US 12,486,258 B2
Compounds and methods for regulating insulin secretion
Sean M. Burns, Boston, MA (US); Bridget K. Wagner, Cambridge, MA (US); and Amedeo Vetere, Cambridge, MA (US)
Assigned to The Broad Institute, Inc., Cambridge, MA (US); The General Hospital Corporation, Boston, MA (US); and Instituto Carlos Slim de la Salud, A.C., Mexico City (MX)
Filed by The Broad Institute, Inc., Cambridge, MA (US); The General Hospital Corporation, Boston, MA (US); and Instituto Carlos Slim de la Salud, A.C., Mexico City (MX)
Filed on Nov. 21, 2022, as Appl. No. 17/991,792.
Application 17/991,792 is a division of application No. 16/494,744, granted, now 11,555,031, previously published as PCT/US2018/023149, filed on Mar. 19, 2018.
Claims priority of provisional application 62/632,865, filed on Feb. 20, 2018.
Claims priority of provisional application 62/473,811, filed on Mar. 20, 2017.
Prior Publication US 2023/0142508 A1, May 11, 2023
Int. Cl. C07D 413/12 (2006.01); A61P 3/08 (2006.01); C07C 235/84 (2006.01); C07D 213/30 (2006.01); C07D 231/12 (2006.01); C07D 237/08 (2006.01); C07D 261/08 (2006.01); C07D 495/04 (2006.01)
CPC C07D 413/12 (2013.01) [A61P 3/08 (2018.01); C07C 235/84 (2013.01); C07D 213/30 (2013.01); C07D 231/12 (2013.01); C07D 237/08 (2013.01); C07D 261/08 (2013.01); C07D 495/04 (2013.01)] 15 Claims
 
1. A method of modulating insulin secretion comprising contacting a β-cell with a compound having the structure of Formula I:

OG Complex Work Unit Chemistry
wherein the “dashed” bond is a single or double bond;
X1 and X2 are independently selected at each occurrence from C(R2) and N, wherein two vicinal R2 groups may together form an optionally aromatic five- or six membered fused ring;
Y is selected from —C(O)N(R3)—, —N(R3)C(O)—, —SO2N(R3)—, and —N(R3)SO2—;
Z1 and Z2 are independently CH2, O, N, CHR5, CR5, or NR5;
R1 is selected from aryl, heteroaryl, heterocyclyl, and —(C(R3)2)-heterocyclyl optionally substituted with one or more substituents independently selected from alkyl, alkenyl, hydroxyalkyl, ether, acyl, and halogen, and wherein any two vicinal substituents of R1 may together form a five- or six-optionally aromatic membered ring;
R2 is selected from hydrogen, alkyl, alkoxy, —CN, —NH2, —(CH2)1-4NH2, —(CH2)1-4N3, —(CH2)1-4NHC(O)CH3; and
R3 is independently selected at each occurrence from hydrogen and alkyl optionally substituted with one to three groups independently selected from halogen, and wherein a substituent of R1 and any R4 may together form a fused five- or six-membered ring optionally substituted with one two three groups Cl, F, OH, CN, N, O, or S;
R4 is a five- or six-membered aromatic heterocycle optionally substituted with one or more alkyl, halogen, alkoxy, and wherein any two vicinal substituents may together form an optionally aromatic five- or six-membered fused ring optionally substituted with alkyl, N, O, S, or C(═O); and wherein R3 may together with R2 of X1 form a five- or six membered optionally substituted fused ring;
R5 is independently at each occurrence hydrogen or alkyl, and R5 and R2 of X2 may together form a five- or six-membered fused ring; and
RQ is independently selected at each occurrence a bivalent optionally aromatic heterocycles;
or a pharmaceutically acceptable form thereof;
wherein insulin secretion from said B-cell occurs only when blood glucose levels exceed normoglycemic conditions.