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JP-2026076168-A - Heterocyclic GLP-1 agonist

JP2026076168AJP 2026076168 AJP2026076168 AJP 2026076168AJP-2026076168-A

Abstract

[Problem] To provide a compound for treating type 2 diabetes in patients. [Solution] The following GLP-1 agonists (including pharmaceutically acceptable salts and solvates thereof) and pharmaceutical compositions containing the same are provided. [Selection Diagram] None

Inventors

  • モン，チンホア
  • リン，シーチェン
  • ジェニングズ，アンドリュー

Assignees

  • ガシャーブラム・バイオ・インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20251225
Priority Date
20200213

Claims (20)

  1. Formula I: Equation I [In the formula, This indicates any single or double bond whose valence is acceptable; Each of X1 , X2 , X3 , X4 , X5 , X6 , X7 , and X8 is independently selected from C, CH, and N, wherein at least two of X1 , X2 , X3 , X4 , X5 , X6 , X7 , and X8 , and no more than four, are N; T1 is a C(=O)OH or carboxylic acid bioisoster; T2 is a ( C1 - C6 ) alkyl which may be appropriately substituted with (C3- C6 ) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, ( C1 - C6 ) alkoxy, CN, or ( C2 - C4 ) alkynyl, and each of the ( C3 - C6 ) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl may be appropriately substituted with 1 to 4 Rx ; Each Rx is independently selected from the group consisting of OH, SH, CN, NO2 , halogens, ( 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, and di( C1 - C6 ) alkylamino; L1 is an alkylene ( C1 - C3 ) which may be appropriately substituted with 1 to 3 R1s ; L2 is a bond, -O-, -S(O)O- 2- , or -NH-; Each R L is independently selected from the group consisting of halogens, ( C1 - C3 ) alkyls, and ( C1 - C3 ) haloalkyls; or A pair of R and L atoms on the same or adjacent carbon atoms, together with the atom to which each is bonded, form a ( C3 - C6 ) cycloalkyl ring; Ring A is, Partially unsaturated monocyclic ( C5 - C8 ) cycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, ( C1 - C3 ) alkyls, ( C1 - C3 ) haloalkyls, ( C1 - C3 ) alkoxys, and ( C1 - C3 ) haloalkoxys; and selected from the group consisting of partially unsaturated monocyclic 5- to 8- membered heterocycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1 - C3 ) alkyls, ( C1 -C3) haloalkyls, (C1- C3 ) alkoxys, and (C1-C3) haloalkoxys; mm indicates the bonding point to L2 , and nn indicates the bonding point to ring B; Ring B is, It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; Each of B1 , B2 , and B3 is independently selected from CR1 and N; Each of B4 and B5 is independently selected from the group consisting of N, NR1 , C, CR1 , O, and S, wherein the rings containing B4 and B5 are heteroaryl; R1 is selected from the group consisting of H, halogens, and ( C1 - C6 ) alkyl groups; Each Ra is independently selected from the group consisting of ( C1 - C6 ) alkyl, ( C1 - C3 ) alkyl ( C3 - C6 ) cycloalkyl, ( C1 - C3 ) alkyl ( 3-5 member heterocycloalkyl), -C(O) NR2R3 , and ( C1 - C6 ) fluoroalkyl; Each R2 and R3 is independently selected from the group consisting of H and ( C1 - C6 ) alkyl groups; a is an integer selected from 0 to 3; Z1 is -O- or -NH-; Each Rc is independently selected from the group consisting of H, ( C1 - C6 ) alkyl, and ( C1 - C3 ) haloalkyl; Ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, ( C3 - C6 ) cycloalkyl, ( C5 - C10 ) bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b is independently selected from the group consisting of ( C1 - C6 ) alkyl, ( C1 - C6 ) alkoxy, halogen, ( C3 - C6 ) cycloalkyl, and CN; and b is an integer selected from 0 to 3. The compound indicated by or its pharmaceutically acceptable salt or solvate.
