US 11,884,676 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)
Filed by Vanderbilt University, Nashville, TN (US)
Filed on Mar. 22, 2023, as Appl. No. 18/187,868.
Application 18/187,868 is a continuation of application No. 18/005,301, previously published as PCT/US2021/041836, filed on Jul. 15, 2021.
Claims priority of provisional application 63/052,085, filed on Jul. 15, 2020.
Prior Publication US 2023/0286991 A1, Sep. 14, 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) 30 Claims
 
1. A compound of formula (Ib):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R1 is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkylene-ORa, C1-C3 alkylene-C3-C6 cycloalkyl, or C3-C6 cycloalkyl;
Ra is C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R2 is H, C1-C4 alkyl, C1-C3 alkylene-ORb, NHRb, NRbRb, ORb, or C3-C6 cycloalkyl;
R7 is H, halo, C1-C4 alkyl, NRbRb, or C3-C6 cycloalkyl;
each R3 is independently C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl; or
two Rb, taken together with the nitrogen heteroatom to which they are attached, form a monocyclic 4- to 7-membered heterocyclyl;
R3 is H, C1-C4 alkyl, C1-C3 alkylene-ORc, or C3-C6 cycloalkyl;
Rc is C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R4 is halo or C1-C4 alkyl;
X is CR5a;
R5a is H, halo, or C1-C4 alkyl;
R5b is halo, CN, C1-C2 alkyl, C1-C2 fluoroalkyl, OC1-C2 alkyl, OC1-C2 fluoroalkyl, or C3-C6 cycloalkyl;
n is 0; and
o is 0 or 1.
 
22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.