1. The phosphoric acid salt of (2S)-(4E)-N-methyl-5-3-(5-isopropoxypyridin)yl-4-penten-2-amine having an X-ray powder diffraction pattern with specific peaks at d-values at 18.6, 9.3, 4.25, 3.99, and 3.11 \u212b, andor essentially as defined in Table 1.
2. The edisylate salt of (2S)-(4E)-N-methyl-5-3-(5-isopropoxypyridin)yl-4-penten-2-amine having an X-ray powder diffraction pattern with specific peaks at d-values at 5.6, 4.33, 4.19, and 3.76 \u212b, andor essentially as defined in Table 2.
3. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the salt of claim 1, in association with one or more pharmaceutically acceptable diluents, excipients andor inert carriers.
4. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the salt of claim 2, in association with one or more pharmaceutically acceptable diluents, excipients andor inert carriers.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of Formula (I):
wherein
one of R1a and R1b is
\u2003and the other is \u2014H;
R2 and R3 are each independently selected from the group consisting of: \u2014H; a \u2014C1-6alkyl group unsubstituted or substituted with \u2014OH, \u2014OC1-4alkyl, \u2014NH2, \u2014N(Ra)Rb, or \u2014F; \u2014CO2C1-4alkyl; and a monocyclic cycloalkyl group unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, halo, or \u2014CF3;
where Ra and Rb are each independently \u2014H, \u2014C1-6alkyl, or monocyclic cycloalkyl, or Ra and Rb taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group;
provided that R2 and R3 are not both H;
or, alternatively,
R2 and R3 taken together with the nitrogen to which they are attached form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted on a carbon ring member with one, two, or three Rd moieties and substituted on a nitrogen ring member with an Re moiety;
where each Rd moiety is independently selected from the group consisting of: \u2014C1-6alkyl; \u2014C1-4alkyl-OH; halo; \u2014OH; \u2014OC1-6alkyl; ipso-substituted \u2014OC2-3alkylO\u2014; \u2014CN; \u2014NO2; \u2014N(Rg)Rh; \u2014C(O)N(Rg)Rh; \u2014N(Rg)SO2C1-6alkyl; \u2014C(O)C1-6alkyl; \u2014S(O)0-2\u2014C1-6alkyl; \u2014SO2N(Rg)Rh; \u2014SCF3; \u2014CF3; \u2014OCF3; \u2014CO2H; and \u2014CO2C1-6alkyl;
where Rg and Rh are each independently \u2014H or \u2014C1-6alkyl, or Rg and Rh taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; and
where Re is selected from the group consisting of: \u2014H; a \u2014C1-6alkyl or \u2014C(O)C1-6alkyl group unsubstituted or substituted with halo, \u2014CN, \u2014OH, \u2014OC1-4alkyl, or \u2014CF3; \u2014C(O)CF3; \u2014S(O)0-2\u2014C1-6alkyl; \u2014CO2C1-6alkyl; and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with \u2014C1-4alkyl, halo, \u2014CN, \u2014OH, \u2014OC1-4alkyl, or \u2014CF3;
q is 0 or 1;
each R4 is independently \u2014H or methyl, or both R4 substituents taken together form a carbonyl;
Y is \u2014O\u2014, \u2014OCH2\u2014, \u2014S\u2014, \u2014SO\u2014, or \u2014SO2\u2014;
R5 is \u2014H or \u2014C1-6alkyl;
R6 is \u2014H; or \u2014C1-6alkyl, \u2014C3-6alkenyl, \u2014C3-6alkynyl, monocyclic cycloalkyl, or \u2014C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, \u2014OC1-4alkyl, halo, \u2014NH2, \u2014NH(C1-4alkyl), \u2014N(C1-4alkyl)2, \u2014CN, \u2014CO2H, or \u2014CO2C1-4alkyl;
R7 is \u2014H; or \u2014C1-6alkyl, \u2014C3-6alkenyl, \u2014C3-6alkynyl, monocyclic cycloalkyl, or \u2014C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, \u2014OC1-4alkyl, halo, \u2014NH2, \u2014NH(C1-4alkyl), \u2014N(C1-4alkyl)2, \u2014CN, \u2014CO2H, or \u2014CO2C1-4alkyl;
or R6 and R7 taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with \u2014C1-4alkyl, \u2014OC1-4alkyl, or halo; and
Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three Rk moieties;
