[go: up one dir, main page]

WO2025222000A1 - Composés 1,1'-biphényle substitués utilisés en tant qu'agonistes du récepteur du glucagon - Google Patents

Composés 1,1'-biphényle substitués utilisés en tant qu'agonistes du récepteur du glucagon

Info

Publication number
WO2025222000A1
WO2025222000A1 PCT/US2025/025163 US2025025163W WO2025222000A1 WO 2025222000 A1 WO2025222000 A1 WO 2025222000A1 US 2025025163 W US2025025163 W US 2025025163W WO 2025222000 A1 WO2025222000 A1 WO 2025222000A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
independently selected
alkyl
halogen
substituents independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/025163
Other languages
English (en)
Inventor
Sarah May ANTHONY
Travis Lamonte BUCHANAN
Scott Eugene Conner
Jaime Nathan CORONADO
Steven J. GREEN
Rachel Rose KNAPP
Jack Lee
Jayana P. Lineswala
Tao Liu
Ifedi ORIZU
Elisabetta RONCHI
Farbod SALAHI
Tabitha Taylor SCHEMPP
Bishnu THAPA
Miguel Angel Toledo Escribano
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of WO2025222000A1 publication Critical patent/WO2025222000A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • glucagon receptor agonists are glucagon receptor agonists. These compounds may be useful as therapeutic agents, either as a monotherapy or in combination with another therapeutic agent, for preventing or treating a disease or condition through the modulation of the glucagon receptor.
  • T2D mellitus is the most common form of diabetes accounting for approximately 90% of all diabetes. T2DM is characterized by high blood glucose levels caused by insulin resistance.
  • the current standard of care for T2DM includes diet and exercise, and treatment with oral and injectable medications including incretinbased therapies, such as glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and glucosedependent insulinotropic polypeptide receptor agonists (GIP RA). Incretin-based therapies such as GLP-1 RA and GIP RA have also been approved for treating obesity and overweight.
  • GLP-1 RA glucagon-like-peptide-1 receptor agonists
  • GIP RA glucosedependent insulinotropic polypeptide receptor agonists
  • Glucagon is a twenty nine amino acid peptide which is secreted from the cells of the pancreas into the hepatic portal vein thereby exposing the liver to higher levels of this hormone than non-hepatic tissues.
  • Glucagon through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis.
  • the glucagon receptor GCGR is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors.
  • GLP-1 glucagon -like peptide- 1 receptor
  • GLP-2 glucagon-like peptide-2 receptor
  • gastric inhibitory polypeptide receptor gastric inhibitory polypeptide receptor.
  • the glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex and gastrointestinal tract. Stimulation of the glucagon receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. Regulation of the glucagon receptor can play an important role in the treatment of T2DM, obesity or overweight, and other conditions modulated by this receptor.
  • glucagon agonists described herein have favorable properties allowing for administration of doses that provide sufficient activity at the glucagon receptor to provide the benefits of agonism of that receptor while avoiding unwanted side effects associated with too much activity.
  • the compound of formula (I) is a glucagon receptor agonist. In one embodiment, the compound of formula (I) is a glucagon receptor agonist which has potent activity at the glucagon receptor. In one embodiment, the compound of formula (I) can be used for preventing or treating a disease or condition through the modulation of the glucagon receptor. DESCRIPTION OF THE INVENTION
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -C1-10 alkyl, and (c) -C(0)Ci-io alkyl,
  • (11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • R g is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-io alkyl optionally substituted with -OH,
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-io alkyl,
  • R d is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
  • each of R 4 , R 4 , R 5 , and R y is independently selected from:
  • R 6 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-io alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-io alkoxy,
  • each of R 6e and R 6f is independently selected from (i) H, (ii) -Ci-io alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • each of R A1 , R A2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
  • (11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl and (b) halogen;
  • R 1 is selected from:
  • R e is selected from:
  • R 1 is selected from:
  • R s is a 4 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with Ci-6 alkyl optionally substituted with -OH,
  • Ci-6 alkoxy optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; wherein each of the heterocyclyl of (1) and the heteroaryl of (2) is optionally substituted with 1 to 4 substituents independently selected from:
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-6 alkyl, (4) -C(O)-R d , wherein R d is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • each of R 4 , R 4 , R 5 , and R 5 is independently selected from:
  • R 6 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy,
  • each of R 6e and R 6t is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • R 1 is selected from:
  • R e is selected from:
  • R. 1 is selected from:
  • R g is a 4 to 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-4 alkyl optionally substituted with -OH,
  • R 1 is selected from:
  • heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from:
  • R e is selected from (a) H and (b) -C1.4 alkyl
  • R 1 is selected from:
  • Ci-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from (i) halogen and (ii) -OH; or a pharmaceutically acceptable salt thereof.
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -Ci-io alkyl, and (c) -C(0)Ci-io alkyl,
  • (11) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -C1-10 alkyl and (b) halogen;
  • R 1 is selected from:
  • R e is selected from: (a) H, (b) -Ci-io alkyl, and
  • R f is selected from:
  • each of R a and R b is independently selected from (i) H and (ii) -Ci-io alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -C1-10 alkyl
  • R d is selected from (a) -C1-10 alkyl; (b) -OH, (c) -C1-10 alkoxy, and
  • each of R 4 , R 4 , R 5 , and R 5 is independently selected from:
  • R 6 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; wherein each of the aryl of (1), heteroaryl of (2), and heterocyclyl of (3) is optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) - Ci-10 alkyl, (ii) halogen, (iii) -OH, and (iv) -C1-10 alkoxy,
  • each of R 6e and R 6f is independently selected from (i) H, (ii) - Ci-10 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b are independently selected from (a) H, (b) -CMO alkyl, and (c) -C(0)Ci-io alkyl;
