Pyrazines as modulators of GPR6

1. The compound of formula I

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-6 heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted C 1-10 heteroaryl;

X 1 is N and X 2 is CH; or

X 1 is CH and X 2 is N; or

X 1 is N and X 2 is N;

when X 1 is N, Z is selected from the group consisting of C 1-6 alkylene, C 1-6 haloalkylene, —C(O)—, and —S(O) 2 —;

when X 1 is CH, Z is selected from the group consisting of C 1-6 alkylene, C 1-6 haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and —S(O) 2 —;

q is 0, 1, or 2;

s is 0, 1, or 2;

R 2 is —OR 5 or —NR 6 R 7 ;

R 3 , each time taken, is independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, and trifluoromethyl;

p is 0, 1, or 2;

R 4 , each time taken, is independently selected from the group consisting of C 1-6 alkyl, cyano, hydroxy, halo, optionally substituted C 3-6 heterocyclyl, —C(O)—R 8 , —C(O)—N(R 9 )(R 10 ), and —C(O)—OR 11 ;

r is 1 or 2;

R 5 is selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl;

R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 7 is selected from the group consisting of optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;

R 8 is selected from the group consisting of optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;

R 9 is selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl;

R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; or

R 9 and R 10 are taken together with the nitrogen to which they are attached form a 4 to 7 membered, saturated, ring optionally having 1 additional ring heteroatom selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with 1 to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, optionally substituted C 3-6 heterocyclyl, C 1-9 amide, optionally substituted C 1-6 alkyl, and C 1-4 alkoxy and substituted on any additional ring nitrogen by a substituent selected from the group consisting of hydrogen, C 3-8 cycloalkyl, and optionally substituted C 1-6 alkyl; and

R 11 is selected from the group consisting of hydrogen and C 3-8 cycloalkyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is CH and X 2 is N.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X 1 is N and X 2 is N.

4. The compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein an R 4 is cyano.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is optionally substituted C 6-10 aryl or a pharmaceutically acceptable salt thereof.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is C 1-6 alkylene.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is —O—.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is —C(O)—.

9. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is —NR 6 R 7 .

10. A compound, which is selected from the group consisting of:

(R)-3-cyano-5-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-(2-(dimethylamino)ethyl)-6-(isopropylamino)-N-methylpyrazine-2-carboxamide;

6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-(2-(dimethylamino)-ethyl)-5-(isopropylamino)-N-methylpyrazine-2-carboxamide; and

6-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5-(isopropylamino)-3-(methoxymethyl)pyrazine-2-carbonitrile; and

6-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-((2-(dimethylamino)ethoxy)methyl)-5-(isopropylamino)pyrazine-2-carbonitrile;

or a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

11. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as defined in claim 1 , and a pharmaceutically acceptable excipient.

12. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of formula I

or pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-6 heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted C 1-10 heteroaryl;

X 1 is N and X 2 is CH; or

X 1 is CH and X 2 is N; or

X 1 is N and X 2 is N;

when X 1 is N, Z is selected from the group consisting of C 1-6 alkylene, C 1-6 haloalkylene, —C(O)—, and —S(O) 2 —;

when X 1 is CH, Z is selected from the group consisting of C 1-6 alkylene, C 1-6 haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and —S(O) 2 —;

q is 0, 1, or 2;

s is 0, 1, or 2;

R 2 is —OR 5 or —NR 6 R 7 ;

R 3 , each time taken, is independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, and trifluoromethyl;

p is 0, 1, or 2;

R 4 , each time taken, is independently selected from the group consisting of optionally substituted C 1-6 alkyl, cyano, hydroxy, halo, optionally substituted C 3-6 heterocyclyl, —C(O)—R 8 , —C(O)—N(R 9 )(R 10 ), and —C(O)—OR 11 ;

r is 1 or 2;

R 5 is selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl;

R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 7 is selected from the group consisting of optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;

R 8 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 3-6 heterocyclyl;

R 9 is selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl;

R 10 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; or

R 9 and R 10 are taken together with the nitrogen to which they are attached form a 4 to 7 membered, saturated, ring optionally having 1 additional ring heteroatom selected from the group N, O, and S and optionally substituted on any of the ring carbon atoms with 1 to 5 substituents independently selected from the group consisting of cyano, halo, hydroxy, amino, optionally substituted C 3-6 heterocyclyl, C 1-9 amide, optionally substituted C 1-6 alkyl, and C 1-4 alkoxy and substituted on any additional ring nitrogen by a substituent selected from the group consisting of hydrogen, C 3-8 cycloalkyl, and optionally substituted C 1-6 alkyl; and

R 11 is selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-8 cycloalkyl;

wherein the disease, disorder or condition is selected from Parkinson's disease, levodopa induced dyskinesias, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorders, and depression.