where each Rk moiety is independently selected from the group consisting of: \u2014C1-6alkyl, \u2014CHF2, \u2014CF3, \u2014C2-6alkenyl, \u2014C2-6alkynyl, \u2014OH, \u2014OC1-6alkyl, \u2014OCHF2, \u2014OCF3, \u2014OC3-6alkenyl, \u2014OC3-6alkynyl, \u2014CN, \u2014NO2, \u2014N(Rl)Rm, \u2014N(Rl)C(O)Rm, \u2014N(Rl)SO2C1-6alkyl, \u2014C(O)C1-6alkyl, \u2014S(O)0-2\u2014C1-6alkyl, \u2014C(O)N(R1)Rm, \u2014SO2N(R1)Rm, \u2014SCF3, halo, \u2014CO2H, and \u2014CO2C1-6alkyl; or two Rk moieties on adjacent carbon atoms of attachment together are \u2014OC1-4alkyleneO\u2014 to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
where Rl and Rm are each independently \u2014H or \u2014C1-6alkyl;
provided that when both R4 substituents taken together form a carbonyl, then R2 and R3 taken together are not diazepanyl;
or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug,
or a pharmaceutically active metabolite thereof.
2. A compound as defined in claim 1, wherein R1b is
3. A compound as defined in claim 1, wherein R2 and R3 are each independently \u2014H; or methyl, ethyl, propyl, isopropyl, sec-butyl, 2-methylpropyl, cyclopropyl, cyclobutyl, or cyclopentyl, each unsubstituted or substituted as previously described.
4. A compound as defined in claim 1, wherein R2 and R3 are each independently \u2014H, methyl, ethyl, propyl, isopropyl, sec-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-(cyclopropyl-methyl-amino)-ethyl, 2-pyrrolidin-1-yl-ethyl, 2-hydroxy-2-methylpropyl, 3-dimethylaminopropyl, cyclopropyl, cyclobutyl, or cyclopentyl.
5. A compound as defined in claim 1, wherein R2 and R3 are each independently \u2014H, methyl, cyclopropyl, dimethylaminoethyl, or dimethylaminopropyl.
6. A compound as defined in claim 1, wherein Ra and Rb are each independently \u2014H, methyl, or cyclopropyl, or Ra and Rb taken together form pyrrolidinyl.
7. A compound as defined in claim 1, wherein R2 and R3 taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1\u03bb6-thiomorpholin-4-yl, homopiperidinyl, diazepanyl, piperazinonyl, or diazepanonyl, each unsubstituted or substituted as previously described.
8. A compound as defined in claim 1, wherein R2 and R3 taken together with the nitrogen to which they are attached form azetidinyl, 3,3-difluoroazetidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl, 3,3-difluoropyrrolidinyl, piperidinyl, 3-fluoropiperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl, 4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl, 4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro4,5dec-8-yl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl, 3-hydroxypiperidinyl, 4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxymethyl piperidinyl, 4-hydroxymethylpiperidinyl, 3-hydroxyethylpiperidinyl, 4-hydroxyethylpiperidinyl, 4-dimethylaminopiperidinyl, 4-morpholin-4-yl-piperidin-1-yl, morpholinyl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl, piperazinyl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2-fluoroethyl)-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-cyclobutyl-piperazin-1-yl, 4-cyclopentyl-piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(2-methoxyethyl)-piperazin-1-yl, 4-(tert-butoxycarbonyl)piperazin-1-yl, 4-phenylpiperazin-1-yl, 4-(2-hydroxyphenyl)piperazinyl, 4-(4-trifluoromethyl-phenyl)-piperazin-1-yl, 4-thiazol-2-yl-piperazin-1-yl, 4-(2-thiophenyl)piperazinyl, 4-pyridin-4-yl-piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-isobutyryl-piperazin-1-yl, 4-piperazin-2-onyl, 1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-1-piperazin-2-onyl, 1-cyclopropyl-4-piperazin-2-onyl, thiomorpholinyl, 1,1-dioxo-1\u03bb6-thiomorpholin-4-yl, 4-isopropyl-1,4diazepan-1-yl, 4-cyclopropyl-1,4diazepan-1-yl, 1-cyclobutyl-4-diazepan-5-onyl, 4-isopropyl-1-diazepan-5-onyl, 1-isopropyl-4-diazepan-5-onyl, or 1-cyclopropyl-4-diazepan-5-onyl.
