Heterocyclic GLP-1 agonists
This disclosure relates to GLP-1 agonists of Formula (I), including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.
1. A compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety:
is represented by the moiety of Formula (I-A):
wherein:
L 3 is —O—;
indicates an optional single or double bond, as allowed by valence;
X 3 , X 5 , and X 8 are C; X 2 and X 4 are N; X 6 and X 1 are CH; and X 1 is CH or N;
T 1 is C(═O)OH;
T 2 is hydrogen or (C 1 -C 6 ) alkyl which is optionally substituted with (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) thioalkoxy, (C 1 -C 6 ) haloalkoxy, S(O) 2 (C 1 -C 6 alkyl), (C 3 -C 6 ) cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of the (C 3 -C 6 ) cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 R T ;
each R T is independently selected from the group consisting of OH, SH, CN, NO 2 , halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cycloalkyl, amino, (C 1 -C 6 )alkylamino, and di(C 1 -C 6 )alkylamino;
n1 is 0, 1, or 2;
W 1 is CR Y1 or N;
each occurrence of R Y is independently selected from the group consisting of halogen, CN, —OH, oxo, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy;
R Y1 and R Y2 are independently selected from the group consisting of hydrogen, halogen, CN, —OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or
when W 1 is CR Y1 ; the R Y1 and R Y2 groups taken together form (C 1 -C 4 )alkylene, wherein one of the CH 2 units of the (C 1 -C 4 )alkylene is optionally replaced by a heteroatom selected from the group consisting of O, S, NH, and N(C 1-3 )alkyl;
each of B 1 , B 2 , B 3 , and B 4 is independently selected from the group consisting of CR 1 and N;
each R 1 is selected from the group consisting of hydrogen, halogen, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl; (C 1 -C 3 )alkyl(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkyl(3- to 5-membered heterocycloalkyl), and —C(O)NR 2 R 3 ;
each R 2 and R 3 is independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl;
L 4 is selected from the group consisting of: —C(R c R c )—; —O—; —S—; —N(C 1-3 alkyl)-; —C(═O)—; and —S(O) 1-2 —,
L 5 is selected from the group consisting of: a bond; —C(R c R c )—; —O—; —S—; —N(H)—; —N(C 1-3 alkyl)-; —C(═O)—; and —S(O) 1-2 —,
provided that when L 4 is —O—, —S—, or —N(C 1-3 alkyl)-, then L 5 is a bond, —C(R c R c )—, —C(═O), or —S(O) 1-2 —, and
provided that when L 5 is —O—, —S—, —N(H)—, or —N(C 1-3 alkyl)-, then L 4 is —C(R c R c )—, —C(═O), or —S(O) 1-2 —;
each occurrence of R c is independently selected from the group consisting of: hydrogen, halogen, CN, —OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or
a pair of R c taken together with the carbon atom to which each is attached forms a (C 3 -C 8 )cycloalkyl ring;
Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 10 )bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl;
each R b is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 3 -C 6 )cycloalkyl, and CN; and
b is an integer selected from 0-3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:
3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:
4. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.