US 11,926,626 B2
Heterocyclic GLP-1 agonists
Qinghua Meng, Shanghai (CN); Weiqiang Xing, Shanghai (CN); Haizhen Zhang, Shanghai (CN); Xichen Lin, Shanghai (CN); Hui Lei, Shanghai (CN); and Andrew Jennings, San Francisco, CA (US)
Assigned to Gasherbrum Bio, Inc., South San Francisco, CA (US)
Filed by Gasherbrum Bio, Inc., South San Francisco, CA (US)
Filed on Sep. 21, 2022, as Appl. No. 17/950,073.
Application 17/950,073 is a continuation of application No. PCT/CN2021/115064, filed on Aug. 27, 2021.
Claims priority of application No. PCT/CN2020/112149 (WO), filed on Aug. 28, 2020.
Prior Publication US 2023/0107793 A1, Apr. 6, 2023
Int. Cl. C07D 471/04 (2006.01); A61K 45/06 (2006.01); C07D 405/14 (2006.01); C07D 417/14 (2006.01)
CPC C07D 471/04 (2013.01) [A61K 45/06 (2013.01); C07D 405/14 (2013.01); C07D 417/14 (2013.01)] 23 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or solvate thereof, wherein:
custom character indicates an optional single or double bond, as allowed by valence;
X3, X5, and X8 are C; X2 and X4 are N; X6 and X7 are CH; and X1 is CH or N;
T1 is C(═O)OH;
T2 is hydrogen or (C1-C6)alkyl which is optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of the (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 RT;
each RT is independently selected from the group consisting of OH, SH, CN, NO2, halogen,
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl,
(C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino,
(C1-C6)alkylamino, and di(C1-C6)alkylamino;
L1 is a bond or (C1-C3)alkylene which is optionally substituted with 1-3 RL;
L2 is a bond, —O—, —S(O)0-2—, or —NH—;
each RL is independently selected from the group consisting of: halogen, (C1-C3)alkyl, and
(C1-C3)haloalkyl; or a pair of RL on the same or on adjacent carbon atoms, taken together with the atom(s) to which each is attached, forms a (C3-C6)cycloalkyl ring;
Ring A is:

OG Complex Work Unit Chemistry
wherein mm represents the point of attachment to L2, and nn represents the point of attachment to L3;
n1 is 0, 1, or 2; m1 and m2 are independently 0 or 1;
W1 is CRY1 or N, provided that when L2 is —O—, —S—, or —N(H)—, then W1 is CRY1;
W2 is CRY2;
each occurrence of RY is independently selected from the group consisting of halogen, CN,
—OH, oxo, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy;
RY1 and RY2 are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or
when W1 is CRY1, the RY1 and RY2 groups taken together form (C1-C4)alkylene, wherein one of the CH2 units of the (C1-C4)alkylene is optionally replaced by a heteroatom selected from the group consisting of O, S, NH, and N(C1-3)alkyl;
L3 is —O—;
Ring B is:

OG Complex Work Unit Chemistry
wherein aa represents the point of attachment to L3;
each of B1, B2, B3, and B4 is independently selected from the group consisting of CR1 and N;
each R1 is selected from the group consisting of hydrogen, halogen, CN, (C1-C6)alkyl,
(C1-C6)haloalkyl; (C1-C3)alkyl(C3-C6)cycloalkyl, (C1-C3)alkyl(3- to 5-membered heterocycloalkyl), and
—C(O)NR2R3;
each R2 and R3 is independently selected from the group consisting of hydrogen and
(C1-C6)alkyl;
L4 is selected from the group consisting of: —C(RcRc)—; —O—; —S—; —N(C1-3 alkyl)-; —C(═O)—; and
—S(O)1-2—;
L5 is selected from the group consisting of: a bond; —C(RcRc)—; —O—; —S—; —N(H)—;
—N(C1-3 alkyl)-; —C(═O)—; and —S(O)1-2—;
provided that when L4 is —O—, —S—, or —N(C1-3 alkyl)-, then L5 is a bond, —C(RcRc)—, —C(═O), or
—S(O)1-2—, and
provided that when L5 is —O—, —S—, —N(H)—, or —N(C1-3 alkyl)-, then L4 is —C(RcRc)—, —C(═O), or
—S(O)1-2—,
each occurrence of R′ is independently selected from the group consisting of: hydrogen, halogen, CN, —OH, (C1-C6)alkyl, (C1-C3)haloalkyl, (C3-C8)cycloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; or
a pair of R′ taken together with the carbon atom to which each is attached forms a
(C3-C8)cycloalkyl ring;
Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl,
(C3-C6)cycloalkyl, (C5-C10)bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl;
each Rb is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl,
(C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, and CN; and
b is an integer selected from 0-3.