US 12,187,738 B2
Imidazolo derivatives, compositions and methods as orexin antagonists
Belew Mekonnen, Bethlehem, PA (US); and Hemantbhai Patel, Bethlehem, PA (US)
Assigned to Hager Biosciences, LLC, Bethlehem, PA (US)
Filed by HAGER BIOSCIENCES, LLC, Bethlehem, PA (US)
Filed on Aug. 12, 2024, as Appl. No. 18/800,565.
Application 18/800,565 is a continuation of application No. 17/616,152, previously published as PCT/US2020/035848, filed on Jun. 3, 2020.
Claims priority of provisional application 62/856,830, filed on Jun. 4, 2019.
Prior Publication US 2024/0409554 A1, Dec. 12, 2024
Int. Cl. C07D 498/04 (2006.01); C07D 513/04 (2006.01)
CPC C07D 498/04 (2013.01) [C07D 513/04 (2013.01)] 18 Claims
 
1. A compound of formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or combination thereof,
wherein:
R1 is independently is selected from the group consisting of aromatic, aryl, five- or six-member heteroaryl, substituted aromatic, substituted aryl, substituted five- or six-member heteroaryl; optionally wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted by one Ria substituent, or di-substituted by two R1a substituents, wherein each R1a substituent is independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C3-7)cycloalkyl; wherein the halogen is optionally selected from the group consisting of F, Cl, Br, and I;
R2 and R3 are independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C3-7)cycloalkyl; wherein each of R2 and R3 is independently and optionally substituted at each substitutable position with up to three R2-R3 substituents, wherein each R2-R3 substituent is independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C3-7)cycloalkyl; wherein the halogen is selected from the group consisting of F, Cl, Br, and I;
R4 is selected from the group consisting of aromatic, aryl, five- or six-member heteroaryl, substituted aromatic, substituted aryl, substituted five- or six-member heteroaryl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted by one R4a substituent, di-substituted by two R4a substituents, or tri-substituted by three R4a substituents, wherein each R4a substituent is independently selected from the group consisting of phenyl, (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3-7)heterocycloalkyl; wherein the halogen is selected from the group consisting of F, Cl, Br, and I;
R5 is selected from the group consisting of:
H, (C1-4)alkyl, and substituted alkyl when X is absent to provide a pyrrolidine ring; and,
(C1-4)alkyl and substituted alkyl when X is CH2 to provide a piperidine ring;
wherein:
the carbon atom at position 2 of the of the piperidine ring or the pyrrolidine ring is optionally in absolute (S)-configuration; and
the carbon atom at position 2 of the morpholine ring is optionally in absolute (R)-configuration;
R6 is selected from the group consisting of H, halogen, alkyl group, and substituted alkyl;
wherein the halogen is selected from the group consisting of F, Cl, Br, and I;
R5 and R6 are optionally connected as alkyl group to form a (C1-3)alkyl bridge cyclic structure;
X is absent to provide a pyrrolidine ring or CH2 to provide a piperidine ring; wherein the carbon atom at position 2 of the piperidine or pyrrolidine is optionally in absolute (S)-configuration;
Y is absent of selected from the group consisting of NH, O, CH2OR4, CH2, and NR4R7 where R7 is H or alkyl; and,
Z1 and Z2 are each independently selected from the group consisting of H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl;
and wherein:
A-B-J-D-E is a five-member heteroaryl;
B-J-G-K-L is a five-member ring selected from the group consisting of aromatic, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
D is C;
E is C;
A is N;
B is C;
J is N;
G is C or N;
K is C; and,
L is O or S.