US Patent 8,357,712 — 4,5-dihydro-oxazol-2yl derivatives

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Abstract

The invention relates to compounds of formula I [structure] wherein R 1 , R 2 , X, Y, and n are defined in the specification and to pharmaceutically acceptable acid addition salts thereof. The invention also provides pharmaceutical compositions and methods of manufacture of such compounds. The compounds are useful for the treatment of diseases related to the biological function of the trace amine associated receptors, which diseases are depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson\'s disease, neurodegenerative disorders, Alzheimer\'s disease, epilepsy, migraine, substance abuse and metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Claims

22 · 2 independent · depth 2

22 granted claims

›1.independentA compound selected from the group consisting ofn(S)-4-[2-(4-benzyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4⬲-fluoro-biphenyl-4-yloxy)…+10

A compound selected from the group consisting ofn(S)-4-[2-(4-benzyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4⬲-fluoro-biphenyl-4-yloxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-chloro-3-fluoro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-bromo-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(3,4-dichloro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-chloro-2-fluoro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-methoxy-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-trifluoromethyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;3-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-benzonitrile;3-[4-(S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-benzoic acid methyl ester;(S)-4-[2-(3,5-difluoro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;3-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-benzoic acid benzyl ester;(S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-difluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-3-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-bromo-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-4-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-2-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(2,4-difluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-dichloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;3-[(S)-2-(S)-2-amino-4,5-dihydro-oxazol-4-yl)-1-methyl-ethoxy]-benzonitrile;(S)-4-[(S)-2-(4-phenoxy-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-(S)-2-phenoxy-propyl)-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-2-(3-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-2-(3-chloro-4-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-2-(3,4-dichloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-(S)-2-phenoxy-butyl)-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-bromo-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-3-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(2,4-difluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-difluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-4-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-trifluoromethyl-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-dichloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-2-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;3-[(S)-1-((S)-2-amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol;(S)-4-[(S)-2-(2,4,5-trifluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(naphthalen-2-yloxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(2,4-dichloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-3-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-3-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine;(4 S)-4-[3-(3,5-difluoro-phenyl)-pentyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-((S)-1-phenyl-propoxymethyl)-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(2,4-difluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3-chloro-4-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3,4-difluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(4-chloro-phenyl)-cyclobutyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3,5-difluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3-chloro-5-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(4-bromo-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[(3-chloro-phenyl)-dimethyl-silanyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine; and(S)-4-{2-[(4-chloro-phenyl)-dimethyl-silanyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine.

›2.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[2-(4-benzyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4⬲-fluoro-bip…d2

›3.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[2-(4-methoxy-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-trifluorom…d2

›4.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-fl…d2

›5.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[(S)-2-(2,4-difluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(…d2

›6.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[(S)-2-(4-chloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-(S)-2-phenoxy…d2

›7.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[(S)-2-(4-trifluoromethyl-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)…d2

›8.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[(S)-3-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-3-(4-fluo…d2

›9.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine; and(S)-4-((S…d2

›10.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2…d2

›11.↳ 1The compound of claim 1, selected from the group consisting ofn(S)-4-{2-[(3-chloro-phenyl)-dimethyl-silanyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine; and(…d2

›12.independentA pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting ofn(S)-4-[2-(4-benzyl-phen…+10

A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting ofn(S)-4-[2-(4-benzyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4⬲-fluoro-biphenyl-4-yloxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-chloro-3-fluoro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-bromo-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(3,4-dichloro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-chloro-2-fluoro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-methoxy-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[2-(4-trifluoromethyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;3-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-benzonitrile;3-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-benzoic acid methyl ester;(S)-4-[2-(3,5-difluoro-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine;3-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethoxy]-benzoic acid benzyl ester;(S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-difluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-3-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-bromo-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-4-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-2-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(2,4-difluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-dichloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;3-[(S)-2-(S)-2-amino-4,5-dihydro-oxazol-4-yl)-1-methyl-ethoxy]-benzonitrile;(S)-4-[(S)-2-(4-phenoxy-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-(S)-2-phenoxy-propyl)-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-2-(3-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-2-(3-chloro-4-fluoro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-2-(3,4-dichloro-phenoxy)-propyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-(S)-2-phenoxy-butyl)-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-bromo-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-3-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(2,4-difluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-difluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-chloro-4-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-trifluoromethyl-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3,4-dichloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(4-chloro-2-fluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;3-[(S)-1-(S)-2-amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol;(S)-4-[(S)-2-(2,4,5-trifluoro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(naphthalen-2-yloxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-2-(2,4-dichloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-3-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(R)-3-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine;(4S)-4-[3-(3,5-difluoro-phenyl)-pentyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine;(S)-4-((S)-1-phenyl-propoxymethyl)-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(2,4-difluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3-chloro-4-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3,4-difluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(4-chloro-phenyl)-cyclobutyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3,5-difluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(3-chloro-5-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[1-(4-bromo-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine;(S)-4-{2-[(3-chloro-phenyl)-dimethyl-silanyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine; and(S)-4-{2-[(4-chloro-phenyl)-dimethyl-silanyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine.

›13.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[2-(4-benzyl-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-yla…d2

›14.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[2-(4-methoxy-phenoxy)-ethyl]-4,5-dihydro-oxazol-2-yl…d2

›15.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-4,5-dihydro-oxazol-…d2

›16.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[(S)-2-(2,4-difluoro-phenoxy)-propyl]-4,5-dihydro-oxa…d2

›17.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[(S)-2-(4-chloro-phenoxy)-butyl]-4,5-dihydro-oxazol-2…d2

›18.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[(S)-2-(4-trifluoromethyl-phenoxy)-butyl]-4,5-dihydro…d2

›19.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[(S)-3-(4-fluoro-phenyl)-butyl]-4,5-dihydro-oxazol-2-…d2

›20.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-ox…d2

›21.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-{2-[1-(4-fluoro-phenyl)-cyclopropyl]-ethyl}-4,5-dihyd…d2

›22.↳ 12The composition of claim 12, wherein the compound is selected from the group consisting ofn(S)-4-{2-[(3-chloro-phenyl)-dimethyl-silanyl]-ethyl}-4,5-di…d2

Classifications

6 codes

IPC · International Patent Classification

Section A — Human necessities

A61K31/421

Section C — Chemistry; metallurgy

C07D263/08

USPC · US Patent Classification

514/377514/374548/233548/215

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Golam M M Shameem

art unit 1622 · TC 1600

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Type	Document	Date
related publication	US 20110144333 A1	16 Jun 2011

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