9. A compound as defined in claim 1, wherein R2 and R3 taken together with the nitrogen to which they are attached form pyrrolidinyl, 3-dimethylaminopyrrolidinyl, piperidinyl, 4-fluoropiperidinyl, 4-dimethylaminopiperidinyl, 4-morpholin-4-yl-piperidin-1-yl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-(2-fluoroethyl)-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-cyclobutyl-piperazin-1-yl, 4-cyclopentyl-piperazin-1-yl, 4-pyridin-4-yl-piperazin-1-yl, 4-piperazin-2-onyl, 1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-1,4diazepan-1-yl, or 1-isopropyl-4-diazepan-5-onyl.
10. A compound as defined in claim 1, wherein each Rd moiety is independently selected from the group consisting of: methyl, ethyl, isopropyl, hydroxyethyl, fluoro, methoxy, dimethylamino, piperidinyl, morpholinyl, acetyl, trifluoromethyl, \u2014CO2H, and \u2014CO2-methyl.
11. A compound as defined in claim 1, wherein Rg and Rh are each independently \u2014H, methyl, ethyl, or isopropyl, or Rg and Rh taken together with their nitrogen of attachment form pyrrolidinyl, piperidinyl, morpolinyl, or thiomorpholinyl.
12. A compound as defined in claim 1, wherein Re is selected from the group consisting of: \u2014H, methyl, ethyl, isopropyl, 2-fluoroethyl, hydroxyethyl, methoxypropyl, acetyl, tert-butoxycarbonyl, phenyl, 4-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, and piperidinyl.
13. A compound as defined in claim 1, wherein Re is selected from the group consisting of: \u2014H, isopropyl, and cyclopropyl.
14. A compound as defined in claim 1, wherein q is 1 and both R4 substituents taken together form a carbonyl.
15. A compound as defined in claim 1, wherein q is 0.
16. A compound as defined in claim 1, wherein q is 1 and each R4 is \u2014H.
17. A compound as defined in claim 1, wherein Y is \u2014O\u2014 or \u2014S\u2014.
18. A compound as defined in claim 1, wherein Cyc is a phenyl or pyridyl group unsubstituted or substituted with one, two, or three Rk moieties.
19. A compound as defined in claim 1, wherein Cyc is a thiophenyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, or pyrazinyl group unsubstituted or substituted with one, two, or three Rk moieties.
20. A compound as defined in claim 1, wherein Cyc is phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-methylphenyl, 3-chloro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl, 4-chloro-3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3-nitrophenyl, 4-nitrophenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl, 4-methanesulfanylphenyl, 4-methanesulfinylphenyl, 4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl, 3-methyl-4-methylsulfanylphenyl, benzo1,3dioxol-4-yl, benzo1,3dioxol-5-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 4-trifluoromethyl-pyridin-2-yl, 2,6-dimethyl-pyridin-3-yl, 6-methyl-pyridin-3-yl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl, 6-methoxy-pyridin-3-yl, 6-methylsulfanyl-pyridin-3-yl, 2-hydroxy-5-pyridinyl, 6-bromo-pyridin-3-yl, or pyrazin-2-yl.