  2. Formula II: Formula II [In the formula, This indicates any single or double bond whose valence is acceptable; Each of X1 , X2 , X3 , X4 , X5 , X6 , X7 , and X8 is independently selected from C, CH, and N, wherein at least two of X1 , X2 , X3 , X4 , X5 , X6 , X7 , and X8 , and no more than four, are N; T1 is a C(=O)OH or carboxylic acid bioisoster; T2 is a ( C1 - C6 ) alkyl which may be appropriately substituted with a (C3-C6 ) cycloalkyl , a 3-6 member heterocycloalkyl, a phenyl, or a 5-6 member heteroaryl, each of which may be appropriately substituted with 1-4 Rx ; Each Rx is independently selected from the group consisting of OH, SH, CN, NO2 , halogens, ( 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, and di( C1 - C6 ) alkylamino; L1 is an alkylene ( C1 - C3 ) which may be appropriately substituted with 1 to 3 R1s ; L2 is a bond, -O-, -S(O)O- 2- , or -NH-; Each R L is independently selected from the group consisting of halogens, ( C1 - C3 ) alkyls, and ( C1 - C3 ) haloalkyls; or a pair of R Ls on the same or adjacent carbon atoms, together with the atom to which each is bonded, form a ( C3 - C6 ) cycloalkyl ring; Ring A is, Phenylene which may be appropriately substituted with 1 to 4 R Y groups ; Selected from the group consisting of 5-6 member heteroarylenes which may be appropriately substituted with 1-3 R Y ; mm indicates the bonding point to L2 , and nn indicates the bonding point to ring B; and Each R Y is independently selected from the group consisting of halogens, cyano, -OH, oxo, ( C1 - C3 ) alkyl, ( C1 - C3 ) haloalkyl, ( C1 - C3 ) alkoxy, and ( C1 - C3 ) haloalkoxy; Ring B is, It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; Each of B1 , B2 , and B3 is independently selected from the group consisting of CR1 and N; Each of B4 and B5 is independently selected from the group consisting of N, NR1 , C, CR1 , O, and S, wherein the rings containing B4 and B5 are heteroaryl; R1 is selected from the group consisting of H, halogens, and ( C1 - C6 ) alkyl groups; Each Ra is independently selected from the group consisting of ( C1 - C6 ) alkyl, ( C1 - C3 ) alkyl ( C3 - C6 ) cycloalkyl, ( C1 - C3 ) alkyl ( 3-5 member heterocycloalkyl), -C(O) NR2R3 , and ( C1 - C6 ) fluoroalkyl; Each R2 and R3 is independently selected from the group consisting of H and ( C1 - C6 ) alkyl groups; a is an integer selected from 0 to 3; Z1 is -O- or -NH-; Each Rc is independently selected from the group consisting of H, ( C1 - C6 ) alkyl, and ( C1 - C3 ) haloalkyl; Ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, ( C3 - C6 ) cycloalkyl, ( C5 - C10 ) bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b is independently selected from the group consisting of ( C1 - C6 ) alkyl, ( C1 - C6 ) alkoxy, halogen, ( C3 - C6 ) cycloalkyl, and CN; and b is an integer selected from 0 to 3. The compound indicated by or its pharmaceutically acceptable salt or solvate.
  3. The compound according to claim 1 or 2, wherein X8 is C and X5 is C.
  4. The compound according to any one of claims 1 to 3, wherein X3 is C.
  5. The compound according to any one of claims 1 to 4, wherein X2 is N.
  6. The compound according to any one of claims 1 to 5, wherein X4 is N.
  7. The compound according to any one of claims 1 to 6, wherein X7 is CH.
  8. The compound according to any one of claims 1 to 7, wherein each of X8 , X5 , and X3 is C, X2 and X4 are N, X7 is CH, and X1 and X6 are independently CH or N.
  9. The compound according to claim 8, wherein X1 and X6 are CH.
  10. The compound according to claim 8, wherein X1 is N and X6 is CH.
  11. The compound according to claim 8, wherein X1 is CH and X6 is N.
  12. The compound according to any one of claims 1 to 11, wherein T1 is C(=O)OH.
  13. The compound according to any one of claims 1 to 12, wherein T2 is a ( C1 - C3 ) alkyl substituted with a ( C3 - C6 ) cycloalkyl, a 3-6 member heterocycloalkyl, a phenyl, or a 5-6 member heteroaryl.
  14. The compound according to any one of claims 1 to 13, wherein T2 is a ( C1 - C3 ) alkyl group substituted with a ( C3 - C6 ) cycloalkyl group or a 3- to 6-membered heterocycloalkyl group.
  15. The compound according to any one of claims 1 to 14, wherein T2 is a ( C1 - C3 ) alkyl group substituted with a 3- to 6-membered heterocycloalkyl group.
  16. The compound according to any one of claims 1 to 15, wherein T2 is a ( C1 - C3 ) alkyl group substituted with a 4- to 6-membered heterocycloalkyl group.
  17. The compound according to any one of claims 1 to 16, wherein T2 is an oxetanyl-substituted ( C1 - C3 ) alkyl group.
  18. T2 is The compound according to any one of claims 1 to 17.
  19. The compound according to any one of claims 1 to 18, wherein L2 is a bond.
  20. The compound according to any one of claims 1 to 18, wherein L2 is -O-.