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-io alkyl,
  • R d is selected from (a) -Ci-io alkyl; (b) -OH, (c) -Ci-io alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-io alkyl, and
  • each of R 4 , R 4 , R 5 , and R 3 is independently selected from:
  • R 6 is an aryl, optionally substituted with 1 to 3 substituents independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-io alkyl, (b) halogen, (c) -OH, and (d) -Ci-io alkoxy,
  • R 6e and R 6f are independently selected from (a) H, (b) -Ci-io alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R 7 is selected from:
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (la):
  • each of R A1 , R A2 , R A3 , and R 44 is independently selected from:
  • each of R a and R h is independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl,
  • R 1 is selected from: (1) a 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • R e is selected from:
  • R 1 is selected from:
  • R a and R b are independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-6 alkyl
  • R d is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • each of R 4 , R 4 , R 5 , and R y is independently selected from:
  • R 6 is selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -Ci-6 alkyl, (ii) halogen, (iii) -OH, and (iv) -Ci-6 alkoxy, (f) -S-Ci-6 alkyl, optionally substituted with 1 to 3 halogens,
  • each of R 6e and R 6f is independently selected from (i) H, (ii) -Ci-6 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b is independently selected from (a) H, (b) -C1-4 alkyl, and (c) -C(O)Ci- 4 alkyl,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R a and R b is independently selected from (i) H and (ii) -Ci-4 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R 4 is -C1-4 alkyl, optionally substituted with 1 to 3 halogens
  • R 6 is selected from: (1) a phenyl
  • each of R A1 , R 2 , R A3 , and R A4 is independently selected from:
  • each of R a and R b is independently selected from (a) H and (b) - C(O)CH 3 ,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R 2 and R 3 is independently selected from: (1) H,
  • R 4 is selected from:
  • R 6 is selected from:
  • each of R A1 , R ⁇ , R A3 , and R A4 is independently selected from:
  • Ci-6 alkyl optionally substituted with 1 to 3 halogens
  • R a and R b are independently selected from (a) H, (b) -Ci-6 alkyl, and (c) -C(O)Ci-6 alkyl.
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • Ci-4 alkyl optionally substituted with 1 to 3 halogens
  • R a and R b are independently selected from (a) H, (b) -Ci-4 alkyl, and (c) -C(O)Ci-4 alkyl.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (le):
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is of formula (If):
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b is independently selected from (a) H and (b) -Ci-6 alkyl,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • R a and R b are independently selected from (i) H and (ii) -C1-6 alkyl, and
  • R a and R b is independently selected from (a) H and (b) -C1-6 alkyl, (6) -C(O)NR a R b , wherein R a and R b is independently selected from (a) H and (b) -Ci-6 alkyl,
  • each of R 2 and R 3 is independently selected from:
  • R c is selected from (a) H and (b) -Ci-6 alkyl
  • R d is selected from (a) -Ci-6 alkyl; (b) -OH, (c) -Ci-6 alkoxy, and
  • each of R 2e and R 2f is independently selected from (i) H and (ii) -Ci-6 alkyl, and
  • R 4 is selected from:
  • each of R 6a , R 6b , R 6e and R 6d is independently selected from:
  • heteroaryl is a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (a) -Ci-6 alkyl, (b) halogen, (c) -OH, and (d) -Ci-6 alkoxy,
  • R 6e and R 6t are independently selected from (a) H, (b) -Ci-6 alkyl, and (c) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • R a and R b is independently selected from (a) H, (b) -C1-4 alkyl, and (c) -C(O)Ci- 4 alkyl,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R a and R b is independently selected from (i) H and (ii) -Ci-4 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R 4 is -Ci-4 alkyl, optionally substituted with 1 to 3 halogens; and each of R 6a , R 6b , R 6c and R 6d is independently selected from:
  • each of R A1 , R ⁇ 2 , R A3 , and R A4 is independently selected from:
  • each of R a and R b is independently selected from (a) H and (b) methyl, (c) ethyl and (d) -C(O)CH ,
  • R 1 is selected from:
  • R e is selected from:
  • R f is selected from:
  • each of R 2 and R 3 is independently selected from:
  • R 4 is selected from:
  • R 6a , R 6b , R 6c and R 6d is independently selected from:
  • (6) a 4-6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) methyl, (ii) ethyl and (iii) halogen,
  • R 1 is selected from:
  • heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is a monocyclic or a spiro bicyclic group,
  • heteroaryl (2) a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is a monocyclic or a fused bicyclic group,
  • R e is selected from (a) H and (b) -Ci-6 alkyl
  • R f is selected from:
  • R 1 is selected from:
  • R c is selected from (a) H and (b) -Ci-4 alkyl
  • R f is selected from:
  • R 1 is selected from:
  • R e is selected from (a) H and (b) -CH3;
  • R 1 is selected from:
  • each of R 2 and R 3 is independently selected from:
  • R d is selected from (a) -C1.4 alkyl; (b) -C1-4 alkoxy, and (c) - NR 2c R 2f , wherein each of R 2c and R 2f is independently selected from (i) H and (ii) -Ci- 4 alkyl, and
  • each of R 2 and R 3 is independently selected from:
  • R 2 is selected from (1) H, (2) -CH 3 and (3) -CH2OH;
  • R 3 is selected from (1) H, (2) -CH 3 and (3) -CH2OH.
  • each of R 4 , R 4 , R ⁇ and R 5 is independently selected from:
  • R 4 is selected from:
  • R 2 is selected from (1) H, (2) -CH3 and (3) -CH2OH;
  • R 3 is selected from (1) H, (2) -CH3 and (3) -CH2OH;
  • R 4 is selected from (1) -CH 3 , (2) -CH 2 OH, (3) -CHF 2 , and (4) -CF 3 .
  • R 2 is selected from (1) H and (2) -CH3;
  • R 3 is selected from (1) H and (2) -CH3;
  • R 4 is -CH 3 .
  • R 2 is -CH 3 ;
  • R 3 is -CH3
  • R 4 is -CH 3 .
  • R 6 is selected from:
  • each of R 6e and R 6t is independently selected from (i) H, (ii) -Ci-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • a phenyl optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -OH, and
  • a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1.4 alkoxy.
  • R 6 is selected from:
  • each of R 6e and R 6f is independently selected from (i) H, (ii) -Ci-4 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, (g) a 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
  • a phenyl optionally substituted with 1 to 3 substituents independently selected from (i) -C1-4 alkyl, (ii) halogen, and (iii) -OH, and
  • a heteroaryl selected from (i) pyridyl, (ii) pyrimidinyl, (iii) pyrazolyl, (iv) triazolyl, (v) thiazolyl, (vi) isothiazolyl, (vii) thienyl, and (viii) oxazolyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (a) -C1-4 alkyl, (b) halogen, (c) -OH, and (d) -C1.4 alkoxy.