21. A compound as defined in claim 1, wherein Cyc is phenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl, 4-methanesulfanylphenyl, 3-methyl-4-methanesulfanylphenyl, 2-pyridinyl, 3-pyridinyl, or 6-methyl-3-pyridinyl.
22. A compound as defined in claim 1, wherein each Rk moiety is independently selected from the group consisting of: methyl, methoxy, fluoro, chloro, trifluoromethyl, methanesulfanyl, trifluoromethanesulfanyl, cyano, and trifluoromethoxy.
23. A compound as defined in claim 1, wherein Rl and Rm are each independently \u2014H or methyl.
24. A compound as defined in claim 1, wherein R5 is \u2014H or methyl.
25. A compound as defined in claim 1, wherein R5 is \u2014H.
26. A compound as defined in claim 1, wherein R6 is \u2014H, methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, or cyclopentyl, each unsubstituted or substituted as previously described.
27. A compound as defined in claim 1, wherein R6 is \u2014H or methyl.
28. A compound as defined in claim 1, wherein R7 is \u2014H, methyl, ethyl, propyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, each unsubstituted or substituted as previously described.
29. A compound as defined in claim 1, wherein R7 is methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, or cyclopentyl.
30. A compound as defined in claim 1, wherein R7 is methyl, ethyl, isopropyl, or cyclopropyl.
31. A compound as defined in claim 1, wherein R6 and R7 taken together with their nitrogen of attachment form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1\u03bb6-thiomorpholin-4-yl, homopiperidinyl, diazepanyl, or homomorpholinyl, each unsubstituted or substituted as previously described.
32. A compound as defined in claim 1, wherein R6 and R7 taken together with their nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, 4-isopropyl-piperazin-1-yl, or homomorpholinyl.
33. A compound selected from the group consisting of:
4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-methanone;
(4-Isopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-methanone;
(4-Isopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl-methanone;
(4-Cyclopropyl-piperazin-1-yl)-4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl-methanone;
(4-Isopropyl-piperazin-1-yl)-4-(3-methoxy-phenoxy)-3-methylaminomethyl-phenyl-methanone;
4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
4-(4-Chloro-phenoxy)-3-cyclopropylaminomethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl-methanone;
4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-(3-methylaminomethyl-4-phenoxy-phenyl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-4-(3-fluoro-phenoxy)-3-methylaminomethyl-phenyl-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(4-trifluoromethyl-phenoxy)-phenyl-methanone;
3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl-methanone;
3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-4-(4-fluoro-phenoxy)-3-methylaminomethyl-phenyl-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(6-methyl-pyridin-3-yloxy)-phenyl-methanone;
4-(3-Chloro-4-fluoro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
4-(4-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-(4-morpholin-4-yl-piperidin-1-yl)-methanone;
4-(3-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
(S)-3-Dimethylamino-pyrrolidin-1-yl)-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-methanone;
4-(3-Chloro-phenoxy)-N-(2-dimethylamino-ethyl)-3-methylaminomethyl-benzamide;
4-(3-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-methylaminomethyl-benzamide;
4-(4-Chloro-phenylsulfanyl)-3-methylaminomethyl-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(pyridin-2-ylsulfanyl)-phenyl-methanone;
4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl-(3-dimethylamino-pyrrolidin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl-methanone;
(4-Cyclopropyl-piperazin-1-yl)-4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl-methanone;
(3-Dimethylamino-pyrrolidin-1-yl)-4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl-methanone;
3-(4-Chloro-phenoxy)-4-methylaminomethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
3-(3,4-Dichloro-phenoxy)-4-methylaminomethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
3-(3-Chloro-phenoxy)-4-methylaminomethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-3-(3,4-dichloro-phenoxy)-4-methylaminomethyl-phenyl-methanone
5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine;
Methyl-5-(4-methyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl-amine;
