Cold menthol receptor antagonists

1. A compound of Formula (I)

wherein

A is phenyl;

provided that R 2 is other than 2-chloro, 2-C 1-4 alkoxy, 4-C 1-4 alkoxy, 2-C 1-4 alkoxycarbonyl, or 4-C 1-4 alkoxycarbonyl;

or L is —N(R 3 )(CH 2 ) n —, and R 1 and L are attached to adjacent carbon atoms of phenyl, R 1 and R 3 are optionally taken with the atoms to which they are attached to form dihydro-indol-1-yl or dihydro-quinolin-1-yl;

R 1 is one to three substituents selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, and hydroxy;

L is —Z —(CH 2 ) n — or —CH 2 —;

n is 0 or 1;

Z is O, S, or NR 3 ; provided that when Z is O or S, A is phenyl;

R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, chloro, fluoro, bromo, carboxy, or C 1-4 alkoxycarbonyl;

R 3 is hydrogen or C 1-3 alkyl;

R 4 is hydrogen or C 1-4 alkyl;

R 5 is isoquinolinyl and quinolinyl; wherein R 5 is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C 1-4 alkyl, hydroxy, C 1-4 alkoxy, trifluoromethyl, chloro, fluoro, bromo, carboxy, C 1-4 alkoxycarbonyl, and cyano;

or an enantiomers, a diastereomer, or a pharmaceutically acceptable salt thereof;

provided that a compound of Formula (I) is other than

a compound wherein A is phenyl, R 1 is 3-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, n is 1, Z is NR 3 , R 3 is hydrogen, R 4 is hydrogen, and R 5 is isoquinolin-5-yl;

and

a compound wherein A is phenyl, R 1 is 4-methoxy, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, n is 0, Z is NR 3 , R 3 is hydrogen, R 4 is hydrogen, and R 5 is isoquinolin-5-yl.

2. The compound according to claim 1 wherein

R 2 is other than 2-chloro, 2-C 1-4 alkoxy, 4-C 1-4 alkoxy, 2-C 1-4 alkoxycarbonyl, or 4-C 1-4 alkoxycarbonyl;

or L is —N(R 3 )(CH 2 ) n —, and R 1 and L are attached to adjacent carbon atoms of phenyl, R 1 and R 3 are optionally taken with the atoms to which they are attached to form dihydro-indol-1-yl or dihydro-quinolin-1-yl.

3. The compound according to claim 2 wherein

R 2 is other than 2-chloro, 2-C 1-4 alkoxy, 4-C 1-4 alkoxy, 2-C 1-4 alkoxycarbonyl, or 4-C 1-4 alkoxycarbonyl;

and, when L is —N(R 3 )(CH 2 ) n —, and R 1 and L are attached to adjacent carbon atoms of phenyl, R 1 and R 3 are optionally taken with the atoms to which they are attached to form dihydro-indol-1-yl.

4. The compound according to claim 3 wherein R 2 is other than 2-chloro, 2-C 1-4 alkoxy, 4-C 1-4 alkoxy, 2-C 1-4 alkoxycarbonyl, or 4-C 1-4 alkoxycarbonyl.

5. The compound according to claim 1 wherein R 1 is one to two substituents selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, and hydroxy.

6. The compound according to claim 5 wherein R 1 is one to two substituents selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, fluoro, and chloro.

7. The compound according to claim 6 wherein R 1 is one to two substituents selected from the group consisting of hydrogen, methyl, fluoro, and chloro.

8. The compound according to claim 1 wherein L is —Z—(CH 2 ) n — or —CH 2 —; wherein n is 0 or 1; and Z is S or NR 3 ; provided that Z is S.

9. The compound according to claim 8 wherein L is —Z—(CH 2 ) n —; wherein n is 0; and Z is S or NR 3 ; provided that Z is S.

10. The compound according to claim 9 wherein L is —Z—(CH 2 ) n —; wherein n is 0; and Z is NR 3 .

11. The compound according to claim 1 wherein R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl, chloro, or bromo; provided that R 2 is other than 2-chloro.

12. The compound according to claim 1 wherein R 2 is t-butyl, trifluoromethyl, chloro, or bromo; provided that R 2 is other than 2-chloro.

13. The compound according to claim 1 wherein is 4-t-butyl, 4-trifluoromethyl, or 4-chloro.

14. The compound according to claim 1 wherein R 3 is hydrogen or methyl.

15. The compound according to claim 1 wherein R 3 is hydrogen.

16. The compound according to claim 1 wherein R 4 is hydrogen.

17. The compound according to claim 1 wherein R 5 quinolinyl or isoquinolinyl; wherein R 5 is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and fluoro.

18. The compound according to claim 17 wherein R 5 is quinolinyl or isoquinolinyl and is optionally substituted with one C 1-4 alkyl substituent.

