertrophy and instability. Underanesthesia, a silk ligature is tied around the proximal urethra ofrodents producing a partial outlet obstruction and subsequenthypertrophied bladder development within 6-9 weeks (Woods, M. etal. J. Urology 2001, 166, 1142-47). Cystometry recordings can thenbe evaluated as described above. Such preclinical procedures aresensitive to compounds having clinical utility for the treatment ofurinary incontinence (Soulard, C. et al. J. Pharmacol. Exp. Ther.1992, 260(3), 1152-8), and the activity of compounds of the Formula(I) in this model would be predictive of clinical utility.

Example 17

In Vivo Model for Cold-Enhanced Central Pain States

[0510] Injury to the brain or spinal cord, such as that caused bytrauma, interrupted blood flow or neurodegenerative diseases, oftenprecipitates a central pain condition. Examples of such injuriescharacterized, in part by, a hypersensitivity to cold stimuliinclude multiple sclerosis (Morin, C. et al. Clin. J. Pain 2002,18(3), 191-5; Svendsen, K. B. et al. Pain 2005, 114(3), 473-81),stroke or cerebral ischemia (Greenspan, J. D. et al. Pain 2004,109(3), 357-66) and spinal cord injury (Defrin, R.; Ohry, A.;Blumen, N.; Urca, G. Pain 2001, 89(2-3), 253-63; Defrin, R. et al.Brain 2002, 125(Pt 3), 501-10; Finnerup, N. B. et al.Anesthesiology 2005, 102(5), 1023-30). Each of these conditions maybe readily modeled in animals for assessment of the ability ofcompounds of the Formula (I) to mollify the hypersensitive state.For example, a spinal cord injury (SCI) can be performed in adultSprague-Dawley rats having a body weight of 150-200 g at time ofsurgery (Erichsen et al. Pain 2005, 116, 347-358). The rats can beanaesthetized with chloral hydrate (300 mg/kg, i.p., Sigma, USA)and a catheter can be inserted into the jugular vein. A midlineskin incision can then be made along the back to expose the T11-L2vertebrae. The animals can be positioned beneath a tunable argonion laser (Innova model 70, Coherent Laser Products Division, CA,USA) operating at a wavelength of 514 nm with an average power of0.17 W. The laser light can be focused into a thin beam coveringthe single T13 vertebra, which can be irradiated for 10 min.Immediately before the irradiation, erythrosin B (Aldrich, 32.5mg/kg dissolved in 0.9% saline) can be injected intravenously viathe jugular catheter. Due to rapid metabolism of erythrosin B, theinjection can be repeated after 5 min in order to maintain adequateblood concentrations. During irradiation, the body core temperaturecan be maintained at 37-38.degree. C. by a heating pad. Afterirradiation the wound can be closed in layers and the skin suturedtogether.

[0511] SCI rats can be routinely tested for the presence ofpain-like behaviors from 3-4 weeks after surgery. The fur of theanimals can be shaved at least a day prior to examination of thecutaneous pain threshold to avoid sensitization of the skinreceptors. During testing, the rats can be gently held in astanding position by the experimenter and the flank area and hindlimbs can be examined for hypersensitivity to sensory stimulation.On the day of drug testing, SCI rats can be administered drugaccording to the experimental schedule and the time course ofpain-like behaviors can be measured. To test for the presence ofcold allodynia, ethyl chloride or acetone can be sprayed onto theskin of the animals, often that which has been previouslydetermined to be sensitive to mechanical stimulation by von Freyfilament testing. The subsequent response to cold stimulation canbe observed and classified according to the following scale: 0, novisible response; 1, localized response (skin twitch) withoutvocalization; 2, transient vocalization; 3, sustained vocalization.Kruskal Wallis ANOVA on ranks can be used to analyze the overalleffects of non-parametric data obtained in response to coldstimulation following pretreatment with either compounds of theFormula (I) or vehicle.