  • R 6 is selected from:
  • each of R 6e and R 6f is independently selected from (i) H, (ii) - C1-2 alkyl, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • a heterocyclyl selected from (i) morpholinyl, (ii) piperidinyl, (iii) tetrahydropyranyl, and (v) 1,4-dioxanyl, optionally substituted with 1 to 3 substituents independently selected from (i) -CH3 and (ii) halogen,
  • a heteroaryl selected from (i) pyridyl, (ii) pyrazolyl, (iii) thiazolyl, (iv) isothiazolyl, and (v) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) ethyl, (iii) halogen, (iv) - OH, and (v) -OCH 3 .
  • R 6 is a phenyl, optionally substituted with 1 to 3 substituents independently selected from:
  • each of R 6e and R 6t is independently selected from (i) H, (ii) -CH3, and (iii) 5 or 6 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S,
  • a heteroaryl selected from (i) pyridyl, (ii) thiazolyl, (iii) isothiazolyl, and (iv) thienyl, each of which is optionally substituted with 1 to 3 substituents independently selected from (i) -CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.
  • R 6 is phenyl, optionally substituted with 1 to 3 substituents independently selected from:
  • a pyridyl optionally substituted with 1 to 3 substituents independently selected from (i) - CH3, (ii) halogen, (iii) -OH, and (iv) -OCH3.
  • the compound herein, or a pharmaceutically acceptable salt thereof may be a solvate, or a non-solvate.
  • the solvent contained in a solvate may be either water or an organic solvent. Alcohols (for example, MeOH, EtOH, n-propanol), dimethylformamide, acetonitrile, acetone, dimethylsulfoxide may be used as the organic solvent.
  • the proportion of the solvent molecule (for example a water molecule) against a single molecule compound herein or a pharmaceutically acceptable salt thereof, is, for example, 0.1 to 10, or more specifically, 0.5 to 6. Further, the proportion may fluctuate by humidity, the production method, and the production season.
  • the solvate of a compound herein, or a pharmaceutically acceptable salt thereof may be obtained by a common method, such as precipitating the compound herein, or a pharmaceutically acceptable salt thereof, from a solvent. Further, a hydrate may be obtained by precipitating a compound herein, or a pharmaceutically acceptable salt thereof, from a water-containing organic solvent.
  • the solvate of a compound herein, or a pharmaceutically acceptable salt thereof may be transformed to the compound herein, or a pharmaceutically acceptable salt thereof, by a common method such as heating in vacuo.
  • a compound used as a pharmaceutical active agent is the compound per se (free form), a hydrate of the free form, a pharmaceutically acceptable salt of the free form, or a hydrate of the salt.
  • the compound herein, or a pharmaceutically acceptable salt thereof, or a solvate of either the compound or the salt of the compound may be used in the form of a crystalline material or in an amorphous state.
  • a compound herein, or a pharmaceutically acceptable salt thereof includes all stereoisomers of the compound, for example, an enantiomer, a diastereomer (including cis- and trans- geometric isomer), the racemic form of the isomers, and other mixtures.
  • the compound herein, or a pharmaceutically acceptable salt thereof may have one or more asymmetric centers.
  • the compound herein, or a pharmaceutically acceptable salt thereof includes an embodiment in which an atom constituting the compound molecule is an isotope, and includes an embodiment in which at least one atom is substituted with an atom having the same atomic number (proton number) and a different mass number (sum of protons and neutrons).
  • isotopes examples include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorous atom, sulfur atom, fluorine atom, and chlorine atom, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 C1.
  • radioisotopes which emit radiation as they decay are useful in pharmaceutical preparations or in vivo topographic tests of compounds.
  • the stable isotope neither decays nor changes in their amount, nor have radioactivity, so they can be used safely.
  • the atom constituting the compound herein, or a pharmaceutically acceptable salt thereof, is an isotope, it may be transformed according to the common method by replacing the reagent used in synthesis with a reagent containing the corresponding isotope.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof are glucagon receptor agonists.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have relative EC50 (Rel EC50) values of greater than 50,000 nM using Functional Assay I or Functional Assay II as described herein.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof have relative EC50 (Rel EC 50) values of less than about 50,000 nM using Functional Assay I or Functional Assay II.
  • compounds of formula (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof have Rel EC50 values of less than about 25,000 nM using Functional Assay I or Functional Assay II. In one preferred embodiment, compounds of formula (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, have Rel EC50 values of less than about 10,000 nM using Functional Assay I or Functional Assay II. [0049] In one embodiment, disclosed herein is a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof for use in the treatment of a type 2 diabetes.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof for use in the treatment of obesity.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof for use in the treatment of overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.
  • a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with one or more of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, and a peptide tyrosine-tyrosine (PYY) agonist, or a pharmaceutically acceptable salt thereof, in the treatment of a type 2 diabetes, obesity, or overweight with at least one weight related comorbidity selected from diabetes, high blood pressure, high cholesterol, obstructive sleep apnea and heart disease.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic polypeptide
  • PYY peptide tyrosine-tyrosine
  • references to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element.
  • the indefinite article “a” or “an” thus usually means “at least one.”
  • the term “about” means within a meaningful range of a value or values such as, a stated amount, activity, concentration, length, molecular weight, pH, time frame, temperature or volume, for example, to account for a statistical or instrument measuring sensitivity range. Such a value or range can be within an order of magnitude typically within 20%, or more specifically within 10%, or even more specifically within 5%, of a given value or range.
  • an effective amount means an amount, concentration or dose of a compound described herein, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment.
