Diazabicyclic central nervous system active agents

1. A compound of formula I

or pharmaceutically acceptable salts thereof, wherein

A is a covalent bond;

B is CH 2 ;

Y is selected from the group consisting of a covalent bond, CH 2 , and CH 2 CH 2 ;

Z is selected from the group consisting of a covalent bond, CH 2 , and CH 2 CH 2 , provided that when Y is CH 2 CH 2 , then Z is a covalent bond and further provided that when Z is CH 2 CH 2 , then Y is a covalent bond;

R 1 is selected from the group consisting of

R 3 is selected from the group consisting of hydrogen, alkyl, and halogen;

R 4 is selected from the group consisting of hydrogen, alkoxy, alkyl, amino, halogen, and nitro;

R 5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, antinocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, halo alkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl, —NR 6 S(O) 2 R 7 , —C(NR 6 )NR 7 R 8 , —CH 2 C(NR 6 )NR 7 R 8 , —C(NOR 6 )R 7 , —C(NCN)R 6 , —C(NNR 6 R 7 )R 8 , —S(O) 2 OR 6 , and —S(O) 2 R 6 ;

R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen and alkyl; and

R 9 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, amino, aminoalkyl, aminocarbonylalkyl, benzyloxycarbonyl, cyanoalkyl, dihydro-3-pyridinylcarbonyl, hydroxy, hydroxyalkyl, and phenoxycarbonyl.

2. A compound according to claim 1 wherein

R 1 is selected from the group consisting of

3. A compound according to claim 1 of formula II

or pharmaceutically acceptable salts thereof.

4. A compound according to claim 3 wherein Y is a covalent bond and Z is CH 2 .

5. A compound according to claim 3 wherein

Y is a covalent bond;

Z isCH 2 ; and

R 1 is

6. A compound according to claim 5 selected from the group consisting of

(cis)-6-(3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(cis)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(5-bromo-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(5-ethynyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(5-vinyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

5-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile;

(−) (cis)-6-(5-bromo-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(cis)-6-(5-bromo-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(6-bromo-5-vinyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

2-bromo-5-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile;

(1R,5S)-6-(5-ethynyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(cis)-6-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(cis)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(6-chloro-5-methyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(6-chloro-5-methyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(cis)-6-(6-chloro-5-methyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1S,5R)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(cis)-6-(5-azido-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;

(1R,5S)-6-(5-azido-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane; and

(1R,5S)-6-(5-azido-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane.

7. A compound according to claim 5 that is 5-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile.

8. A compound according to claim 3 wherein Y is CH 2 and Z is a covalent bond.

9. A compound according to claim 3 wherein

Y is CH 2 ;

Z is a covalent bond; and

R 1 is

10. A compound according to claim 9 selected from the group consisting of

(1R,5R)-6-(6-chloro-3-pyridinyl)-2,6-diazabicyclo[3.2.0]heptane and

(1R,5R)-6-(3-pyridinyl)-2,6-diazabicyclo[3.2.0]heptane.

11. A compound according to claim 3 wherein Y is CH 2 CH 2 and Z is a covalent bond.

12. A compound according to claim 3 wherein Y is CH 2 and Z is CH 2 .

13. A compound according to claim 3 wherein Y is a covalent bond and Z isCH 2 CH 2 .

14. A compound according to claim 3 wherein

Y is a covalent bond;

Z is CH 2 CH 2 ; and

R 1 is

15. A compound according to claim 14 selected from the group consisting of

(cis)-8-(3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1S,6R)-(cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(−) (cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

5-[(1R,6S)-3,8-diazabicyclo[4.2.0]oct-8-yl]nicotinonitrile;

(1S,6R)-5-[3,8-diazabicyclo[4.2.0]oct-8-yl]nicotinonitrile;

(1S,6R)-8-(5-methoxy-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(cis)-8-(5-methoxy-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1R,6S)-8-(5-methoxy-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(cis)-8-(6-chloro-5-methyl-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1S,6R)-8-(6-chloro-5-methyl-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1R,6S)-8-(6-chloro-5-methyl-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1S,6R)-8-(3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1R,6S)-8-(3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(cis)-8-(5,6-dichloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;

(1S,6R)-8-(5,6-dichloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane; and

(1R,6S)-8-(5,6-dichloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

17. A method of treating a disorder in a mammal in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 1 , wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, amyotrophic lateral sclerosis, anxiety depression, mania, schizophrenia, eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease, migraines, pain, PMS, erectile dysfunction, substance abuse, smoking cessation, and inflammatory bowel syndrome.

18. The method of claim 17 wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, nicotinic withdrawal syndrome, Tourette's syndrome, and schizophrenia.

19. The method of claim 17 wherein the disorder is pain.