Bicyclic-substituted amines as histamine-3 receptor ligands

1. A compound of the formula:

or a pharmaceutically acceptable salt, ester, or amide thereof, wherein:

Y, and Y′ are each independently selected from the group consisting of CH, CF, and N, provided that one of Y or Y′ is N and the other is CH or CF;

X, X′, Z, and Z′ are each C;

one of R 1 and R 2 is selected from the group consisting of halogen, and L 2 R 6 ;

the other of R 1 and R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, and thioalkoxy;

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

R 3a is selected from the group consisting of hydrogen, methyl, alkoxy, halogen, and cyano;

R 3b is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, and thioalkoxy;

R 4 and R 5 taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:

R 6 is selected from the group consisting of heteroaryl, heterocycle, and cycloalkyl;

R 7 , R 8 , R 9 , and R 10 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl; or one of the pair R 7 and R 8 or the pair R 9 and R 10 is taken together with the carbon atom to which each is attached to form a C 3 -C 6 ring, wherein 0, 1, or 2 heteroatoms selected from O, N, or S replace a carbon atom in the ring;

R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro;

Q is selected from the group consisting of a bond, O, S, and NR 15 ;

L is —[C(R 16 )(R 17 )] n — or —[C(R 16 )(R 17 )] p O—;

L 2 is selected from the group consisting of a bond, —O—, —C(═O)—, —S—, —[C(R 18 )(R 19 )] q —, —O—[C(R 18 )(R 19 )] q —, —NH— and —N(alkyl)-;

R 15 is selected from the group consisting of hydrogen, alkyl, acyl, amido, and formyl;

R 16 and R 17 at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and fluoro;

R 18 and R 19 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro;

R x and R y at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, dialkylamino, and fluoro, or one of R x or R y represents a covalent bond when taken together with R x or R y on an adjacent carbon atom such that a double bond is represented between the adjacent carbon atoms;

m is an integer from 1 to 5;

n is an integer from 1 to 6;

q is an integer from 2 to 6;

q is integer from 1 to 4.

2. The compound of claim 1 , wherein R 1 is bromo, or L 2 R 6 .

3. The compound of claim 1 , wherein R 1 is L 2 R 6 , L 2 is —CH(OH)—, —C(═O)—, or a bond, and R 6 is heteroaryl, heterocycle, or cycloalkyl.

4. The compound of claim 1 , wherein R 1 is L 2 R 6 , L 2 is a bond, and R 6 is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl, substituted with 0, 1, 2, or 3 substituents selected from the group consisting of —NR A R B , halogen, alkyl, cyano, alkoxyimino, alkoxycarbonyl, (NR A R B )carbonyl, alkylcarbonyl, haloalkyl, and alkoxy.

5. The compound of claim 1 , wherein R 1 is L 2 R 6 , L 2 is a bond, and R 6 is selected from the group consisting of azepanyl, azetidinyl, aziridinyl, azocanyl, dihydrothiazolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, tetrahydropyridinyl, tetrahydrofuryl, and tetrahydropyranyl.

6. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a).

7. The compound of claim 6 , wherein the 4- to 8-membered non-aromatic ring is selected from the group consisting of azetidinyl, azepanyl, azepinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, and tetrahydropyridinyl, substituted with 0, 1, or 2 substituents selected from the group consisting of alkyl, hydroxyalkyl, fluoroalkyl, and —NR A R B .

8. The compound of claim 6 , wherein at least one substituent represented by R 7 , R 8 , R 9 , and R 10 is selected from the group consisting of alkyl, halogen, fluoroalkyl, and hydroxyalkyl or at least one substituent represented by R x or R y is selected from the group consisting of hydrogen, hydroxy, and fluoro.

9. The compound of claim 6 , wherein the 4- to 8-membered non-aromatic ring is selected from the group consisting of methylpyrrolidinyl, ethylpyrrolidinyl, dimethylaminopyrrolidinyl, isopropylpyrrolidinyl, isobutylpyrrolidinyl, hydroxymethylpyrrolidinyl, and fluoromethylpyrrolidinyl.

10. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen atom to which each is attached form morpholinyl or thiomorpholinyl.

11. The compound of claim 1 , wherein at least one substituent represented by R 7 , R 8 , R 9 , and R 10 is hydroxyalkyl, fluoroalkyl, or alkyl.

12. The compound of claim 1 , wherein at least one substituent represented by R 7 , R 8 , R 9 , and R 10 is methyl, ethyl, fluoromethyl, or hydroxymethyl.

13. The compound of claim 1 , wherein one substituent represented by R 7 , R 8 , R 9 , and R 10 is alkyl and the other three substituents are hydrogen.

14. The compound of claim 1 , wherein R 11 , R 12 , R 13 , and R 14 are each hydrogen.

15. The compound of claim 1 , wherein R 11 and R 12 each are hydrogen, and R 13 and R 14 are each independently selected from the group consisting of hydrogen and alkyl.

16. The compound of claim 1 , wherein R 15 is selected from the group consisting of hydrogen, alkyl, amido, and formyl.

17. The compound of claim 1 , wherein R 16 and R 17 are hydrogen.

18. The compound of claim 1 , wherein R 18 and R 19 are hydrogen.

19. The compound of claim 1 , wherein m is 2 or 3.

20. The compound of claim 1 , wherein n is 2 or 3.

21. The compound of claim 1 , wherein p is 2.

22. The compound of claim 1 , wherein q is 1.

23. The compound of claim 1 , wherein

Y is CH;

X, X′, Z, and Z′ are C;

R 2 , R 3 , R 3a , and R 3b are hydrogen; and

Y′ is N.

24. The compound of claim 1 , wherein

Y′ is CH;

X, X′, Z and Z′ 0 C;

R 2 , R 3 , R 3a , and R 3b are hydrogen; and

Y is N.

25. The compound of claim 1 , selected from the group consisting of

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(3-pyridinyl)quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(4-pyridinyl)quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2-pyridinyl)quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(1,3-thiazol-2-yl)quinoline;

2-(2,4-dimethyl-1,3-thiazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2-pyrazinyl)quinoline;

1-[6-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-pyridinyl]ethanone;

2-cyclopropyl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;

2,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)nicotinonitrile;

2-(3-methyl-2-pyrazinyl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;

ethyl 5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-3-isoxazolecarboxylate;

5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-thiophenecarbonitrile;

ethyl 5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-2-thiophenecarboximidoate;

2-(2,4-dimethyl-1,3-oxazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline;

ethyl 3-methyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-quinolinyl)-4-isoxazolecarboxylate;

2-(2,5-dimethyl-furan-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

2-(6-methyl-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-thiophen-3-yl-quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-pyrimidin-5-yl-quinoline;

2-(2,6-dimethyl-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

1-[2,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-pyridin-3-yl]-ethanone;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(2H-pyrazol-3-yl-quinoline;

2-(3-bromo-isoxazol-5-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

2-(6-chloro-pyridin-3-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

2-(3,5-dimethyl-thiophen-2-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-thiophen-2-yl-quinoline;

2-furan-3-yl-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

2-(4,5-dihydro-thiazol-2-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

3-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-2-trifluoromethyl-pyridin-4-ol;

2-(3,5-dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline;

6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-2-(1H-pyrazol-4-yl)-quinoline;

2,6-dimethyl-5-(6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinolin-2-yl)-nicotinamide; and

2-(1,5-dimethyl-1H-pyrazol-4-yl)-6-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-quinoline.

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

27. A method of treating a condition or disorder modulated by the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of claim 1 , wherein the condition or disorder is selected from the group consisting of attention-deficit hyperactivity disorder, and schizophrenia.