US 11,680,060 B2
Bicycloheptane pyrrolidine orexin receptor agonists
Stephane L. Bogen, Somerset, NJ (US); Dane James Clausen, Rahway, NJ (US); Deodial Guy Guiadeen, Chesterfield, NJ (US); Jinsong Hao, Belle Meade, NJ (US); Shishi Lin, Somerset, NJ (US); Michael T. Rudd, Collegeville, PA (US); Lan Wei, N. Berkeley Heights, NJ (US); Li Xiao, Cranbury, NJ (US); and Dexi Yang, Livingston, NJ (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
Filed on Aug. 16, 2021, as Appl. No. 17/402,932.
Claims priority of provisional application 63/226,798, filed on Jul. 29, 2021.
Claims priority of provisional application 63/066,908, filed on Aug. 18, 2020.
Prior Publication US 2022/0056017 A1, Feb. 24, 2022
Int. Cl. C07D 403/14 (2006.01); C07D 207/14 (2006.01); C07D 401/12 (2006.01); C07D 403/12 (2006.01); C07D 405/14 (2006.01); C07D 417/12 (2006.01); C07D 491/048 (2006.01)
CPC C07D 403/14 (2013.01) [C07D 207/14 (2013.01); C07D 401/12 (2013.01); C07D 403/12 (2013.01); C07D 405/14 (2013.01); C07D 417/12 (2013.01); C07D 491/048 (2013.01)] 37 Claims
 
1. A compound of the formula I:

OG Complex Work Unit Chemistry
wherein:

OG Complex Work Unit Chemistry
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.