US 12,760,005 B2 · Bicycloheptane pyrrolidine orexin receptor agonists

Abstract

I: wherein is wherein n is 0 or 1; The present invention is directed to bicyclo[4.1 0]heptane pyrrolidine compounds of formula (I) which are agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

A compound of the formula I:

wherein:
is
wherein n is 0 or 1;
X is —O— or —NH—, or X may be a direct bond to R1;
Y is O or CH2;
R1 is selected from:
(1) —C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R4,
(2) —C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R4;
and
(3) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R4;
R2a and R2b are selected from:
(1) hydrogen,
(2) —C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R4,
(3) —C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R4,
(4)-phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R4, and
(5) -heteroaryl, where the heteroaryl is selected from:
pyridyl, pyrimidinyl, benzothiazolyl, thiazolyl and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R4,
Provided that at least one of R2a and R2b is hydrogen;
R2c and R2d are independently selected from:
(1) hydrogen, and
(2) fluoro;
R3 is selected from:
(1) —C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R4,
(2) —C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R4,
(3) -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(4) —NR10R11, wherein R10 and R11 are independently selected from:
(a) hydrogen, and
(b) C1-6alkyl, which is unsubstituted or substituted with one to six R4,
(5) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R4,
(6) —CHF2, and
(7) —CF3;
R4 is independently selected from:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R7,
(4) C2-4alkenyl,
(5) C2-4alkynyl,
(6) —C3-6cycloalkyl, which is unsubstituted or substituted with one to six substituents independently selected from R7,
(7)—O—C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R7,
(8)—O(C═O)—C1-6alkyl,
(9)—NH2,
(10)—NH—C1-6alkyl,
(11) —NO2,
(12) phenyl,
(13) —CO2H,
(14) —SO2—C1-6alkyl,
(15) —C3-5cycloalkyl (SO2),
(16) —CN,
(17) -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from R7,
(18) —CHF2, and
(19) —CF3;
R5 and R6 are independently selected from:
(1) hydrogen,
(2) C1-6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R4, and
(3) —C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R4,
or R5 and R6 are joined together with the carbon atoms to which they are attached to form a —C3-6cycloalkyl ring, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R4;
R7 is independently selected from:
(1) halogen,
(2) C1-6alkyl, which is unsubstituted or substituted with one to six substituents independently selected from halo, phenyl or cycloalkyl,
(3) —CHF2, and
(4) —CF3;
or a pharmaceutically acceptable salt thereof;
provided that the compound of Formula I is other than:
methyl (2R,3S,5R)-3-((fluoromethyl) sulfonamido)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-((trifluoromethyl) sulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-(ethylsulfonamido)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((difluoromethyl) sulfonamido)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methylpyrrolidine-1-carboxylate;
2.2-difluoroethyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((difluoromethyl) sulfonamido)-5-methyl-2-(((6-(pyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((difluoromethyl) sulfonamido)-5-methyl-2-((((1S,3S,6R)-6-(pyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((difluoromethyl) sulfonamido)-5-methyl-2-((((1R,3R,6S)-6-(pyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl) pyrrolidine-1-carboxylate;
methyl (2R,3S,5S)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-(methoxymethyl)-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-(((6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1R,3R,6S)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-(((6-(5-chloropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1R,3R,6S)-6-(5-chloropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-2-((((1S,3S,6R)-6-(5-chloropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methyl-3-(methylsulfonamido) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1R,3R,6S)-6-(thiazol-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-((((1S,3S,6R)-6-(thiazol-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-5-methyl-3-(methylsulfonamido)-2-(((6-(thiazol-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl) pyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl) amino)-2-((((1R,3R,6S)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methylpyrrolidine-1-carboxylate;
methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl) amino)-2-((((1S,3S,6R)-6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methylpyrrolidine-1-carboxylate;
and
methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl) amino)-2-(((6-(5-fluoropyrimidin-2-yl) bicyclo[4.1.0] heptan-3-yl) oxy) methyl)-5-methylpyrrolidine-1-carboxylate.

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Bicycloheptane pyrrolidine orexin receptor agonists

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Bicycloheptane pyrrolidine orexin receptor agonists

Life of this patent

Abstract

Claims19