  • An effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • An effective amount can be determined by one of ordinary skill in the art through the use of known techniques and by observing results obtained under analogous circumstances.
  • a number of factors are considered including, but are not limited to, the size, age and general health of a subject; the specific disease or disorder involved; the degree of or involvement of or the severity of the disease or disorder; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • treat means attenuating, restraining, slowing, stopping or reversing the progression or severity of an existing condition, disease, disorder or symptom.
  • Treating includes administering a compound herein or a composition comprising a compound herein to the subject to prevent the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the condition, disease, disorder or symptom.
  • Treating includes administering a compound or a composition comprising a compound herein to the individual to result in, for example, a reduced HbAlc level or a weight loss to the subject.
  • a pharmaceutically acceptable salt refers to a derivative of the compound herein, where a compound herein is modified by making an acid or a base salt thereof.
  • Pharmaceutically acceptable salts, and processes for preparing the same, are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Ed., 22nd Edition, Pharmaceutical Press, 2012).
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically acceptable salts include the conventional non -toxic salts or the quaternary ammonium salts of a compound herein formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
  • Pharmaceutically acceptable salts are those forms of a compound herein, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salt forms of a compound herein can be synthesized to contain a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, EtOAc, EtOH, isopropanol, or acetonitrile are preferred (see, e.g., Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley-VCH 2nd ed. 2011)).
  • a pharmaceutical composition means a composition having an effective amount of a compound herein in combination with at least one pharmaceutically acceptable excipient, such as a binder, a carrier, a diluent, a lubricant, a pharmaceutical flow agent, and/or other pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable excipient such as a binder, a carrier, a diluent, a lubricant, a pharmaceutical flow agent, and/or other pharmaceutically acceptable excipients.
  • halogen means a fluorine, a chlorine, a bromine, or an iodine. In one embodiment, a halogen is selected from fluorine and chlorine. In one embodiment, a halogen is a fluorine.
  • alkoxy refers to the following chemical group: , wherein R is an alkyl group as defined herein and the point of attachment is through the oxygen.
  • R is an alkyl group as defined herein and the point of attachment is through the oxygen.
  • Ci-io j-o-c dlK? 1 alkoxy has 1 to 10 carbons with the following structure: ’ .
  • Ci-6 alkoxy has 1 to 6 carbons with the following structure:
  • Ci-io alkyl means a straight chain or a branched chain alkyl group containing 1 to 10 carbons.
  • Ci-6 alkyl means a straight chain or a branched chain alkyl group containing 1 to 6 carbons.
  • Ci-6 alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, 1 -methylpropyl, n-pentyl, isopentyl, 2- methylbutyl, 1,1 -dimethylpropyl, 1 -ethylpropyl, n-hexyl, 4-methylpentyl, and 2-ethylbutyl.
  • alkylene refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group which may be linear or branched.
  • a "Ci-6 alkylene” means an alkylene group having 1 to 6 carbon atoms.
  • Ci-4 alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH 3 )-), propylene (e.g., -CH2- CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(- CH 3 )-CH 2 -), or butylene (e.g, -CH 2 - CH2-CH2-CH2-).
  • ethylene e.g., -CH2-CH2- or -CH(-CH 3 )-
  • propylene e.g., -CH2- CH2-CH2-, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(- CH 3 )-CH 2 -
  • butylene e.g, -CH 2 - CH2-CH2-CH2-
  • C 3 -6 cycloalkyl means a monovalent group derived by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When two groups together form a C 3 -6 cycloalkane ring, the resulting group is bivalent. Non-limiting examples include cyclopropane- 1,1 -diyl, cyclobutane- 1,1 -diyl, cyclopentane-l,l-diyl, and cyclohexane- 1,1 -diyl.
  • aryl means an aromatic carbocyclic group, and it may contain a non-aromatic portion in addition to the aromatic portion.
  • the ring may be monocyclic, or it may be a bicyclic aryl that is condensed with a benzene ring or a monocyclic aryl ring.
  • Examples include, but are not limited to, phenyl, naphthyl, azulenyl, isochromanyl, 2,4-dihydro-lH-isoquinolin-3-onyl, and l,3-dihydrobenzimidazol-2-onyl.
  • an aryl is a phenyl.
  • an aryl is a naphthyl.
  • heteroaryl refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, for example, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • aromatic ring group comprises one or more (such as, for example, one, two, three, or four)
  • the term “5 to 10 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S” means an heteroaryl group that contains 5 to 10 ring atoms including 1 to 3 hetero atoms independently selected from N, O, and S.
  • the ring may be a monocyclic heteroaryl, or it may be a bicyclic heteroaryl that is condensed with a benzene ring or a monocyclic heteroaryl ring.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl , triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imi
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring, and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group contains one or more (such as, for example, one, two, three, or four) ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated or partially unsaturated (i.e., unsaturated but not aromatic).
  • the term “5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S” means a heterocyclyl group that contains 5 to 10 ring atoms including 1 to 3 heteroatoms independently selected from N, O, and S.
  • the ring may be a monocyclic ring, a bicyclic ring or a spiro ring.
  • Examples include, but are not limited to, oxetanyl, azetidinyl, 3,7-dioxa-9- azabicyclo[3.3.1]nonanyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 2,6- diazaspiro[3.3]heptyl, 2-thia-6-azaspiro[3.3]heptyl, 1,3 -benzodioxolyl, 1,3- diazaspiro[4.4]nonanyl, 2-oxa-5,7-diazaspiro[3.4]octanyl, 8-oxa-l,3-diazaspiro[4.5]decanyl, oxazolidinyl,
  • the compound herein, or a pharmaceutically acceptable salt thereof has a glucagon receptor agonist effect, and may be used for the prevention or therapy of a disease or condition through a modulation of the glucagon receptor.
