Substituted prolines / piperidines as orexin receptor antagonists
The present invention is directed to compounds that modulate the bioactivity of an orexin receptor such as OX 1 or OX 2 , or both; to pharmaceutical compositions and combinations comprising a compound of the invention; to methods of treatment of malconditions in patients wherein modulation of an orexin receptor is medically indicated; and to methods of preparation of compounds of the invention. For example, orexin receptor-modulatory compounds of the present invention can be used in treatment of an eating disorder, obesity, alcoholism or an alcohol-related disorder, drug abuse or addiction including addiction to cocaine, opiates, amphetamines, or nicotine, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, headache, migraine, pain, gastrointestinal diseases, epilepsy, inflammations, immune-related diseases, endocrine-related diseases, cancer, hypertension, behavior disorder, mood disorder, manic depression, dementia, sex disorder, psychosexual disorder, or renal disease.
1. A compound of Formula (VI):
wherein
R 10 is H or methyl;
Het 2 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each optionally fused to phenyl or a monocyclic heteroaryl, and each optionally substituted with one or two substituents R x ; wherein each R x is independently selected from the group consisting of —F, —Cl, —Br, methyl, methoxy, —CN, —CF 3 , cyclopropyl, and cyano-cyclopropyl;
X, Y, and Z are defined as in (a), (b), or (c), wherein:
(a) X is N, Y is CH, and Z is S;
(b) X is N, Y is CHCH, and Z is CH; and
(c) X is CH, Y is CHCH, and Z is CH;
each R 11 is independently selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy; t is 0, 1, or 2;
and B is selected from the group consisting of phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each optionally substituted with one or two substituents R y ; wherein R y is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, isopropoxy, —F, —Cl, —Br, —CN, and —CF 3 ,
or a pharmaceutically acceptable salt thereof;
provided that the compound is not:
2. The compound of claim 1 , wherein the compound is a compound of Formula (VIA):
wherein
B is selected from the group consisting of phenyl, pyridyl, and pyrimidinyl, each unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, cyano, chloro, fluoro, and methoxy;
X 2 is CH or N;
R 10 is H or methyl;
R 200 is H, —CF 3 , or chloro; and
(a) one of R 20 and R 22 is methyl, chloro, or fluoro, the other of R 20 and R 22 is H, and R 21 is H; or (b) R 21 is H, chloro, or fluoro, and R 20 and R 22 are both H;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein Het 2 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each optionally fused to phenyl or a monocyclic heteroaryl, and each optionally substituted with one or two substituents R x , wherein each R x is independently selected from the group consisting of —F, —Cl, —Br, methyl, methoxy, —CN, —CF 3 , cyclopropyl, and cyano-cyclopropyl.
4. The compound of claim 1 , wherein Het 2 is selected from the group consisting of thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzoxazolyl, quinazolinyl, and triazolo-pyrimidinyl, each optionally substituted with one or two substituents R x , wherein each R x is independently selected from the group consisting of —F, —Cl, —Br, methyl, methoxy, —CN, —CF 3 , cyclopropyl, and cyano-cyclopropyl.
5. The compound of claim 1 , wherein X is N, Y is CHCH, and Z is CH; or X is CH, Y is CHCH, and Z is CH.
6. The compound of claim 1 , wherein ring B is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each optionally substituted with one or two substituents R y , wherein each R y is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, isopropoxy, —F, —Cl, —Br, —CN, and —CF 3 .
7. The compound of claim 1 , wherein ring B is pyrazolyl or triazolyl.
8. The compound of claim 1 , wherein ring B is pyridyl or pyrimidinyl.
9. The compound of claim 1 , wherein each R 11 is independently selected from the group consisting of methyl, chloro, fluoro, and —CN.
10. The compound of claim 1 , wherein the group (XX):
is a group of Formula (Xa), or is a group of Formula (Xb), or is a group of Formula (Xc):
wherein X 1 is CH or N; and
B is unsubstituted or is substituted as described in claim 1 .
11. The compound of claim 1 , wherein the group (XX)
is a group of Formula (Xd):
where (a) one of R 101 and R 103 is methyl, chloro, or fluoro, the other of R 101 and R 103 is H, and R 102 is H; or (b) R 102 is H, chloro, or fluoro, and R 101 and R 103 are both H.
12. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.