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US-20260124271-A1 - COMPOSITIONS AND METHODS FOR THE TREATMENT OF METABOLIC AND LIVER DISORDERS

US20260124271A1US 20260124271 A1US20260124271 A1US 20260124271A1US-20260124271-A1

Abstract

Disclosed herein are small molecule GIP/GLP-1 dual receptor agonist compositions, pharmaceutical compositions, the use and preparation thereof.

Inventors

  • Brian Lian
  • Geoffrey E. Barker
  • Maureen Barnes
  • Kader Yagiz
  • Erland Stevens

Assignees

  • VIKING THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20251219

Claims (20)

  1. 1 . A method of making a compound of formula I: or a pharmaceutically acceptable salt thereof, comprising: deprotecting a compound of formula IV: or a pharmaceutically acceptable salt thereof, to form the compound of formula I, or the pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of —C(═O)(OZ 1 ), —P(═O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R 7 ; R 2 is selected from the group consisting of —C(═O)(OZ 2 ), —P(═O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R 7 ; each R 7 is independently selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, —OR 5 , C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; X and Y each are independently selected from the group consisting of —OR 4 , NR 5 R 6 , C 1-6 alkyl and haloC 1-6 alkyl; each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 6-10 aryl and C 6-10 arylalkyl; each R 5 is independently hydrogen or C 1-6 alkyl; each R 6 is independently hydrogen or C 1-6 alkyl; and Z 1 and Z 2 each are independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-10 cycloalkyl and C 6-10 aryl; wherein “*” indicates a chiral carbon with “S” configuration or “R” configuration, with the proviso that when Z 1 and Z 2 are both present, at least one of Z 1 and Z 2 is not hydrogen.
  2. 2 . The method of claim 1 , wherein deprotecting the compound of formula IV, or the pharmaceutically acceptable salt thereof, comprises reacting the compound of formula IV, or the pharmaceutically acceptable salt thereof, with trifluoroacetic acid.
  3. 3 . The method of claim 1 , further comprising combining via amide coupling a compound of formula II: or a pharmaceutically acceptable salt thereof, and a compound of formula III: or a pharmaceutically acceptable salt thereof, to form the compound of formula IV, or the pharmaceutically acceptable salt thereof.
  4. 4 . The method of claim 1 , wherein the compound of formula I has the structure of formula I-a: or a pharmaceutically acceptable salt thereof.
  5. 5 . The method of claim 1 , wherein the compound of formula I has the structure of formula I-b: or a pharmaceutically acceptable salt thereof.
  6. 6 . The method of claim 1 , wherein the compound of formula I has the structure of formula I-c: or a pharmaceutically acceptable salt thereof.
  7. 7 . The method of claim 1 , wherein the compound of formula I has the structure selected from the group consisting of: and pharmaceutically acceptable salts thereof.
  8. 8 . The method of claim 1 , wherein R 1 is —C(═O)(OZ 1 ).
  9. 9 . The method of claim 8 , wherein Zi is hydrogen.
  10. 10 . The method of claim 1 , wherein R 1 is —P(═O)(X)(Y).
  11. 11 . The method of claim 1 , wherein R 2 is —C(═O)(OZ 2 ).
  12. 12 . The method of claim 11 , wherein Z 2 is hydrogen.
  13. 13 . The method of claim 1 , wherein R 1 is —P(═O)(X)(Y).
  14. 14 . A method of making a compound of formula IV: or a pharmaceutically acceptable salt thereof, comprising: combining via amide coupling a compound of formula II: or a pharmaceutically acceptable salt thereof, and a compound of formula III: or a pharmaceutically acceptable salt thereof, to form a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of —C(═O)(OZ 1 ), —P(═O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R 7 ; R 2 is selected from the group consisting of —C(═O)(OZ 2 ), —P(═O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R 7 ; each R 7 is independently selected from the group consisting of halogen, C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, —ORS, C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; X and Y each are independently selected from the group consisting of —OR 4 , NR 5 R 6 , C 1-6 alkyl and haloC 1-6 alkyl; each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 6-10 aryl and C 6-10 arylalkyl; each R 5 is independently hydrogen or C 1-6 alkyl; each R 6 is independently hydrogen or C 1-6 alkyl; and Z 1 and Z 2 each are independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 3-10 cycloalkyl and C 6 .io aryl; wherein “*” indicates a chiral carbon with “S” configuration or “R” configuration, with the proviso that when Z 1 and Z 2 are both present, at least one of Z 1 and Z 2 is not hydrogen.
  15. 15 . The method of claim 14 , wherein R 1 is —C(═O)(OZ 1 ).
  16. 16 . The method of claim 15 , wherein Z 1 is hydrogen.
  17. 17 . The method of claim 14 , wherein R 1 is —P(═O)(X)(Y).
  18. 18 . The method of claim 14 , wherein R 2 is —C(═O)(OZ 2 ).
  19. 19 . The method of claim 18 , wherein Z 2 is hydrogen.
  20. 20 . The method of claim 14 , wherein R 1 is —P(═O)(X)(Y).

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/447,990, filed Aug. 10, 2023, which is a division of U.S. application Ser. No. 17/990,629, filed Nov. 18, 2022, now U.S. Pat. No. 11,744,873, which is a continuation of International Application No. PCT/US2022/012807, filed Jan. 18, 2022, which claims the benefit of U.S. Provisional Application No. 63/139,676, filed Jan. 20, 2021, each of which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled VIKNG.016C3.xml, created on Dec. 18, 2025, which is 4,606 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety. BACKGROUND Field of the Invention The present disclosure relates generally to the field of treatments for metabolic disorders and fatty liver diseases. More specifically, the present disclosure relates to the field of small molecule drugs for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD). Description of the Related Art Incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are metabolic hormones. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet β-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is the most common cause of chronic liver disease. NAFLD may progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. GIP/GLP-1 dual receptor agonists have been developed for treating NAFLD, non-alcoholic steatohepatitis (NASH), diabetes, obesity, and other diseases. However, the use of GIP/GLP-1 dual receptor agonists is associated with nausea, vomiting, and/or diarrhea. For example, clinical trials of a GIP/GLP1 dual receptor agonist compound found that tolerability at high doses was limited by gastrointestinal adverse events. The dose limitation associated with gastrointestinal adverse events may prevent dosing to the desired effective dose, may compromise patient compliance with treatment, and may limit the effectiveness of the treatment regimen. Therefore, a need exists for novel GIP/GLP1 dual agonist compounds that can be used to treat fatty liver diseases and other diseases and disorders. SUMMARY Some embodiments disclosed herein include a compound having the structure of the formula I. or a pharmaceutically acceptable salt thereof, wherein:R1 is selected from the group consisting of —C(═O)(OZ1), —P(═O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R7;R2 is selected from the group consisting of —C(═O)(OZ2), —P(═O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R7;each R7 may be independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, —OR5, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y may each be independently selected from the group consisting of —OR4, NR5R6, C1-6 alkyl and haloC1-6 alkyl;each R4 may be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C6-10 aryl and C6-10 arylalkyl;each R5 may be independently hydrogen or C1-6 alkyl;each R6 may be independently hydrogen or C1-6 alkyl; andZ1 and Z2 may each be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C3-10 cycloalkyl and C6-10 aryl;wherein “*” indicates a chiral carbon with “S” configuration or “R” configuration,with the proviso that when Z1 and Z2 are both present, at least one of Z1 and Z2 is not hydrogen. Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient. Other embodiments disclosed herein include a method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject, by administering the compounds disclosed herein, or a pharmaceutically acceptable salt thereof,