  • the disease or condition is selected from Type 2 diabetes, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, overweight, hypertension, dyslipidemia, metabolic syndrome, hyperinsulinemia, nighttime hypoglycemia, hyperlipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, brain infarction, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis.
  • the compound disclosed herein, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a pharmaceutical composition in an effective amount by an appropriate administration method.
  • treatment of a subject with obesity or overweight is also known as chronic weight management.
  • weight with at least one weight related comorbidity refers to a disease or condition of being overweight and at least one weight related comorbidity selected from cancer, depression, diabetes, dyslipidemia, high blood pressure, high cholesterol, obstructive sleep apnea, osteoarthritis, and heart disease.
  • a subject being overweight is defined as having a body mass index (BMI) of >25 to ⁇ 30.
  • Diabetes herein is a state or a disease in which the metabolism for generating and using glucose becomes deficient due to a failure in maintaining an appropriate blood glucose level in the body, and encompasses insulin-dependent diabetes mellitus (Type 1 diabetes) and non- insulin-dependent diabetes mellitus (Type 2 diabetes).
  • “Hyperglycemia” refers to a state in which the plasma glucose level while fasting or after administration of glucose is higher than the normal value (e.g. 80 to 110 mg/dL in human while fasting), and it is a typical symptom of diabetes.
  • “Impaired glucose tolerance” includes insulin-resistant impaired glucose tolerance and insulin hyposecretion.
  • Diabetic complication is a complication caused by diabetes or hyperglycemia, and may be acute complex or chronic complex.
  • the term “acute complex” includes, for example, ketoacidosis, and infectious disease (e.g. skin infection, soft tissue infection, biliary system infection, respiratory system infection, urinary tract infection), and the “chronic complex” includes, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy (e.g. sensory nerve disorder, motor nerve disorder, autonomic nerve disorder), and gangrene.
  • Major diabetes complexes include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.
  • Chronic heart disease includes myocardial infarction and angina pectoris.
  • ementia includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.
  • the administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream.
  • a method for treating a disease or condition regulated by a glucagon receptor agonist comprises administering an effective amount of a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
  • the effective amount to be administered may be appropriately determined according to the severity of the symptom, the age, the body weight, the relative health state, whether other drugs are combined, and the method of administration.
  • the effective daily amount is from 0.01 to 1000 mg, or more specifically, from 0.05 to 500 mg, or even more specifically, from 0.1 to 200 mg, or still more specifically, from 0.1 to 100 mg once daily.
  • the above effective amount is administered once daily or twice daily for a few days, a few weeks, a few months, or several years.
  • the above dosage is administered once daily for a few days, a few weeks, a few months, or several years.
  • the compound herein is co-administered with a second active agent.
  • additional active agent is selected from, the second active agent is selected from the group consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist, an amylin receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) agonist, a peptide tyrosine-tyrosine (PYY) agonist, and a mixture thereof.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic polypeptide
  • PYY peptide tyrosine-tyrosine
  • the administration method may be systemic administration including oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravaginal administration, intraperitoneal administration, intravesical administration, and aspiration, as well as local administration by ointment, gels, and cream.
  • a pharmaceutical composition comprises a compound of formula (I), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound herein, or a pharmaceutically acceptable salt thereof, is formulated into a certain pharmaceutical formulation (dosage form). Examples of such pharmaceutical formulations include a tablet, a capsule, granules, powders, subtle granules, pills, aqueous or non-aqueous solution or suspension.
  • the compound herein, or a pharmaceutically acceptable salt thereof may also be used in the form of various controlled release preparations.
  • controlled release preparations include, for example, those to be imbedded in the body, those applied to the oral mucosa or nasal mucosa.
  • the solution or suspension may be filled in containers suited for dividing into respective administration amounts to be stored.
  • the various pharmaceutical formulations may be produced by a well-known method by mixing a compound herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  • additives include, but are not limited to, an excipient, a lubricant, a binding agent, a disintegrator, a stabilizer, a dispersant, a diluent, a surfactant, or an emulsifier.
  • Examples of an excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and dicalcium phosphate.
  • Examples of a lubricant include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.
  • Examples of a binding agent include polyvinyl pyrrolidone, macrogol, and compounds that are the same as the above excipient.
  • Examples of a disintegrator include chemically modified starch and cellulose, such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and compounds that are the same as the above excipient.
  • Examples of a stabilizer include para-oxybenzoates such as methyl paraben, and propyl paraben; benzalkonium chloride; phenols such as phenol, and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • Examples of a dispersant include cellulose derivative (Arabic rubber, tragacanth, methyl cellulose, etc ), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, and sorbitan fatty acid ester.
  • Examples of the solvent or diluent in a liquid formulation include phenol, chlorocresol, purified water, distilled water, etc.
  • Examples of a surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol.
  • the content of the compound herein, or a pharmaceutically acceptable salt thereof, in the pharmaceutical formulation can vary by the dosage form, and is generally from 0.01 to 90 wt%.
  • R 1 , R 2 , R 3 , R 4 , R 4 ’, R 5 , R 5 , R 6 , R 6b , R 6c , R 7 , R A1 , R 42 , R 43 , R A4 , R a , and R b are as defined in Formula (I) and (la).
  • R 1 , R 2 , R 3 , R 4 , R 4 ’, R 5 , R 5 , R 6 , R 6b , R 6c , R 7 , R A1 , R 42 , R 43 , R A4 , R a , and R b are as defined in Formula (I) and (la).
