US 12,331,055 B2
Substituted pyrimido[1,2-b]pyridazines as positive allosteric modulators of the muscarinic acetylcholine receptor M4
Craig W. Lindsley, Brentwood, TN (US); P. Jeffrey Conn, Nashville, TN (US); Darren W. Engers, Brentwood, TN (US); Alison R. Gregro, Mount Juliet, TN (US); Kayla J. Temple, Spring Hill, TN (US); Madeline F. Long, Nashville, TN (US); Anna E. Ringuette, Nashville, TN (US); Logan A. Baker, Thompson's Station, TN (US); and Thomas Jensen, Valby (DK)
Assigned to Vanderbilt University, Nashville, TN (US)
Appl. No. 18/005,301
Filed by Vanderbilt University, Nashville, TN (US)
PCT Filed Jul. 15, 2021, PCT No. PCT/US2021/041836
§ 371(c)(1), (2) Date Jan. 12, 2023,
PCT Pub. No. WO2022/015988, PCT Pub. Date Jan. 20, 2022.
Claims priority of provisional application 63/052,085, filed on Jul. 15, 2020.
Prior Publication US 2023/0257381 A1, Aug. 17, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/519 (2006.01); C07D 487/04 (2006.01)
CPC C07D 487/04 (2013.01) 45 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R1 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, -L1-ORa, -L1-C3-C6 cycloalkyl, ORa, or C3-C6 cycloalkyl;
L1 is —C1-C3 alkylene-;
Ra is C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R2 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, -L2-ORb, NHRb, NRbRb, ORb, or C3-C6 cycloalkyl;
R7 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, -L2-ORb, NHRb, NRbRb, ORb, or C3-C6 cycloalkyl;
each L2 is independently —C1-C3 alkylene-;
each Rb is independently C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl; or
any two Rb, taken together with the nitrogen atom to which they are attached, independently forms a monocyclic 4- to 7-membered heterocyclyl, wherein the 4- to 7-membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, and C1-C4 haloalkyl;
R3 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, -L3-ORc, ORc, or C3-C6 cycloalkyl;
L3 is —C1-C3 alkylene-;
Rc is C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
each R4 is independently halo, C1-C4 alkyl, -L4-ORd, or ORd;
each L4 is independently —C1-C3 alkylene-;
each Rd is independently C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
X is CR5, or N;
R5a is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, -L5-ORe, ORe, or C3-C6 cycloalkyl;
each R5 is independently halo, C1-C4 alkyl, C1-C4 haloalkyl, -L5-ORe, ORe, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each L5 is independently —C1-C3 alkylene-;
each Re is independently C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl; or
two R5, taken together with the carbon atoms to which they are attached, form a fused monocyclic 5- to 8-membered heterocycle;
wherein the 5- to 8-membered heterocycle contains one or two heteroatoms independently selected from the group consisting of N, O, and S; and
wherein the 5- to 8-membered heterocycle is optionally substituted with 1, 2, 3, or 4 independently selected R6 substituents;
each R6 is independently halo, C1-C4 alkyl, -L6-ORf, ORf, or ═O;
each L6 is independently —C1-C3 alkylene-;
each Rf is independently C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
each R5b is independently halo, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, OC1-C2 alkyl, OC1-C2 fluoroalkyl, or C3-C4 cycloalkyl;
m is 0, 1, or 2;
n is 0, 1, or 2; and
o is 0, 1, or 2.
 
39. A method for modulating muscarinic acetylcholine receptor (mAChR) M4 activity in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.