Example 18

In Vivo Model for Post-Anesthetic Shivering

[0512] Spontaneous post-anesthetic tremor that resembles shiveringis common during recovery from anesthesia. Risks to postoperativepatients include an increase in metabolic rate of up to 400%,hypoxemia, wound dehiscence, dental damage, and disruption ofdelicate surgical repairs. The etiology of spontaneouspost-anesthetic tremor is most commonly attributed to normalthermoregulatory shivering in response to intraoperativehypothermia. In most operating and recovery rooms, shivering iscontrolled by the use of humidifiers, warming blankets, andinhalation of humidified heated oxygen. However, pharmacologicalcontrol is an effective alternate treatment modality (Bhatnagar, S.et al. Anesth. Intensive Care 2001, 29(2), 149-54; Tsai, Y. C.;Chu, K. S. Anesth. Analg. 2001, 93(5), 1288-92). Compounds of theFormula (I) may be assessed for their ability to mitigatepost-anesthetic induced-shaking by using animal models such as thatdescribed by Nikki et al. (Nikki, P.; Tammisto, T. Acta Anaesth.Scand. 1968, 12(3), 125-34) and Grahn (Grahn, D. A. et al. J.Applied Physiology 1996, 81, 2547-2554). For example, Wistar rats(males, weighing 250-450 g) may be surgically implanted with anEEG/EMG recording array to assess post anesthetic tremor activity.The EEG electrodes are located bilaterally 2 mm off midline andadjacent to bregma and lamda. Following a one-week recovery period,frontal-occipital EEG, raw EMG, and integrated EMG activities, aswell as three temperatures (skin, rectal, and water blankettemperatures during anesthesia), and ambient temperaturepost-anesthesia can be monitored throughout the experiment usingcopper-constantin thermocouples. The EEG and EMG signals can berecorded on polygraph paper (5 mm/s, Grass model 7E polygraph) and,during recovery from anesthesia, the EEG is computer scored in 10second epochs as either synchronized: high amplitude (0.100 .mu.V),low frequency (1-4 Hz dominated) activity characteristic ofslow-wave sleep (SWS-like) or desynchronized: low amplitude (75.mu.V), high frequency (5-15 Hz dominated), characteristic ofwaking and rapid-eye-movement sleep (W-like). The EMG activity canbe quantified as the averaged summed voltage/time interval byprocessing the raw EMG signal through an integrator (Grass model7P3, 0.5 s time constant). On the day of an experiment, the animalcan be placed in a small acrylic box (15.times.15.times.15 cm) andexposed to a halothane vapor-air mixture (4% halothane).Immediately after the induction of anesthesia, the animal can beremoved from the enclosure and subsequently anesthetized through anose cone. Following cessation of anesthesia, two stages ofrecovery can be judged: emergence from anesthesia and restorationof behavioral activity (behavioral recovery). Emergence fromanesthesia may be defined as an increase in tonic EMG activity anda change in the EEG from a SWS-like pattern to a W-like pattern.Behaviorally, recovery has occurred when the animal rises from aprone position and initiated coordinated movements. The timeintervals from termination of anesthesia to emergence andbehavioral recovery can be measured in all animals. Time intervaldata can be subjected to a repeated measure analysis of variance,and the Scheffe's method can be employed for testing differencesbetween pairs of means.