Description

Cross-reference of related applications This application claims the benefits of International Patent Application No. PCT/CN2020/075105 filed on 13 February 2020; and International Patent Application No. PCT/CN2020/075103 filed on 13 February 2020 (each of these is incorporated herein by reference in whole). Technical field This disclosure relates to GLP-1 agonists, pharmaceutical compositions, and methods of using them. Incretin-metabolizing hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are crucial for regulating glucose homeostasis. Drugs targeting this family of gastric tubal peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, reduce gastric motility, and increase satiety. Diabetes mellitus refers to a group of metabolic diseases characterized by persistently high blood sugar levels. The most common type, type 2 diabetes mellitus (T2DM), is an acquired disease that accounts for over 90% of diabetes cases. Typical onset occurs in obese or sedentary adults and begins with insulin resistance. While lifestyle changes can be helpful in managing the disease, T2DM patients may need to take diabetes medications, including, among others, dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas. In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate the insulin secretion response to glucose digestion. While this incretin effect is significantly reduced in T2DM (all cases), GLP-1 retains its insulin-secreting properties even when the pancreatic endocrine response to GIP is effectively suppressed. Thus, incretin mimetic substances and other GLP-1 therapies can assist in activating insulin production in T2DM patients. This application describes heterocyclic GLP-1 agonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating GLP-1-related diseases, disorders, and illnesses are also provided. Therefore, equation I: Equation I [In the formula: This indicates any single or double bond whose valence is acceptable; Each of X1 , X2 , X3 , X4 , X5 , X6 , X7 , and X8 is independently selected from the group consisting of C, CH, and N, wherein at least two of X1 , X2 , X3 , X4 , X5 , X6 , X7 , and X8 , and four or fewer, are N; T1 is a C(=O)OH or carboxylic acid bioisoster; T2 is a ( C1 - C6 ) alkyl which may be appropriately substituted with (C3- C6 ) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, ( C1 - C6 ) alkoxy, CN, or ( C2 - C4 ) alkynyl, and each of the ( C3 - C6 ) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl may be appropriately substituted with 1 to 4 Rx ; Each Rx is independently selected from the group consisting of OH, SH, CN, NO2 , halogens, ( 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, and di( C1 - C6 ) alkylamino; L1 is an alkylene ( C1 - C3 ) which may be appropriately substituted with 1 to 3 R1s ; L2 is a bond, -O-, -S(O)O- 2- , or -NH-; Each R L is independently selected from the group consisting of halogens, ( C1 - C3 ) alkyls, and ( C1 - C3 ) haloalkyls; or a pair of R Ls on the same or adjacent carbon atoms, together with the atom to which each is bonded, form a ( C3 - C6 ) cycloalkyl ring; Ring A is, Partially unsaturated monocyclic ( C5 - C8 ) cycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, ( C1 - C3 ) alkyls, ( C1 - C3 ) haloalkyls, ( C1 - C3 ) alkoxys, and ( C1 - C3 ) haloalkoxys; and selected from the group consisting of partially unsaturated monocyclic 5- to 8- membered heterocycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1 - C3 ) alkyls, ( C1 -C3) haloalkyls, (C1- C3 ) alkoxys, and (C1-C3) haloalkoxys; mm indicates the bonding point to L2 , and nn indicates the bonding point to ring B; Ring B is, It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; Each of B1 , B2 , and B3 is independently selected from CR1 and N; Each of B4 and B5 is independently selected from the group consisting of N, NR1 , C, CR1 , O, and S, wherein the rings containing B4 and B5 are heteroaryl; R1 is selected from the group consisting of H, halogens, and ( C1 - C6 ) alkyl groups; Each Ra is independently selected from the group consisting of ( C1 - C6 ) alkyl, ( C1 - C3 ) alkyl ( C3 - C6 ) cycloalkyl, ( C1 - C3 ) alkyl ( 3-5 member heterocycloalkyl), -C(O) NR2R3 , and ( C1 - C6 ) fluoroalkyl; Each R2 and R3 is independently selected from the group consisting of H and ( C1 - C6 ) alkyl groups; a is an integer selected from 0 to 3; Z1 is -O- or -