US 11,807,659 B2
TGR5 modulators and methods of use thereof
Roberto Pellicciari, Perugia (IT); Antimo Gioiello, Perugia (IT); Antonio Macchiarulo, Perugia (IT); Francoise Perron-Sierra, Paris (FR); and Klaus Seedorf, Hamburg (DE)
Assigned to INTERCEPT PHARMACEUTICALS, INC., Morristown, NJ (US)
Filed by INTERCEPT PHARMACEUTICALS, INC., Morristown, NJ (US)
Filed on Apr. 14, 2022, as Appl. No. 17/720,938.
Application 17/720,938 is a continuation of application No. 17/010,505, filed on Sep. 2, 2020, granted, now 11,345,721.
Application 17/010,505 is a continuation of application No. 15/742,595, granted, now 10,800,807, issued on Oct. 13, 2020, previously published as PCT/US2016/037812, filed on Jun. 16, 2016.
Claims priority of provisional application 62/182,081, filed on Jun. 19, 2015.
Claims priority of application No. 15305976 (EP), filed on Jun. 24, 2015.
Prior Publication US 2022/0380404 A1, Dec. 1, 2022
Int. Cl. C07J 9/00 (2006.01); C07J 43/00 (2006.01); A61P 1/16 (2006.01); C07J 41/00 (2006.01); A61P 3/08 (2006.01)
CPC C07J 9/005 (2013.01) [A61P 1/16 (2018.01); A61P 3/08 (2018.01); C07J 41/00 (2013.01); C07J 41/0061 (2013.01); C07J 43/003 (2013.01)] 15 Claims
 
1. A method of treating a metabolic disease or disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula A:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is

OG Complex Work Unit Chemistry
 oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R1 is H or OH;
R2 is H or OH;
R3 is CR11R12C(O)OH, C(O)NHR31, tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O)2—(C1-C3) alkyl;
R11 and R12 are each independently H, F, OH, CH2OH, or CH2F, provided that Ru and R12 are not both H;
R31 OH, (CH2)pOH, or (CH2)pOSO3H; and
p is 1 or 2,
wherein the metabolic disease or disorder is selected from obesity, diabetes, diabesity, metabolic syndrome, insulin resistance, including pre-diabetic insulin resistance, hypertension, and dyslipidemia.