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WO2022246019A1 - Agonistes macrocycliques du récepteur du peptide 1 de type glucagon - Google Patents

Agonistes macrocycliques du récepteur du peptide 1 de type glucagon Download PDF

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Publication number
WO2022246019A1
WO2022246019A1 PCT/US2022/029958 US2022029958W WO2022246019A1 WO 2022246019 A1 WO2022246019 A1 WO 2022246019A1 US 2022029958 W US2022029958 W US 2022029958W WO 2022246019 A1 WO2022246019 A1 WO 2022246019A1
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preparation
mmol
methyl
title compound
pharmaceutically acceptable
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PCT/US2022/029958
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English (en)
Inventor
Francisco Javier Agejas Chicharro
Renato Alejandro BAUER
Michael Gregory Bell
Qi Chen
Graham Robert Cumming
Todd Fields
Douglas Linn Gernert
Joseph Daniel HO
Talbi Abelkader KAOUDI
Thierry Jean MASQUELIN
José Miguel MÍNGUEZ ORTEGA
Julian PRIEGO SOLER
Antonio Rodriguez Hergueta
Eric Michael Woerly
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to KR1020237039778A priority Critical patent/KR20230173166A/ko
Priority to IL308397A priority patent/IL308397A/en
Priority to AU2022275931A priority patent/AU2022275931B2/en
Priority to CA3218345A priority patent/CA3218345A1/fr
Priority to EP22729392.5A priority patent/EP4341255A1/fr
Priority to BR112023022851A priority patent/BR112023022851A2/pt
Priority to JP2023571304A priority patent/JP7703691B2/ja
Priority to MX2023013717A priority patent/MX2023013717A/es
Priority to US18/562,568 priority patent/US20240343740A1/en
Priority to CN202280036421.2A priority patent/CN117355517A/zh
Publication of WO2022246019A1 publication Critical patent/WO2022246019A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • This invention relates to glucagon-like peptide-1 receptor agonists and therapeutic uses of the compounds to treat type II diabetes mellitus.
  • Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose dependent manner. However, GLP-1 is rapidly metabolized so that only a small percentage of the GLP-1 can be utilized to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists have been developed to enhance insulin secretion as a treatment for type II diabetes mellitus.
  • GLP-1R GLP-1 receptor
  • GLP-1R agonists that have been approved to treat type II diabetes mellitus are injectable agents. Patients often prefer orally administered drugs because of the drawbacks associated with injection such as inconvenience, pain, and the potential for injection site irritation.
  • W02018/109607 discloses certain benzimidazole derivatives, which are described as GLP-1R agonists. Further GLP-1 agonist compounds are disclosed in WO20 19/239371, WO2019/239319, WO2020/103815, WO2020/207474, WO2020/263695, WO2021/018023, WO2021/081207, WO2021/096284,
  • GLP-1R agonists which can be administered orally.
  • potent GLP-1R agonists which have a favorable toxicology profile and/or a pharmacokinetic profile which supports once daily dosing.
  • the present invention provides a compound of the formula: wherein -A- is -CR a R b CR a R b CR b R b O-, -OCR b R b CR a R b CR a R b -, -OCR b R b CR b R b O-, -CR a R b CR b R b OCR b R b -, -CR b R b OCR b R b CR a R b -, -CR b R b OCR b R b -, -CR a R b CR b R -, -CR a R b CR b R b O-, or -OCR b R b CR a R b -; R a at each occurrence is independently H, halo, C 1 -C 2 alkyl, OH or C 1 -C 3 alkoxy; R b at each
  • a compound of the formula: or a pharmaceutically acceptable salt thereof there is provided a compound of the formula: or a pharmaceutically acceptable salt thereof.
  • a compound of the formula: or a pharmaceutically acceptable salt thereof In an embodiment, there is provided a compound of the formula: or a pharmaceutically acceptable salt thereof.
  • Va and VI, Y 4 , Y 5 , Y 6 and Y 7 are all CH.
  • Y 4 , Y 5 , Y 6 and Y 7 are all CH.
  • X 1 , X 3 and X 4 are CH
  • X 2 is CR 1 .
  • X 1 is N
  • X 2 is CR 1
  • X 3 and X 4 are CH.
  • X 1 , X 3 and X 4 a 2 re CH
  • X is N.
  • X 1 and X 4 are CH; X 2 is CR 1 ; and X 3 is N.
  • 1 3 2 ; X and X are CH; X is CR 1 ; and X 4 is N.
  • 1 3 ; X and X are CH; and X 2 and X 4 are CR 1 .
  • only one of X 1 , X 2 , X 3 and X 4 is N.
  • X 5 , X 7 an 8 6 1 d X are CH; and X is CR .
  • X 5 is N; X 6 is CR 1 ; and X 7 and X 8 are CH. In an embodiment, only one of X 5 , X 6 , X 7 and X 8 is N.
  • R 1 is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 - C 3 haloalkyl; wherein each R e is independently selected from: H, C 1 -C 3 alkyl or halo, and R h is H or halo; 5- or 6- membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one substituent selected from: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 - C 3 alkyl, C 4 -C 5 heterocyclyl, -CH 2 -C 4 -C 5 heterocyclyl, halo, -CONR c R
  • R 1 is CN, halo, CF 3 , -CH 2 OH, , , .