5-(4-Cyclobutyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine;
Methyl-2-(4-methylsulfanyl-phenoxy)-5-(4-pyridin-4-yl-piperazin-1-yl)-benzyl-amine;
5-4-(2-Fluoro-ethyl)-piperazin-1-yl-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine;
5-(4-Cyclopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine
5-(4-Cyclopropyl-piperazin-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl-methyl-amine;
2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazin-1-yl)-benzyl-methyl-amine;
1-3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-piperazin-2-one;
4-Isopropyl-1-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-piperazin-2-one;
1-4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl-4-isopropyl-piperazin-2-one;
Methyl-2-(4-methylsulfanyl-phenoxy)-5-(4-morpholin-4-yl-piperidin-1-yl)-benzyl-amine;
5-(4-Isopropyl-1,4diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine;
5-(4-Cyclopropyl-1,4diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine;
1-Isopropyl-4-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-1,4diazepan-5-one;
2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-1,4diazepan-1-yl)-benzyl-methyl-amine;
5-(4-Cyclopropyl-1,4diazepan-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl-methyl-amine;
1-Cyclopropyl-4-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-1,4diazepan-5-one;
(S)-Dimethyl-{1-3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl-pyrrolidin-3-yl}-amine;
(4-Cyclopropyl-piperazin-1-yl)-4-(3,4-dichloro-benzyloxy)-3-methylaminomethyl-phenyl-methanone;
Cyclopropyl-5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl-amine;
5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl-methyl-amine;
5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl-dimethyl-amine;
Ethyl-5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl-amine;
Isopropyl-5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl-amine;
5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzylamine;
4-4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl-1-isopropyl-piperazin-2-one;
1-4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl-4-isopropyl-piperazin-2-one;
1-4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl-4-isopropyl-1,4diazepan-5-one;
4-4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl-1-isopropyl-1,4diazepan-5-one;
1-Cyclobutyl-4-4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-benzyl-1,4diazepan-5-one;
4-(3-Chloro-phenoxy)-3-methylaminomethyl-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;
4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclobutyl-piperazin-1-yl)-methanone;
4-4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl-1-isopropyl-1,4diazepan-5-one;
(4-Cyclobutyl-piperazin-1-yl)-4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl-methanone;
(4-Cyclopentyl-piperazin-1-yl)-4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl-methanone;
4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopentyl-piperazin-1-yl)-methanone;
4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclobutyl-piperazin-1-yl)-methanone;
4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl-(4-cyclopentyl-piperazin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-3-methylaminomethyl-4-(4-trifluoromethyl-pyridin-2-ylsulfanyl)-phenyl-methanone;
(4-Cyclopropyl-piperazin-1-yl)-4-dimethylaminomethyl-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl-methanone;
(3-Benzyloxy-4-dimethylaminomethyl-phenyl)-(4-cyclopropyl-piperazin-1-yl)-methanone;
4-{Bis-(2-methoxy-ethyl)-amino-methyl}-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl-(4-cyclopropyl-piperazin-1-yl)-methanone;
3-(2,6-Dimethyl-pyridin-3-yloxy)-4-morpholin-4-ylmethyl-phenyl-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Dimethylaminomethyl-3-phenoxy-phenyl)-piperidin-1-yl-methanone;
(4-{Bis-(2-methoxy-ethyl)-amino-methyl}-3-phenoxy-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;
4-{Bis-(2-methoxy-ethyl)-amino-methyl}-3-(pyridin-3-yloxy)-phenyl-(4-dimethylamino-piperidin-1-yl)-methanone;
4-(4-Isopropyl-piperazin-1-ylmethyl)-3-phenoxy-phenyl-piperidin-1-yl-methanone;
4-(4-Isopropyl-piperazin-1-ylmethyl)-3-(pyridin-3-yloxy)-phenyl-piperidin-1-yl-methanone;
4-Dimethylaminomethyl-N-(2-methylamino-ethyl)-3-(pyridin-3-yloxy)-benzamide;
N-2-(Cyclopropyl-methyl-amino)-ethyl-4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzamide; and
5-(4-Isopropyl-piperazine-1-carbonyl)-2-(3-methoxy-phenoxy)-benzyl-methyl-carbamic acid tert-butyl ester;
and pharmaceutically acceptable salts thereof.