  • Scheme 1 shows the preparation of intermediates (ii, iii, iv, v, vi, and vii) useful for the preparation of compounds of the present invention.
  • aryl or heteroaryl halide i, wherein “Y” is CH or N, “X” is a halogen such as Cl, Br, or F, and the carboxylic acid is optionally protected as an ester “-O-PG”, wherein “PG” is an alkyl group such as methyl
  • the halogen “X” can be substituted in a variety of ways.
  • Intermediate (i) can be coupled with boronic acids or esters using a palladum catalyst and an inorganic base.
  • a palladium catalyst such as Pd(dppf)C12
  • a carbonate base such as K2CO3
  • an aqueous- organic solvent mix such as water and 1,4-dioxane at elevated temperatures to give (iv)
  • a palladium on carbon catalyst under hydrogen gas at elevated temperatures to give (v).
  • (i) can be coupled with cyclopropaneboronic acid using a palladium catalyst such as Pd(OAc)2 and tri cyclohexylphosphine and an inorganic base such as K3PO4 at elevated temperatures in a mixture of toluene and water to give (vi).
  • a palladium catalyst such as Pd(OAc)2 and tri cyclohexylphosphine and an inorganic base such as K3PO4
  • Y is N
  • (i) can undergo nucleophilic aromatic substitution, for example with 3,3-difluoroazetidine hydrochloride and a carbonate base such as K2CO3 in a solvent such as DMF at elevated temperatures to give (vii).
  • Scheme 2 depicts the preparation of the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (xiv) beginning with a suitable protected amine (viii).
  • the PG moiety on the amine (viii) is a standard amine protecting group well known to a skilled artisan, including carbamate protecting groups such as Boc.
  • the amine (viii) is reacted with NFEOAc and KCN in an appropriate solvent, such as EtOH at elevated temperatures.
  • the resulting intermediate (ix) is reacted with a suitable acyl chloride (R 6 -C(O)C1) in the presence of an appropriate base, such as ISfeCCh, Nal ICO3 or EtaN, in a suitable solvent, such as DCM or THF.
  • an appropriate base such as ISfeCCh, Nal ICO3 or EtaN
  • a suitable solvent such as DCM or THF.
  • the amine (ix) is reacted under amide coupling conditions well known to a skilled artisan and include reacting an appropriate carboxylic acid (R 6 -CO2H) with the amine (ix) in a suitable solvent, such as DMF, with an appropriate coupling agent, such as HATU, in the presence of a suitable base, such as DIEA.
  • the intermediate (x) is cyclized to form the l,3,8-triazaspiro[4.5]dec-l-en-4-one core in the presence of an appropriate oxidizing agent, such as H2O2, and a suitable base, such as NaOH, in an appropriate solvent, such as EtOH, DMSO or MeOH, at 80 °C to give (xiii).
  • an appropriate oxidizing agent such as H2O2
  • a suitable base such as NaOH
  • the nitrile group of intermediate (ix) is first converted in the carbamoyl group under the aforementioned conditions for the formation of intermediate (xi).
  • the intermediate (xii) is obtained then by the sequential amidation (previously described) and cyclization conditions in the presence of a suitable base, such as PyO/Bu or KO/Bu, in an appropriate solvent, such as /-BuOH or EtOH, at 60 °C at least to give (xiii).
  • the removal of the PG moiety on (xiii) is achieved under conditions standard to the art.
  • the intermediate amine (xiv) is obtained by reacting a suitable acid, such as HC1 in 1,4-di oxane, in an appropriate solvent, such as DCM.
  • Halide (xv, where “X” is a halogen such as Br and “PG” is a protecting group such as Boc) is coupled with a heteroaryl boronic acid (or ester thereof) using a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) and a base such as K3PO4 in an aqueous- organic solvent mix such as water and 1,4-dioxane at elevated temperatures to give (xvi).
  • the protecting group is removed to give (xvii), under suitable conditions well known to the skilled artisan, e.g. HC1 in an organic solution to remove a -Boc group.
  • Scheme 5 illustrates the preparation of the biphenyl intermediate (xviii) beginning with a suitable aryl bromide (xxii).
  • the aryl boronic ester (xxiii) is produced from the reaction of (xxii) with bis(pinacolato)diborane and the appropriate catalyst system, such as Pd(OAc)2 and tris(4- methoxyphenyl)phosphine, in the presence of a suitable base, such as CS2CO3, in an appropriate solvent, such as 1,4-dioxane, at elevated temperatures.
  • aryl boronic ester (xxiii) is reacted under Suzuki coupling conditions standard to the art and include a suitable substituted aryl bromide (xxiv) and the appropriate catalyst system, such as Pd(PPh3)4, in presence of a suitable base, such as CS2CO3, in an appropriate solvent, such as 1,4-dioxane, stirred at 80 °C for 72 h to give biphenyl intermediate (xviii).
  • Scheme 6 shows the preparation of intermediate (xxx), which is useful for the preparation of compounds of Formula la.
  • Amide (xi) is cyclized to (xxv) using toluenesulfonic acid and 2,2- dimethoxypropane in an alcohol solvent such as EtOH at elevated temperature.
  • Amine (xxv) is reacted with halo-benzene (xxvi, wherein X is Br or Cl and X’ is I or Br) using lithium bis(trimethylsilyl)amide in a solvent such as 1,4-dioxane at elevated temperature to give (xxvii), which is then converted to amide-amine (xxviii) using aq. HC1 in MeOH and water at elevated temperature.
  • Amine (xxviii) is then reacted with an acid chloride R 6 -C(O)C1 using an amine base such as TEA in a solvent such as THF to give amide (xxix), which is then cyclized using a base such as aq. NaOH in MeOH at elevated temperature to give (xxx).
  • Compounds of Formula la may be prepared via the synthetic route presented in Scheme 7 by reacting the l,3,8-triazaspiro[4.5]dec-l-en-4-one intermediate (xiv) with an appropriate halo- benzene (xxxiv, wherein X is Br or Cl and X’ is I or Br) under Buchwald-Hartwig cross coupling conditions well known to a skilled artisan to give intermediate (xxx) wherein X is Br or Cl.
  • Such conditions include using a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2 l ,6'-bis(dimethylamino)-l , l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) and an alkoxide base such as sodium 2- methylbutan-2-olate at elevated temperature.
  • a palladium catalyst such as methanesulfonato(2-bis(3,5- di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2 l ,6'-bis(dimethylamino)-l , l '-biphenyl )(2'- methylamino-l,r-biphenyl-2-yl)palladium(II) and
  • an aryl bromide can be reacted with lithium bis(trimethylsilyl)amide, followed by amine intermediate (xiv) in a solvent such as 1,4- dioxane at elevated temperature to give intermediate (xxx) wherein X is Cl, Br, or I.
  • amine (xiv) can also be reacted with (xxxiv) under SNAT reaction conditions using a base such as DIEA or K3PO4 in a solvent such as DMSO at elevated temperature.
  • the halogen in the resulting intermediate (xxx) may be reacted with a suitable aryl boronic ester (xxiii) or acid thereof under Suzuki coupling conditions, e.g.
