Glp-1r agonists and uses thereof

A compound represented by structural formula (I):

• or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
• indicates a single bond or a double bond;
• X1, X2, X3, X4, and X5 are each independently selected from N and CH;
• wherein no more than three of X1, X2, X3, X4, and X5 are N and wherein ring A does not contain 3 nitrogen ring atoms at 3 contiguous positions;
• W is selected from O, S, CR5R6, and NR5′;
• Y1, Y3, Y4, and Y5 are each independently selected from N, NH, CH, and CH2;
• Y2 and Y6 are each independently selected from N, C, or CH;
• wherein there is no more than 3 nitrogen ring atoms in ring B and wherein ring B does not contain 3 nitrogen ring atoms at 3 contiguous positions;
• Z1 and Z2 are each independently selected from N, C, and CH;
• wherein at least one of Z1 and Z2 is N;
• Z3 and Z4 are each independently selected from a bond, CH, CH2, CH═CH, CH2CH2, CH2CH, and CHCH2;
• wherein ring C contains no more than two double bonds;
• provided that when ring B is
• then (1) W is not O, and/or (2) ring C is not
• and/or (3) ring C is not
• wherein Z1 is N, and/or (4) ring A is not phenyl;
• wherein:
• T2, T3, and T4 are each independently selected from N, NR4, O, S, C, and CR4;
• T6, T7, and T8 are each independently selected from N and CR4;
• wherein no more than 4 of T2, T3, T4, T6, T7, and T8 are selected from N, O, and S;
• EE is —COOH or a carboxylic group surrogate, optionally, the carboxylic group surrogate is:
• Ra is selected from hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl or C1-C6 alkoxy represented by Ra is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl;
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Ra or in the group represented by Ra is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5′R6′;
• Rb is selected from hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl or C1-C6 alkoxy represented by Rb is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl;
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Rb or in the group represented by Rb is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5′R6′;
• Rc is selected from hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl or C1-C6 alkoxy represented by Rc is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, and C3-C6 saturated or partially saturated cycloalkyl;
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Rc or in the group represented by Rc is optionally substituted with one or more groups selected from halogen, oxo, CN, and NR5′R6′;
• Rd is selected from hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl or C1-C6 alkoxy represented by Rd is optionally substituted with one or more groups selected from halogen, oxo, CN, and saturated or partially saturated C3-C6 cycloalkyl;
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by Rd or in the group represented by Rd is optionally substituted with one or more groups selected from halogen, oxo, CN, and NR5′R6′;
• each R1 is independently selected from halogen, —CN, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6alkynyl represented by R1 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R1 or in the group represented by R1 is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5′R6′;
• each R2 is independently selected from halogen, —CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl or C1-C6 alkoxy represented by R2 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R2 or in the group represented by R2 is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5′R6′;
• each R3 is independently selected from halogen, —CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl or C1-C6 alkoxy represented by R3 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R3 or in the group represented by R3 is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5′R6′;
• each R4 is H, deuterium, halogen, OH, —CN, C1-C6 alkyl, C1-C6 alkoxy, or NR5′R6′, wherein the C1-C6 alkyl and C1-C6 alkoxy represented by R4 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
• R5 and R6 are each independently selected from hydrogen, deuterium, halogen, CN, OH, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR5′R6′, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 alkynyl represented by R5 or R6 is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl (optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3);
• and wherein the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or saturated or partially saturated heterocyclyl represented by R5 or R6 or in the group represented by R5 or R6 is optionally substituted with one or more groups selected from halogen, oxo, CN, OH, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and C1-C3 alkoxy (optionally substituted with 1 to 3 groups selected from F, OH, and OCH3), and NR5′R6′.
• R5′ and R6′ are each independently selected from hydrogen, deuterium, and C1-C6 alkyl;
• wherein optionally two R1;
• two R2;
• two R3;
• two R4;
• R1 and R2;
• R2 and R3;
• Ra and R1;
• Ra and R2;
• R1 and any of R5, R5′ (in the group represented by W), or R6;
• Ra and any of R5, R5′ (in the group represented by W), or R6;
• R2 and any of R5, R5′ (in the group represented by W), or R6;
• R5 and R6;
• any of two groups selected from Rc, Rd, Re, and Rf;
• or R4 and any one of Rc, Rd, Re, and Rf;
• taken together with their respective intervening carbon or hetero atom(s), form phenyl, 5-6 membered heteroaryl, 4-8 membered saturated or partially saturated cycloalkyl or 4-8 membered saturated or partially saturated heterocyclyl, each of which is optionally substituted with one or more groups selected from halogen, —CN, —OH, CF3, C1-C6 alkyl, C1-C6 alkoxy, —NH2, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, oxo, and saturated or partially saturated C3-C6 cycloalkyl, wherein the C1-C6 alkyl and C1-C6 alkoxy is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3, and saturated or partially saturated C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, oxo, CN, CF3, OH, OCH3, OCH2CH3;
• m is an integer selected from 0, 1, 2, 3, and 4,
• n is an integer selected from 0, 1, 2, 3, 4, and 5, and
• o is an integer selected from 0, 1, 2, 3, 4, and 5.