Bicyclic-substituted amines as histamine-3 receptor ligands

1. A compound of the formula:

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

Y and Y′ are each independently CH or CF;

X is N;

X′, Z, and Z′ are each C;

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

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

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

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

R 3b is absent;

R 4 and R 5 are each independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NR A R B ) alkyl, or 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 aryl, heteroaryl, heterocycle, and cycloalkyl, wherein each R 6 is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, cyano, halo, —NR A R B , alkoxy, alkoxyimino, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, (NR A R B )carbonyl, cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, and thioalkoxy;

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 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 —;

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;

R A and R B are each independently selected from the group consisting of hydrogen, alkyl, acyl, and formyl;

m is an integer from 1 to 5;

n is an integer from 1 to 6; and

q is an integer from 1 to 4.

2. The compound of claim 1 , wherein R 1 is bromo, cyano, 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 aryl, heteroaryl, heterocycle, or cycloalkyl, wherein each R 6 is optionally substituted with 1, 2 or 3 substituents selected from the group consisiting of alkyl, cyano, halo, —NR A R B , alkoxy, alkoxyimino, hydroxyalkyl, alkycarbonyl, alkoxycarbonyl, (NR A R B )carbonyl, cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, and thioalkoxy.

4. The compound of claim 1 , wherein R 1 is L 2 R 6 , L 2 is a bond, and R 6 is aryl wherein the aryl is phenyl substituted with 0, 1, or 2 substituents selected from the group consisting of cyano, halogen, —NR A R B , alkoxy, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, and thioalkoxy.

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 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.

6. 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.

7. The compound of claim 1 , wherein R 4 and R 5 are each independently selected from methyl, ethyl, and propyl.

8. 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).

9. The compound of claim 8 , 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 .

10. The compound of claim 8 , 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.

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

12. 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.

13. 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.

14. 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.

15. 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.

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

17. 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.

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

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

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

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

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

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

24. The compound of claim 1 , wherein

Y and Y′ are CH;

X′, Z′, and Z are C;

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

X is N; and

R 3b is absent.

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

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

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

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

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

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

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

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

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

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

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

6-(6-methoxy-pyridin-3-yl)-2-[2(R)-(2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

6-(2,6-difluoro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

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

6-(2,6-dichloro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-6-pyrazin-2-yl-quinoline;

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

6-(2,4-dimethoxy-pyrimidin-5-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

dimethyl-(4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-phenyl)-amine;

1-(4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-phenyl)-ethanone;

6-(4-chloro-phenyl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

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

6-(5-methoxy-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

6-(3,5-dimethyl-isoxazol-4-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;

4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-benzoic acid methyl ester;

2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-6-(4-methylsulfanyl-phenyl)-quinoline;

6-(6-fluoro-pyridin-3-yl)-2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinoline; and

5-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-6-yl}-nicotinonitrile.

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.

28. A compound that is 6-(2,6-dimethyl-pyridin-3-yl)-2-[2(R)-methyl-pyrrolidin-l-yl)-ethyl]-quinoline or a salt thereof.