  • a palladium catalyst such as Pd(PPh3)4, methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,l'-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II), or l,l'-bis(di-t-butylphosphino)ferrocene palladium dichloride, a carbonate base such as K2CO3, and an aqueous-organic solvent mix such as MeOH, THF, or 1,4-dioxane in water at elevated temperature.
  • a carbonate base such as K2CO3
  • an aqueous-organic solvent mix such as MeOH, THF, or 1,4-dioxane in water at elevated temperature.
  • (xxx) is converted to boronate (xxxiv) using conditions known to the skilled artisan e.g. using bis(pinacolato)diborane, a palladium catalyst such as methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino- l,l'-biphenyl-2-yl)palladium(II) or chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl- l,l'-biphenyl) palladium(II), a base such as potassium acetate or K2CO3, a solvent such as methoxycyclopentane or 2-methyltetrahydrofuran at elevated temperature. Boronate (xiv) is then coupled with aryl hal
  • halo-phenol (xxxi, where R A4 is trimethyl silyl) is coupled with aryl boronic ester (xxiii) or ester thereof under Suzuki coupling conditions, e.g. using a palladium catalyst such as Pd(dppf)C12, a carbonate base such as K2CO3, and an aqueous-organic solvent mix such as 1,4-dioxane in water at elevated temperature to give (xxxii), which is converted to trifluoromethanesulfonate (xxxiii) using N-phenyl- bis(trifluoromethanesulfonimide) and K2CO3 in ACN at elevated temperature. Reaction of (xxxiii) with amine (xiv) using CsF and ACN at elevated temperature gives (xxxv), converting - R A4 to -H.
  • a palladium catalyst such as Pd(dppf)C12
  • a carbonate base such as K2CO3
  • H2O2 (63 mL, 50% Wt, 1000 mmol) was added slowly to a vigorously stirred solution of a mixture of diastereomers of tert-butyl (2S)-4-cyano-2-methyl-4-(2- (trifluoromethoxy)benzamido)piperidine-l -carboxylate (48.2 g, 112.8 mmol), NaOH (270 mL, 5 M, 1354 mmol) in EtOH (564 mL) at 80 °C. After 16 h, the reaction mixture was diluted with 500 mL of NH4CI sat. aq. solution and 30 mL of Na2S2O3 aq. solution.
  • the mixture was purged with nitrogen and heated to 110 °C for 2 days, then diluted with EtOAc (0.3 L) and 5% aq. NH4OH (0.3 L). The layers were separated and the organics were washed successively with 0.1 L of each of 5% aq. NH4OH and water, then 1 M aq. KH2PO4 (2 x 50 mL) and brine (50 m ). The organics were dried over MgSCU, filtered, then concentrated to a volume of 0.1 L. Heptane (0.4 L) was then added slowly and the mixture was stirred at RT for 1 h.
  • Tetrakis(triphenylphosphine)palladium(0) (0.238 g, 0.206 mmol) was added to a solution of l-bromo-3,5-difluoro-2-nitrobenzene (0.016 g, 0.69 mmol), 4-(3, 5-dimethyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (0.25 g, 0.76 mmol), and CS2CO3 (0.67 g, 2.06 mmol) in 1,4-di oxane (0.
  • DIEA (0.228 mb, 1.32 mmol) was added to a solution of (7S)-7-methyl-2-(2- (trifluoromethoxy)phenyl)-l,3,8-triazaspiro[4.5]dec-l-en-4-one hydrochloride (mixture of diastereomers, 0.15 g, 0.44 mmol) and 4-(3',5'-difluoro-2,6-dimethyl-2'-nitro-[l,r-biphenyl]-4- yl)morpholin-3-one (0.160 g, 0.44 mmol) in DMSO (2.21 mL, 0.2 M) and stirred at 110 °C.
  • Oxalyl chloride (6.09 m , 69.4 mmol) was added to a stirred solution of 2-cyclopropyl- benzoic acid (10.0 g, 55.5 mmol) in DCM (100 mL) under nitrogen at ambient temperature.
  • EtsN 22 mL, 160 mmol was added to terz-butyl (2S,4R)-4-amino-4-carbamoyl-2- methylpiperidine-1 -carboxylate (14.42 g, 56.04 mmol) in DCM (100 mL) and stirred at ambient temperature under nitrogen in 500 mL RBF.
  • the free base of the title compound was prepared by stirring the hydrochloride salt in water and adding 2 M aq. K3PO4 to bring the pH to 11.7 and collecting the solid, washing with water, and drying the solid in a vacuum oven overnight.
  • reaction mixture was stirred at 55 °C for 2 h under irradiation with 395 nm (200 W) LED module in an integrated photoreactor under nitrogen.
  • the reaction mixture was poured into 500 mL water at 25 °C, and then extracted with EtOAc (800 mL x 3). The combined organic layers were washed with water (500 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography using a gradient of 0 to 70% EtOAc in PE to give the title compound (14.4 g) as a solid.
  • the free base of the title compound was prepared by reverse-phase prep-HPLC of the dihydrochloride using a gradient of 1 to 50% ACN in 10 mM aq. NH4HCO3.
  • KCN (5.04 g, 77.4 mmol) was added to a mixture of 4-bromo-3,5-dimethylbenzaldehyde (10.0 g, 46.9 mmol) in water (50 mL).
  • Pd(dppf)C12 (3.4 g, 4.6 mmol) at 25 °C was added to a mixture of 2-(4-bromo-3,5- dimethylphenyl)-2-hydroxyacetamide (29 g, 110 mmol), potassium acetate (33 g, 330 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (31 g, 120 mmol) in 1,4-dioxane (300 mb) and the reaction mixture was stirred at 100 °C for 15 h.
  • Pd(dppf)Ch (3.20 g, 4.29 mmol) was added under nitrogen to a mixture of 2-chloro-6- (trifluoromethyl)nicotinic acid (10.00 g, 43.45 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (14.00 g, 65.31 mmol) in 1,4-dioxane (100 mL) and water (10 mL). K2CO3 (18.00 g, 130.2 mmol) was then added and the reaction mixture was heated to 110 °C with stirring under nitrogen for 16 h.
  • NBS (5.11 g, 27.3 mmol) was added to a -60 °C mixture of 4-(3'-hydroxy-2-methyl-2'- (trimethylsilyl)-[l,l'-biphenyl]-4-yl)morpholin-3-one (10.3 g, 22.6 mmol) in DCM (100 mL) and the reaction mixture was stirred vigorously at -60 °C for 1 h. The mixture was washed with water (100 mL) and extracted with DCM (3 x 50 mL). The organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure.
  • N-Phenyl-bis(trifluoromethanesulfonimide) (4.2 g, 11 mmol) at 0 °C was added to a mixture of 4-(4'-cyclopropyl-3'-hydroxy-2-methyl-2'-(trimethylsilyl)-[l, l'-biphenyl]-4- yl)morpholin-3-one (1.2 g, 2.6 mmol) and K2CO3 (3.1 g, 21 mmol) in ACN (10 mL), and the reaction mixture was stirred vigorously at 80 °C. After 16 h, the mixture was poured into water (20 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I) : ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également une composition pharmaceutique comprenant un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, et un véhicule pharmaceutiquement acceptable. L'invention concerne en outre une méthode de prévention ou de traitement d'une maladie ou d'un état par modulation du récepteur du glucagon à l'aide d'un composé de formule (I), ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2025/025163 2024-04-19 2025-04-17 Composés 1,1'-biphényle substitués utilisés en tant qu'agonistes du récepteur du glucagon Pending WO2025222000A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463636132P 2024-04-19 2024-04-19
US63/636,132 2024-04-19
US202563757356P 2025-02-12 2025-02-12
US63/757,356 2025-02-12