19. The compound according to claim 1 wherein R 5 is quinolin-5-yl or isoquinolin 5yl.

20. A compound of Formula (I)

wherein

A is phenyl;

provided that R 2 is other than 2-chloro;

or, L is —N(R 3 )(CH 2 ) n —, and R 1 and L are attached to adjacent carbon atoms, R 1 and R 3 are optionally taken with the atoms to which they are attached to form dihydro-indol-1-yl or dihydro-quinolin-1-yl;

R 1 is one to two substituents selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, and hydroxl;

L is —Z—(CH 2 ) n — or —CH 2 —; wherein n is 0 or 1; and Z is S or NR 3 ; provided that when Z is S, A is phenyl

R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl, chloro, or bromo;

R 3 is hydrogen or methyl;

R 4 is hydrogen;

and

R 5 is quinolinyl or isoquinolinyl, wherein R 5 is optionally substituted with 1-2 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, and fluoro;

or an enantiomers, a diastereomer, or a pharmaceutically acceptable salt thereof;

provided that a compound of Formula (I) is other than

a compound wherein R 1 is 3-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, n is 1, Z is NR 3 , R 3 is hydrogen, R 4 is hydrogen, and R 5 is isoquinolin-5-yl or

a compound wherein R 1 is 4-methoxy, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, n is 0, Z is NR 3 , R 3 is hydrogen, R 4 is hydrogen, and R 5 is isoquinolin-5-yl.

21. A compound of Formula (I)

wherein

A is phenyl;

provided that R 2 is other than 2-chloro; or, L is —N(R 3 )(CH 2 ) n —, and R 1 and L are attached to adjacent carbon atoms, R 1 and R 3 are optionally taken with the atoms to which they are attached to form dihydro-indol-1-yl;

R 1 is one to two substituents selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, fluoro, and chloro;

L is —Z—(CH 2 ) n —; wherein n is 0; and Z is S or NR 3 ;

R 2 is t-butyl, trifluoromethyl, chloro, or bromo;

R 3 is hydrogen;

R 4 is hydrogen;

and

R 5 is quinolinyl or isoquinolinyl wherein R 5 is optionally substituted with one to two C 1-4 alkyl substituents;

or an enantiomers, a diastereomer, or a pharmaceutically acceptable salt thereof;

provided that a compound of Formula (I) is other than

a compound wherein R 1 is 4-methoxy, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, n is 0, Z is NR 3 , R 3 is hydrogen, R 4 is hydrogen, and R 5 is isoquinolin-5-yl.

22. A compound of Formula (I)

wherein

A is phenyl; provided that R 2 is other than 2-chloro;

R 1 is one to two substituents selected from the group consisting of hydrogen, C 1-3 alkyl, methoxy, fluoro, and chloro;

L is —Z—(CH 2 ) n —; wherein n is 0; and Z is NR 3 ;

R 2 is t-butyl, trifluoromethyl, chloro, or bromo;

R 3 and R 4 are each hydrogen;

and

R 5 is quinolinyl or isoquinolinyl;

or an enantiomers, a diastereomer, or a pharmaceutically acceptable salt thereof;

provided that a compound of Formula (I) is other than

a compound wherein R 1 is 4-methoxy, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, n is 0, Z is NR 3 , R 3 is hydrogen, R 4 is hydrogen, and R 5 is isoquinolin-5-yl.

23. A compound of Formula (I)

wherein

A is phenyl;

R 1 is one to two substituents selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

L is —Z—(CH 2 ) n —; wherein n is 0; and Z is NR 3 ;

R 2 is 4-t-butyl, 4-trifluoromethyl, or 4-chloro;

R 3 and R 4 are each hydrogen;

and

R 5 is quinolin-5-yl or isoquinolin-5-yl;

or an enantiomers, a diastereomer, or a pharmaceutically acceptable salt thereof.

24. A compound of Formula (I)

Formula (I)selected from the group consisting of

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-t-butyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is t-butyl, R 2 is H, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-t-butyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is methyl, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-t-butyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is quinolin-6-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-t-butyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-6-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 3-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 4-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 1, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 4-chloro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 1, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is taken with R 3 to form 2,3-dihydro-indol-1-yl, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is taken with R 3 to form 3,4-dihydro-2H-quinolin-1-yl, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-methoxy, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-methyl, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-isopropyl, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-fluoro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,6-dimethyl, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is taken with R 3 to form 7-methyl-2,3-dihydro-indol-1-yl, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is quinolin-8-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl (*S);

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl (*R);

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-bromo, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 4-fluoro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 3-fluoro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-fluoro, R 2 is 4-bromo, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 3-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-fluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 4-fluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,4-difluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 4-methoxy, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is quinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,6-difluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,6-difluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is quinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,4-difluoro, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,3-difluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,3-difluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is quinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2,5-difluoro, R 2 is 4-chloro, L is —Z—(CH 2 ) n —, Z is NR 3 , R 3 is H, n is 0, R 4 is H, and R 5 is quinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is 2-fluoro, R 2 is 4-trifluoromethyl, L is —-CH 2 —, R 4 is H, and R 5 is isoquinolin-5-yl;

a compound of Formula (I) wherein A is phenyl, R 1 is H, R 2 is 4-trifluoromethyl, L is —Z—(CH 2 ) n —, Z is S, R 3 is H, n is 0, R 4 is H, and R 5 is isoquinolin-5-yl;

or an enantiomers, a diastereomer, or a pharmaceutically acceptable salt thereof.

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

26. The pharmaceutical composition of claim 25 , wherein the composition is a solid oral dosage form.

27. A pharmaceutical composition of claim 25 , wherein the composition is a syrup, an elixir, or a suspension.