Pyrazines as delta opioid receptor modulators

1. A compound of Formula I

wherein

R 1 is selected from the group consisting of

i) phenyl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, chloro, and fluoro;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, fluoro, chloro, and cyano; and

iii) pyrimidin-5-yl;

or, R 1 is optionally methoxy-methyl when Y is ethynyl;

Y is ethynyl or a bond;

R 2 is phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol -5-yl, indolyl, or pyridinyl optionally substituted with methyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy;

or R 2 is phenyl substituted with one C 1-4 alkylcarbonylamino or 1H-imidazol-1-yl substituent;

X is O or CH 2 ;

L is absent and R 3 is 4-amino-cyclohexyl; or, L is methylene and R 3 is selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-amino-eth- 1-yl; and

iii) 1-amino-cyclopent- 1-yl;

or, R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazinyl optionally substituted with 4-C 1-4 alkyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R 1 is selected from the group consisting of

i) phenyl;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkoxy, fluoro, chloro, and cyano; and

iii) pyrimidin-5-yl;

or, R 1 is optionally methoxy-methyl when Y is ethynyl.

3. The compound of claim 2 wherein R 1 is selected from the group consisting of

i) phenyl;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkoxy and cyano; and

iii) pyrimidin-5-yl.

4. The compound of claim 3 wherein R 1 is selected from the group consisting of

i) phenyl;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of methoxy and cyano; and

iii) pyrimidin-5-yl.

5. The compound of claim 1 wherein Y is a bond.

6. The compound of claim 1 wherein R 2 is phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol -5-yl, indolyl, or pyridinyl optionally substituted with methyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy;

or, R 2 is phenyl substituted with one C 1-4 alkylcarbonylamino substituent.

7. The compound of claim 6 wherein R 2 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy;

or, R 2 is phenyl substituted with one C 1-4 alkylcarbonylamino substituent.

8. The compound of claim 7 wherein R 2 is phenyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy.

9. The compound of claim 1 wherein X is O.

10. The compound of claim 1 wherein L is methylene and R 3 is selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-amino-eth-1-yl; and

iii) 1-amino-cyclopent-1-yl;

or, R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazinyl.

11. A compound of Formula (I)

wherein

R 1 is selected from the group consisting of

i) phenyl;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkoxy, fluoro, chloro, and cyano; and

iii) pyrimidin-5-yl;

or, R 1 is optionally methoxy-methyl when Y is ethynyl;

Y is a bond or ethynyl;

R 2 is phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol -5-yl, indolyl, or pyridinyl optionally substituted with methyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy;

or, R 2 is phenyl substituted with one C 1-4 alkylcarbonylamino substituent;

X is O or CH 2 ;

L is absent and R 3 is 4-amino-cyclohexyl; or L is methylene and R 3 is selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-amino-eth-1-yl; and

iii) 1-amino-cyclopent-1-yl;

or, R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazinyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

12. A compound of Formula (I)

wherein

R 1 is selected from the group consisting of

i) phenyl;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkoxy and cyano; and

iii) pyrimidin-5-yl;

Y is a bond;

R 2 is phenyl optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy;

or, R 2 is phenyl substituted with one C 1-4 alkylcarbonylamino substituent;

X is O;

L is methylene and R 3 is selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-amino-eth-1-yl; and

iii) 1-amino-cyclopent- 1-yl;

or, R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazinyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

13. A compound of Formula (I)

wherein

R 1 is selected from the group consisting of

i) phenyl;

ii) pyridinyl optionally substituted with one substituent selected from the group consisting of methoxy and cyano; and

iii) pyrimidin-5-yl;

Y is a bond;

R 2 is phenyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, fluoro, chloro, cyano, cyanomethyl, difluoromethoxy, trifluoromethoxy, and hydroxy;

X is O;

L is methylene and R 3 is selected from the group consisting of

i) pyrrolidin-2-yl;

ii) 1-amino-eth-1-yl; and

iii) 1-amino-cyclopent-1-yl;

or, R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazinyl;

and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof

14. A compound of Formula (I)

selected from the group consisting of

a compound wherein R 1 is 6-methoxy-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyridin-3-yl, Y is ethynyl, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is methoxy-methyl, Y is ethynyl, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-ethylphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is benzo[1,3]dioxol-5-yl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 3-fluoro-4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 2-fluoro-4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-chlorophenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 3-chlorophenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 2-chlorophenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 3-methylcarbonylamino-phenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-(1H-imidazol-1-yl)phenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 3-hydroxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is CH 2 , L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is CH 2 , L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-cyanophenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is 1-amino-eth-1-yl; (1S)

a compound whereinR 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is 1-amino-eth-1-yl; (1S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is 1-amino-cyclopent-1-yl;

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is 1-amino-cyclopent-1-yl;

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is CH 2 , L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 3-fluoro-4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 2-fluoro-4-methoxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-cyanomethyl-phenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 6-methyl-pyridin-3-yl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-difluoromethoxy-phenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, and R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazin- 1 -yl;

a compound wherein R 1 is pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, and R 3 is cyclized with L and the nitrogen atom to which L is attached to form piperazin-1-yl;

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is benzofuran-5-yl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is pyrimidin-5-yl, Y is a bond, R 2 is 2,3-dihydro-benzofuran-5-yl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is absent, and R 3 is trans-4-amino-cyclohexyl;

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-methoxyphenyl, X is O, L is absent, and R 3 is cis-4-amino-cyclohexyl;

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-trifluoromethoxy-phenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 4-ethylphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 3-hydroxyphenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is benzofuran-5-yl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is indol-5-yl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 2-chlorophenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S) and

a compound wherein R 1 is 5-cyano-pyridin-3-yl, Y is a bond, R 2 is 3-chlorophenyl, X is O, L is methylene, and R 3 is pyrrolidin-2-yl; (2S)

and pharmaceutically acceptable salts thereof.

15. 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.

16. The pharmaceutical composition of claim 15 , wherein the composition is a solid, oral dosage form.

17. The pharmaceutical composition of claim 15 , wherein the composition is a syrup, an elixir, or a suspension.