Example 19

Cold-Evoked Cardiovascular Pressor Responses

[0513] Compounds of the Formula (I) can be tested in animals andhumans for their ability to mitigate cardiovascular pressorresponses evoked by cold exposure. Seasonal environmental coolingis directly associated with elevated blood pressure and anincreased incidence of coronary events in human populationsworldwide (Barnett, A. G. et al. J. Epidemiol. Community Heath2005, 59, 551-557). Cold-evoked pulmonary hypertension and coldaggravation of chronic obstructive pulmonary disease are clinicalindications susceptible to heightened cardiopulmonary sensitivityto cold (Marno, P. et al. Eur. Respiratory Review 2006, 15(101),185; Acikel, M. et al. Int. J. of Cardiol. 2004, 97, 187-192). Theclinical cold pressor test assesses changes in blood pressure (BP)and cold pain perception during a 2-3 minute immersion of one handinto ice water. This test may be utilized to characterize analgesiccompounds (Koltzenberg, M. et al. Pain 2006, 126(1-3), 165-74) andto assess cold hypersensitivity (Desmeules, J. A. et al. Arthritisand Rheumatism 2003, 48(5), 1420-9). Compounds of the Formula (I)can be studied in an anesthetized rat cold pressor paradigm todetermine whether TRPM8 antagonism would interfere with the bloodpressure pressor response to cold stimulation of the forepaws. MaleSprague-Dawley rats (300-450 g) anesthetized with sodiumpentobarbital are instrumented with a jugular catheter and anindwelling carotid artery cannula connected to a pressuretransducer. Vehicle (e.g. 20% HPbCD in sterile water) or testcompound is infused (1 mL/kg) over one minute through theintravenous catheter. Ten minutes later both forelimbs are packedin crushed ice for 5 minutes. Alternatively, the test compound andvehicle treatments may be administered orally at an appropriatedtime prior to the surgical cannulations and cold challenge. Percentchanges in mean arterial pressure in response to this cold stimulusare calculated for vehicle and test compound pretreatments. Percentinhibition attributed to treatment with test compound is thendetermined using the following formula: % Inhibition=[1-(coldevoked % change in BP post-test compound/cold evoked % change in BPpost-vehicle)].times.100.

Example 20

Cold-Induced Vasoconstriction

Ramifications for Tissue Perfusion

[0514] Damage may occur to a bodily tissue when blood flow iscompromised or interrupted. Reasons for vascular compromise includeperipheral vascular disease (Lamah, M. et al. European Journal ofVascular and Endovascular Surgery 1999, 18(1), 48-51), priortraumatic or frostbite injury, Raynaud's syndrome (Lutolf, O. etal. Microvascular Research 1993, 46(3), 374-82), diabeticneuropathy (Forst, T. et al. Clinical Science 1998, 94(3), 255-61),surgical intervention and autonomic dysregulation (Gherghel, D. etal. Investigative Opthalmology and Visual Science 2004, 45(10),3546-54). In the case of marginal resting perfusion,vasoconstriction as enhanced by cool temperature may aggravatesymptoms and potentiate tissue injury (Cankar, K. et al. Journal ofHand Surgery 2000, 25(3), 552-8; Lutolf, O. et al. MicrovascularResearch 1993, 46(3), 374-82.). Several of these conditions may bereadily modeled in animals to assess of the ability of TRPM8antagonists such as compounds of the Formula (I) to preserve tissueperfusion in the face of local cooling. For example, laser Dopplerassessment of skin blood flow may be studied in the paws ofanesthetized rats (Hord, A. H. et al. Anesthesia and Analgesia1999, 88(1), 103-8), wherein the paw is subject to a series ofdecreasing temperature steps as applied by physical contact with aPeltier cooling element under computer control. The laser Dopplermeasures skin perfusion in the face of cooling-inducedvasoconstriction thereby generating a temperature.times.perfusionrelationship. Systemic administration of a TRPM8 antagonist isanticipated to shift this curve toward preserving perfusion atreduced temperatures relative to vehicle pretreatment. Thisactivity is envisioned to be therapeutic in protecting tissue fromhypo-perfusion and ischemia thereby minimizing the associatedsymptoms (e.g. pain) and potential tissue damage.

[0515] While the foregoing specification teaches the principles ofthe present invention, with examples provided for the purpose ofillustration, it will be understood that the practice of theinvention encompasses all of the usual variations, adaptationsand/or modifications as come within the scope of the followingclaims and their equivalents.

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