US 12,187,727 B2
Methods for antagonizing a melanocortin 4 receptor
Christopher Ryan Butler, Canton, MA (US); Michelle Renee Garnsey, Medford, MA (US); Kevin Alexander Ogilvie, Gales Ferry, CT (US); Jana Polivkova, Mystic, CT (US); Matthew Forrest Sammons, Quincy, MA (US); Aaron Christopher Smith, North Providence, RI (US); and Qingyi Yang, Lexington, MA (US)
Assigned to Pfizer Inc., New York, NY (US)
Filed by Pfizer Inc., New York, NY (US)
Filed on Jan. 31, 2023, as Appl. No. 18/162,052.
Application 18/162,052 is a continuation of application No. 17/341,877, filed on Jun. 8, 2021, granted, now 11,643,412.
Claims priority of provisional application 63/036,798, filed on Jun. 9, 2020.
Claims priority of provisional application 63/167,271, filed on Mar. 29, 2021.
Prior Publication US 2023/0174532 A1, Jun. 8, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/438 (2006.01); A61P 1/08 (2006.01); A61P 3/04 (2006.01); A61P 19/00 (2006.01); A61P 21/00 (2006.01); A61P 29/00 (2006.01); C07D 471/20 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/20 (2013.01) [C07D 519/00 (2013.01); C07B 2200/13 (2013.01)] 20 Claims
 
1. A method for treating an MC4R-related condition, disease, or disorder in a human, where the method comprises administering to the human in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof, and wherein the condition, disease, or disorder is selected from cachexia; anorexia or anorexia nervosa; weight loss; failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; and malnutrition;
wherein the compound of Formula I is:

OG Complex Work Unit Chemistry
wherein:
R1 is H, halogen, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or R1a, wherein each of the C3-6 cycloalkyl and 4- to 7-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RB, wherein each RB is halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, or RB1; or two adjacent RB together with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
R1a is 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RA is halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, —N(C1-4 alkyl)2, RA1, or (C3-4 cycloalkyl)-C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RA together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6-membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
RA1 is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
RB1 is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
X1 is C (RX)2, wherein each RX is independently H or C1-4 alkyl;
each of R2 and R3 is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, (C1-4 alkoxy)-C1-4 alkyl-, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4 alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
or R2 and R3 together with the carbon atom to which they are attached form C3-6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
each of Y1, Y2, Y3, Y4, and Y5 is independently CR4 or N, provided that no more than 3 of Y1, Y2, Y3, Y4, and Y5 are N; and
each R4 is independently H, halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, —N(C1-2 alkyl)2, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.