34. A compound or pharmaceutically acceptable salt according to claim 1.
35. A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by histamine H3 receptor andor serotonin transporter activity, comprising:
(a) an effective amount of a compound of Formula (I):
wherein
one of R1a and R1b is
\u2003and the other is \u2014H;
R2 and R3 are each independently selected from the group consisting of: \u2014H; a \u2014C1-6alkyl group unsubstituted or substituted with \u2014OH, \u2014OC1-4alkyl, \u2014NH2, \u2014N(Ra)Rb, or \u2014F; \u2014CO2C1-4alkyl; and a monocyclic cycloalkyl group unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, halo, or \u2014CF3;
where Ra and Rb are each independently \u2014H, \u2014C1-6alkyl, or monocyclic cycloalkyl, or Ra and Rb taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group;
provided that R2 and R3 are not both H;
or, alternatively,
R2 and R3 taken together with the nitrogen to which they are attached form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted on a carbon ring member with one, two, or three Rd moieties and substituted on a nitrogen ring member with an Re moiety;
where each Rd moiety is independently selected from the group consisting of: \u2014C1-6alkyl; \u2014C1-4alkyl-OH; halo; \u2014OH; \u2014OC1-6alkyl; ipso-substituted \u2014OC2-3alkylO\u2014; \u2014CN; \u2014NO2; \u2014N(Rg)Rh; \u2014C(O)N(Rg)Rh; \u2014N(Rg)SO2C1-6alkyl; \u2014C(O)C1-6alkyl; \u2014S(O)0-2\u2014C1-6alkyl; \u2014SO2N(Rg)Rh; \u2014SCF3; \u2014CF3; \u2014OCF3; \u2014CO2H; and \u2014CO2C1-6alkyl;
where Rg and Rh are each independently \u2014H or \u2014C1-6alkyl, or Rg and Rh taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; and
where Re is selected from the group consisting of: \u2014H; a \u2014C1-6alkyl or \u2014C(O)C1-6alkyl group unsubstituted or substituted with halo, \u2014CN, \u2014OH, \u2014OC1-4alkyl, or \u2014CF3; \u2014C(O)CF3; \u2014S(O)0-2\u2014C1-6alkyl; \u2014CO2C1-6alkyl; and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with \u2014C1-4alkyl, halo, \u2014CN, \u2014OH, \u2014OC1-4alkyl, or \u2014CF3;
q is 0 or 1;
each R4 is independently \u2014H or methyl, or both R4 substituents taken together form a carbonyl;
Y is \u2014O\u2014, \u2014OCH2\u2014, \u2014S\u2014, \u2014SO\u2014, or \u2014SO2\u2014;
R5 is \u2014H or \u2014C1-6alkyl;
R6 is \u2014H; or \u2014C1-6alkyl, \u2014C3-6alkenyl, \u2014C3-6alkynyl, monocyclic cycloalkyl, or \u2014C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, \u2014OC1-4alkyl, halo, \u2014NH2, \u2014NH(C1-4alkyl), \u2014N(C1-4alkyl)2, \u2014CN, \u2014CO2H, or \u2014CO2C1-4alkyl;
R7 is \u2014H; or \u2014C1-6alkyl, \u2014C3-6alkenyl, \u2014C3-6alkynyl, monocyclic cycloalkyl, or \u2014C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, \u2014OC1-4alkyl, halo, \u2014NH2, \u2014NH(C1-4alkyl), \u2014N(C1-4alkyl)2, \u2014CN, \u2014CO2H, or \u2014CO2C1-4alkyl;
or R6 and R7 taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with \u2014C1-4alkyl, \u2014OC1-4alkyl, or halo; and
Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three Rk moieties;
