Heterocyclic glp-1 agonists

A compound of Formula I:

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• X1, X2, and X5 are independently C or N;
• X3 and X4 are independently selected from the group consisting of:
• N, NRx, CRY, C(═O), O, and S;
• X6 is selected from the group consisting of:
• a bond, N, NRx, CRy, and C(═O);
• each is a single bond or a double bond, provided that at least one of X1-X6 is an independently selected heteroatom or heteroatomic group;
• at least one of X1-X6 is C or CRY;
• and the ring including X1-X6 is aromatic;
• each Rx is independently selected from the group consisting of:
• hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(═O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(═O)O(C1-C6)alkyl;
• each Ry is independently selected from the group consisting of:
• hydrogen, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, CN, and halogen;
• L0 is a bond or #-P0-P1, wherein #represents the point of attachment to X5;
• -P0 is a bond, —NH—, —N(C1-C6 alkyl)-, —O—, or S(O)0-2;
• -P1 is selected from the group consisting of:
• (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene, and 4- to 8-membered heterocycloalkylene, each of which is optionally substituted with 1-3 R0;
• each R0 is independently selected from the group consisting of:
• halogen, CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, and (C1-C6)haloalkoxy;
• T1 is C(═O)OH or a carboxylic acid bioisostere;
• T2 is hydrogen, CN, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl or (C1-C6)alkyl which is optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)-S(O)2(C1-C6 alkyl), —NH—S(O)2(C1-C6 alkyl), (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, 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, ═O, (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, (C1-C6)alkylamino(C1-C6 alkyl)-C(O)—C1-C6 alkyl, S(O)2(C1-C6 alkyl) 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 selected from the group consisting of:
• wherein n1 is 0, 1, or 2, W1 is CRY1 or N, and W2 is CRY2 or N;
• wherein W3 is C, CRY3, or N, Lw is (C1-C3)alkylene, and each is independently a single bond or a double bond, as allowed by valence;
• phenylene optionally substituted with 1-4 RY;
• 5- to 6-membered heteroarylene optionally substituted with 1-3 RY;
• partially unsaturated monocyclic (C5-C8)cycloalkylene optionally substituted with 1-4 RY;
• and
• partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with 1-4 RY;
• wherein mm represents the point of attachment to L2, and nn represents the point of attachment to Ring B;
• 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, RY2, and RY3 are each 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 and W2 is CRY2, the RY1 and RY2 groups taken together can 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;
• Ring B is selected from the group consisting of:
• (B-I), (B-II), (B-III), (B-IV), (B-V), and (B-VI):
• wherein aa represents the point of attachment to Ring A;
• each of B1, B2, B3, and B4 is independently selected from the group consisting of CR1 and N;
• each of B5 and B6 is independently selected from the group consisting of N, NR1, C, CR1, O, and S, provided that the ring containing B5 and B6 is heteroaryl;
• wherein aa represents the point of attachment to Ring A;
• B7 and B8 are independently selected from the group consisting of:
• —O—, —NRN—, and —C(R1)2—;
• B9 is N or CRaa;
• nb is 0 or 1;
• B10, B11, and B12 are independently selected from the group consisting of CR1 and N;
• each R1 is independently 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 H and (C1-C6)alkyl;
• each RN is independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, C(═O)(C1-C6)alkyl, S(O)2(C1-C6)alkyl, and C(═O)O(C1-C6)alkyl;
• Raa, Rab, and Rac are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)haloalkyl;
• L3 is a bond or —Z1—Z2—*, wherein * represents the point of attachment to Ring C;
• —Z1 is a bond, NH, N(C1-C6 alkyl), O, or S(O)0-2;
• —Z2 is C1-3 alkylene optionally substituted with 1-2 R0;
• each R0 is independently selected from the group consisting of halogen, (C1-C6)alkyl, and (C1-C3)haloalkyl;
• 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.