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;

each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently selected from the group consisting of C, CH, and N, provided that at least two and no more than four of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are 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 selected from the group consisting of: (A-1), (A-2), and (A-3):

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 ;

L w is (C 1 -C 3 )alkylene;

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;

L 3 is —O—;

each occurrence of R a 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 a taken together with the carbon atom to which each is attached forms a (C 3 -C5)cycloalkyl ring;

Ring B is selected from the group consisting of: (B-I), (B-II), and (B-III):

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 of B 5 and B 8 is independently selected from the group consisting of: C and N, provided that:

when Ring B is (B-III), then B 5 is C, and when L 4 is —O—, —S—, —N(H)—, or —N(C 1-3 alkyl)-, and Ring B is (B-III), then B 8 is C;

each of B 6 , B 7 , and B 9 is independently selected from the group consisting of: O, S, CR 1 , NR N , and N,

each in (B-III) is independently a single bond or a double bond,

provided that at least one of B 5 , B 6 , B 7 , B 8 , and B 9 is an independently selected heteroatom, at least one of B 5 , B 6 , B 7 , B 8 , and B 9 is C or CR 1 , and the ring including B 5 , B 6 , B 7 , B 8 , and B 9 is heteroaryl;

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;

each R N is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, C(═O)(C 1 -C 6 )alkyl, S(O) 2 (C 1 -C 6 )alkyl, and C(═O)O(C 1 -C 6 )alkyl;

L 4 is selected from the group consisting of: —C(R c R c )—; —O—; —S—; —N(H)—; —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—, —N(H)—, 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 - 256 . (canceled)

257 . The compound of claim 1 , wherein X 8 , X 5 , and X 3 are C; X 2 and X 4 are N; X 7 is CH; and X 1 and X 6 are independently CH or N.

258 . The compound of claim 257 , wherein X 1 and X 6 are CH.

259 . The compound of claim 257 , wherein X 1 is N and X 6 is CH.

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

261 . The compound of claim 1 , wherein T is

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

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

264 . The compound of claim 263 , wherein n1 is 0.

265 . The compound of claim 1 , wherein Ring B is

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

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

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

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

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

271 . 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.

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

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

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

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

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

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

278 . The compound of claim 22 , wherein each occurrence of R b is independently selected from the group consisting of —F, —Cl, —CH 3 , —CF 3 , and CN.

279 . The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

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

281 . A method of treating type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

282 . The method of claim 281 , the method comprising administering to the patient a therapeutically effective amount of an additional therapy or therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent to treat non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or any combinations thereof.

283 . A method for modulating insulin levels in a patient in need of such modulating, the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.