Publications (1)

Publication Number Publication Date
WO2025222000A1 true WO2025222000A1 (fr) 2025-10-23

Family

ID=95714765

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/025163 Pending WO2025222000A1 (fr) 2024-04-19 2025-04-17 Composés 1,1'-biphényle substitués utilisés en tant qu'agonistes du récepteur du glucagon

Country Status (1)

Country Link
WO (1) WO2025222000A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021113362A1 (fr) * 2019-12-03 2021-06-10 Kallyope, Inc. Antagonistes de sstr5
WO2023151574A1 (fr) * 2022-02-09 2023-08-17 Gasherbrum Bio Inc. Agonistes hétérocycliques de glp-1
WO2023164358A1 (fr) * 2022-02-28 2023-08-31 Ascletis Bioscience Co., Ltd. Composés modulateurs de glp-1r

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021113362A1 (fr) * 2019-12-03 2021-06-10 Kallyope, Inc. Antagonistes de sstr5
WO2023151574A1 (fr) * 2022-02-09 2023-08-17 Gasherbrum Bio Inc. Agonistes hétérocycliques de glp-1
WO2023164358A1 (fr) * 2022-02-28 2023-08-31 Ascletis Bioscience Co., Ltd. Composés modulateurs de glp-1r

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2012, PHARMACEUTICAL PRESS
STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2011, WILEY-VCH
WILLARD, F.S ET AL., ADV. PHARMACOL, vol. 88, no. 1310584-14-5, 2020, pages 173 - 191

Similar Documents

Publication Publication Date Title
TWI874443B (zh) KRas G12D抑制劑
EP3381896B1 (fr) Composé de biphényle ou un sel de celui-ci
TWI618700B (zh) 化合物及其作為β－位置ＡＰＰ裂解酶（ＢＡＣＥ）抑制劑之用途
TWI848972B (zh) 心臟肌小節抑制劑
CN104918935B (zh) 二氢吡唑gpr40调节剂
CN104812748B (zh) 二氢吡唑gpr40调节剂
KR20190117006A (ko) 키나제 억제제로서의 아미노트리아졸로피리딘
TW201211053A (en) Spiro compound and drug for activating adiponectin receptor
TW202423442A (zh) Kras g12d降解劑及其製備方法與應用
US10947218B2 (en) Aminopyridine derivatives and their use as selective ALK-2 inhibitors
EP3681883B1 (fr) Dérivés de diphenyle et utilisations associées
CN115380036A (zh) Sstr5拮抗剂
CN109071548A (zh) 可用于治疗尤其是癌症的吡咯并咪唑衍生物或其类似物
IL322853A (en) History of 1-(([1,1'-biphenyl]-2-yl)sulfonyl)-4-fluoro-n-(3-(methylsulfonyl)allyl)piperidine-4-carboxamide as ras-pi3k modulators for exemplary cancer therapy
WO2025222000A1 (fr) Composés 1,1'-biphényle substitués utilisés en tant qu'agonistes du récepteur du glucagon
WO2025096710A1 (fr) Modulateurs de bcl6 en tant qu'agents de dégradation dirigés vers un ligand
CA3235682A1 (fr) Derives de naphtyridinone pour le traitement d'une maladie ou d'un trouble
HK40069664B (en) Aminopyridine derivatives and their use as selective alk-2 inhibitors
HK40117528A (en) Aminopyridine derivatives and their use as selective alk-2 inhibitors
HK40069664A (en) Aminopyridine derivatives and their use as selective alk-2 inhibitors
EP4393919A1 (fr) Modulateurs de lsd1
CN117659023A (zh) 吡啶乙酰胺类衍生物、包含其的药物组合物及其医药用途
HK40007022B (en) Aminopyridine derivatives and their use as selective alk-2 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25725375

Country of ref document: EP

Kind code of ref document: A1