Heterocyclic GLP-1 agonists

1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

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 7 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;

L 1 is a bond or (C 1 -C 3 )alkylene which is optionally substituted with 1-3 R L ;

L 2 is a bond, —O—, —S(O) 0-2 —, or —NH—;

each R L is independently selected from the group consisting of: halogen, (C 1 -C 3 )alkyl, and

(C 1 -C 3 )haloalkyl; or a pair of R L on the same or on adjacent carbon atoms, taken together with the atom(s) to which each is attached, forms a (C 3 -C 6 )cycloalkyl ring;

Ring A is:

wherein mm represents the point of attachment to L 2 , and nn represents the point of attachment to L 3 ;

n1 is 0, 1, or 2; m1 and m2 are independently 0 or 1;

W 1 is CR Y1 or N, provided that when L 2 is —O—, —S—, or —N(H)—, then W 1 is CR Y1 ;

W 2 is CR Y2 ;

each occurrence of RY 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;

L 3 is —O—;

Ring B is:

wherein aa represents the point of attachment to L 3 ;

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′ 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′ 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 , wherein X 1 and X 6 are CH.

3. The compound of claim 1 , wherein X 1 is N and X 6 is CH.

4. The compound of claim 1 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with 4- to 6-membered heterocycloalkyl.

5. The compound of claim 1 , wherein T 2 is

6. The compound of claim 1 , wherein L 1 is CH 2 ; and L 2 is a bond.

7. The compound of claim 1 , wherein Ring A is

8. The compound of claim 7 , wherein n1 is 0.

9. The compound of claim 1 , wherein B 2 is N.

10. The compound of claim 1 , wherein L 4 is —CH 2 —.

11. The compound of claim 1 , wherein L 4 is —CF 2 —, —CH(Me)—, or

12. The compound of claim 1 , wherein L 4 is —O—; and L 5 is a bond.

13. The compound of claim 1 , wherein L 4 is —C(R c R c )—; and L 5 is —O—.

14. The compound of claim 1 , wherein Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicycloheteroaryl.

15. The compound of claim 1 , wherein Ring C is phenyl.

16. The compound of claim 1 , wherein b is 1-3.

17. The compound of claim 1 , wherein b is 2.

18. The compound of claim 1 , wherein b is 1.

19. The compound of claim 1 , wherein b is 0.

20. The compound of claim 1 , wherein Ring C is phenyl; and b is 2.

21. The compound of claim 1 , wherein each occurrence of R b is independently selected from the group consisting of —F, —Cl, —CH 3 , —CF 3 , and CN.

22. The compound of claim 1 , wherein the compound is selected from the group consisting of:

23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.