where each Rk moiety is independently selected from the group consisting of: \u2014C1-6alkyl, \u2014CHF2, \u2014CF3, \u2014C2-6alkenyl, \u2014C2-6alkynyl, \u2014OH, \u2014OC1-6alkyl, \u2014OCHF2, \u2014OCF3, \u2014OC3-6alkenyl, \u2014OC3-6alkynyl, \u2014CN, \u2014NO2, \u2014N(Rl)Rm, \u2014N(Rl)C(O)Rm, \u2014N(Rl)SO2C1-6alkyl, \u2014C(O)C1-6alkyl, \u2014S(O)0-2\u2014C1-6alkyl, \u2014C(O)N(Rl)Rm, \u2014SO2N(Rl)Rm, \u2014SCF3, halo, \u2014CO2H, and \u2014CO2C1-6alkyl; or two Rk moieties on adjacent carbon atoms of attachment together are \u2014OC1-4alkyleneO\u2014 to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
where Rl and Rm are each independently \u2014H or \u2014C1-6alkyl;
provided that when both R4 substituents taken together form a carbonyl, then R2 and R3 taken together are not diazepanyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and
(b) a pharmaceutically acceptable excipient.
36. A pharmaceutical composition according to claim 35, further comprising: an active ingredient selected from the group consisting of H1 receptor antagonists, H2 receptor antagonists, H3 receptor antagonists, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors, acetylcholinesterase inhibitors, and modafinil.
37. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by histamine H3 receptor andor serotonin transporter activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I):
wherein
one of R1a and R1b is
\u2003and the other is \u2014H;
R2 and R3 are each independently selected from the group consisting of: \u2014H; a \u2014C1-6alkyl group unsubstituted or substituted with \u2014OH, \u2014OC1-4alkyl, \u2014NH2, \u2014N(Ra)Rb, or \u2014F; \u2014CO2C1-4alkyl; and a monocyclic cycloalkyl group unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, halo, or \u2014CF3;
where Ra and Rb are each independently \u2014H, \u2014C1-6alkyl, or monocyclic cycloalkyl, or Ra and Rb taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group;
provided that R2 and R3 are not both H;
or, alternatively,
R2 and R3 taken together with the nitrogen to which they are attached form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted on a carbon ring member with one, two, or three Rd moieties and substituted on a nitrogen ring member with an Re moiety;
where each Rd moiety is independently selected from the group consisting of: \u2014C1-6alkyl; \u2014C1-4alkyl-OH; halo; \u2014OH; \u2014OC1-6alkyl; ipso-substituted \u2014OC2-3alkylO\u2014; \u2014CN; \u2014NO2; \u2014N(Rg)Rh; h \u2014C(O)N(Rg)Rh; \u2014N(Rg)SO2C1-6alkyl; \u2014C(O)C1-6alkyl; \u2014S(O)0-2\u2014C1-6alkyl; \u2014SO2N(Rg)Rh; \u2014SCF3; \u2014CF3; \u2014OCF3; \u2014CO2H; and \u2014CO2C1-6alkyl;
where Rg and Rh are each independently \u2014H or \u2014C1-6alkyl, or Rg and Rh taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; and
where Re is selected from the group consisting of: \u2014H; a \u2014C1-6alkyl or \u2014C(O)C1-6alkyl group unsubstituted or substituted with halo, \u2014CN, \u2014OH, \u2014OC1-4alkyl, or \u2014CF3; \u2014C(O)CF3; \u2014S(O)0-2\u2014C1-6alkyl; \u2014CO2C1-6alkyl; and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with \u2014C1-4alkyl, halo, \u2014CN, \u2014OH, \u2014OC1-4alkyl, or \u2014CF3;
q is 0 or 1;
each R4 is independently \u2014H or methyl, or both R4 substituents taken together form a carbonyl;
Y is \u2014O\u2014, \u2014OCH2\u2014, \u2014S\u2014, \u2014SO\u2014, or \u2014SO2\u2014;
R5 is \u2014H or \u2014C1-6alkyl;
R5 is \u2014H; or \u2014C1-6alkyl, \u2014C3-6alkenyl, \u2014C3-6alkynyl, monocyclic cycloalkyl, or \u2014C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, \u2014OC1-4alkyl, halo, \u2014NH2, \u2014NH(C1-4alkyl), \u2014N(C1-4alkyl)2, \u2014CN, \u2014CO2H, or \u2014CO2C1-4alkyl;
