US 12,319,701 B2
Antagonists of the muscarinic acetylcholine receptor M4
Craig W. Lindsley, Brentwood, TN (US); P. Jeffrey Conn, Nashville, TN (US); Aaron M. Bender, Spring Hill, TN (US); Matthew Spock, Nashville, TN (US); and Changho Han, Nashville, TN (US)
Assigned to Vanderbilt University, Nashville, TN (US)
Appl. No. 17/766,341
Filed by Vanderbilt University, Nashville, TN (US)
PCT Filed Oct. 2, 2020, PCT No. PCT/US2020/053942
§ 371(c)(1), (2) Date Apr. 4, 2022,
PCT Pub. No. WO2021/067696, PCT Pub. Date Apr. 8, 2021.
Claims priority of provisional application 62/910,863, filed on Oct. 4, 2019.
Prior Publication US 2024/0083907 A1, Mar. 14, 2024
Int. Cl. C07D 495/04 (2006.01); C07B 59/00 (2006.01); C07D 405/14 (2006.01)
CPC C07D 495/04 (2013.01) [C07B 59/002 (2013.01); C07D 405/14 (2013.01); C07B 2200/05 (2013.01)] 20 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
A is a 5- to 6-membered heteroarene, a 5- to 6-membered heterocycle, a 6-membered arene, or a 5- to 6-membered carbocycle, the heteroarene and heterocycle having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
L is NR or O;
R is hydrogen, C1-4alkyl, C3-4cycloalkyl, or —C1-3alkylene—C3-4cycloalkyl;
R1 is G1, —L′—G1, —L′—C1-3alkylene—G1, —C1-3alkylene—G1, hydrogen, C1-6alkyl, C1-6haloalkyl, —L′—C1-6alkyl, —L′—C1-6haloalkyl, —C(O)NH2, or halogen;
L′ is O, —N(R1a)—, S, S(O), SO2, —C(O)—, or —N(R1a)C(O)—;
G1 is a 5- to 12-membered heteroaryl, a 6- to 12-membered aryl, a 4- to 12-membered heterocyclyl, or a C3-12carbocyclyl, wherein G1 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4haloalkyl, —OR10, —N(R10)2, —NR10C(O)R10, —CONR10R10, —NR10SO2R11, —C1-3alkylene—OR10, C3-6cycloalkyl, and —C1-3alkylene—C3-6cycloalkyl;
R1a is hydrogen, C1-4alkyl, C1-4haloalkyl, C3-4cycloalkyl, or —C1-3alkylene—C3-4cycloalkyl;
R10, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4haloalkyl, C3-4cycloalkyl, or —C1-3alkylene—C3-4cycloalkyl, wherein alternatively two R10, together with a nitrogen to which the two R10 attach form a 4-to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl;
R11 is C1-4alkyl, C1-4haloalkyl, C3-4cycloalkyl, or —C1-3alkylene—C3-4cycloalkyl;
R2, at each occurrence, is independently halogen, cyano, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C3-6cycloalkyl, or —C1-3alkylene—C3-4cycloalkyl;
n is 0, 1, 2, 3, or 4;
R3 is —L1—G2, G2, —L2—G2, —L2L1—G2, —C2-6alkylene—R3a, or C3-7alkyl;
L1 is C1-3alkylene;
L2 is 1,1-cyclopropylene;
G2 is a 4-to 12-membered heterocyclyl a 6-to 12-membered aryl, a 5-to 12-membered heteroaryl, or a C3-12carbocyclyl optionally fused to a 6-membered arene, wherein G2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4haloalkyl, —OR13, —N(R13)2, —C1-3alkylene—OR13 or —C1-3alkylene—N(R13)2;
R3a is —OR14 or —N(R14)2; and
R13 and R14, at each occurrence, are independently hydrogen, C1-4alkyl, C1-4haloalkyl, C3-4cycloalkyl, or —C1-3alkylene—C3-4cycloalkyl, wherein alternatively two R13 or two R14, together with a nitrogen to which the two R13 or two R14 attach form a 4-to 6-membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and C1-4alkyl.