R7 is \u2014H; or \u2014C1-6alkyl, \u2014C3-6alkenyl, \u2014C3-6alkynyl, monocyclic cycloalkyl, or \u2014C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with \u2014C1-4alkyl, \u2014OH, \u2014OC1-4alkyl, halo, \u2014NH2, \u2014NH(C1-4alkyl), \u2014N(C1-4alkyl)2, \u2014CN, \u2014CO2H, or \u2014CO2C1-4alkyl;
or R6 and R7 taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with \u2014C1-4alkyl, \u2014OC1-4alkyl, or halo; and
Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three Rk moieties;
where each Rk moiety is independently selected from the group consisting of: \u2014C1-6alkyl, \u2014CHF2, \u2014CF3, \u2014C2-6alkenyl, \u2014C2-6alkynyl, \u2014OH, \u2014OC1-6alkyl, \u2014OCHF2, \u2014OCF3, \u2014OC3-6alkenyl, \u2014OC3-6alkynyl, \u2014CN, \u2014NO2, \u2014N(Rl)Rm, \u2014N(Rl)C(O)Rm, \u2014N(Rl)SO2C1-6alkyl, \u2014C(O)C1-6alkyl, \u2014S(O)0-2\u2014C1-6alkyl, \u2014C(O)N(Rl)Rm, \u2014SO2N(Rl)Rm, \u2014SCF3, halo, \u2014CO2H, and \u2014CO2C1-6alkyl; or two Rk moieties on adjacent carbon atoms of attachment together are \u2014OC1-4alkyleneO\u2014 to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
where Rl and Rm are each independently \u2014H or \u2014C1-6alkyl;
provided that when both R4 substituents taken together form a carbonyl, then R2 and R3 taken together are not diazepanyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof.
38. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
39. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: dementia, Alzheimer’s disease, cognitive dysfunction, mild cognitive impairment, pre-dementia, attention deficit hyperactivity disorders, attention-deficit disorders, and learning and memory disorders.
40. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: learning impairment, memory impairment, and memory loss.
41. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: insomnia, disturbed sleep, narcolepsy with or without associated cataplexy, cataplexy, disorders of sleepwake homeostasis, idiopathic somnolence, excessive daytime sleepiness, circadian rhythm disorders, fatigue, lethargy, and jet lag.
42. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: sleep apnea, perimenopausal hormonal shifts, Parkinson’s disease, multiple sclerosis, depression, chemotherapy, and shift work schedules.
43. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: schizophrenia, bipolar disorders, manic disorders, depression, obsessive-compulsive disorder, and post-traumatic stress disorder.
44. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: motion sickness, vertigo, epilepsy, migraine, neurogenic inflammation, eating disorders, obesity, and substance abuse disorders.
45. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: depression, disturbed sleep, fatigue, lethargy, cognitive impairment, memory impairment, memory loss, learning impairment, attention-deficit disorders, and eating disorders.
46. A pharmaceutical composition according to claim 35, further comprising topiramate.
47. The method according to claim 37, wherein the disease, disorder, or medical condition is selected from the group consisting of: age-related cognitive decline, REM-behavioral disorder, benign postural vertigo, tinitus, movement disorders, restless leg syndrome, eye-related disorders, macular degeneration, and retinitis pigmentosis.