  • R is CN, Cl, F, CF 3 , .
  • 1 R is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; wherein each R e is independently selected from: H or C 1 -C 3 alkyl; 5- or 6- membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one substituent selected from: C 1 - C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 -C 3 alkyl, -CH 2 -C 4 -C 5 heterocyclyl, -CONR c R d or C 1 - C 3 alkyl optionally substituted with OH, wherein R c and R d are each independently H or
  • R 1 is CN, halo, CF 3 , -CH 2 OH, .
  • R 1 is CN, Cl, F, CF 3 , , .
  • R 1 is CN, halo, C 1 - C 3 alkyl or C 1 -C 3 haloalkyl.
  • R 1 is CN, halo or CF 3 .
  • R 1 is CN or halo.
  • X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; wherein each R e is independently selected from: H, C 1 -C 3 alkyl or halo, and R h is H or halo; 5- or 6- membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one substituent selected from: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 - C 3 alkyl, C 4 -C 5 heterocyclyl, -CH 2 -C 4 -C 5 heterocyclyl, halo, -CONR c R d , -NR c R d , or C 1 - C 3 alkyl optionally substituted with OH, where
  • R 1 is CN, halo, CF 3 , -CH 2 OH, , , 1 . More preferably, R is CN, Cl, F, CF 3 , In one embodiment, ; X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN; halo; C 1 -C 3 alkyl optionally substituted with OH; C 1 -C 3 haloalkyl; wherein each R e is independently selected from: H or C 1 -C 3 alkyl; 5- or 6- membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one substituent selected from: C 1 -C 3 alkoxy, C 3 -C 5 cycloalkyl, -SO 2 C 1 - C 3 alkyl, -CH 2 -C 4 -C 5 heterocyclyl, -CONR c R d or C 1 -C 3 alkyl
  • R 1 is CN, halo, CF 3 , -CH 2 OH, , , , , , , . Mor 1 e preferably, R is CN, Cl, F, CF 3 , , , , , .
  • X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CN.
  • X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is Cl.
  • X 1 , X 3 and X 4 are CH; X 2 is CR 1 ; and R 1 is CF 3 .
  • X 1 is N; X 2 is CR 1 ; X 3 and X 4 are CH; and R 1 is CF 3 .
  • 1 4 2 ; X and X are CH; X is CR 1 ; X 3 is N; and R 1 is CF 3 .
  • X 1 and X 3 are CH; X 2 is CR 1 ; X 4 is N; and R 1 is CN.
  • X 1 and X 3 are CH; X 2 and X 4 are CR 1 ; and each R 1 is independently selected from halo and CN.
  • each R 1 is independently selected from F, Cl and CN.
  • X 5 , X 7 and X 8 are CH; X 6 is CR 1 ; and R 1 is CN or Cl. Particularly, R 1 is CN. In an alternate embodiment, 5 6 1 7 ; X is N; X is CR ; X and X 8 are CH; and R 1 is CN.
  • -A- is -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 O-, -CH 2 CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -OCH 2 CH 2 - or -CF2CH 2 OCH 2 -.
  • -A- is -CH 2 CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 -, CH 2 OCH 2 CH 2 - or -CF2CH 2 OCH 2 -.
  • -A- is -CHR a CHR a CHR b O-, -CHR b OCHR b - or -OCHR b CHR b O-.
  • -A- is -CHR a CHR a CHR b O-.
  • -A- is -CHR a CHR a CHR b O- and each R a and R b is H.
  • -A- is -CHR b OCHR b -. In a particular embodiment, -A- is -CHR b OCHR b - and each R b is H. In an alternate embodiment, -A- is -OCHR b CHR b O-. In a particular embodiment, -A- is -OCHR b CHR b O- and each R b is H.
  • -A- is -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 O-, -CH 2 CH 2 OCH 2 -, -CH 2 OCH 2 -, or -CH 2 CH 2 O-; preferably, A- is -CH 2 CH 2 CH 2 O- or -CH 2 OCH 2 -.
  • -B- is -CH 2 O- or -CH 2 NH-.
  • B is -CH 2 O- or -OCH 2 -.
  • -B- is -CH 2 O-.
  • Y 3 is N or CH. In an embodiment, Y 3 is N. In an alternate embodiment, Y 3 is CH.
  • Y 4 is CH. In an embodiment, Y 5 is CH. In an embodiment, Y 6 is CH or CR 2 . In an embodiment, Y 3 is N; and Y 4 , Y 5 are CH; and Y 6 is CH or CR 2 . In a further embodiment, Y 3 is N; and Y 4 , Y 5 are CH; and Y 6 is CH. In yet a further embodiment, Y 3 is N; and Y 4 , Y 5 are CH; and Y 6 is CR 2 , preferably R 2 is F. In an alternate embodiment, Y 3 , Y 4 , Y 5 and Y 6 are all CH.
  • Y 3 and Y 6 are N; and Y 4 and Y 5 are CH.
  • Y 1 is CH or CR 2 .
  • Y 2 is CH.
  • Y 7 is CH.
  • R 2 is F or methyl.
  • Y 1 , Y 2 and Y 7 are all CH.
  • Y 1 is CR 2 ; Y 2 is CH; Y 7 is CH; and R 2 is F.
  • Y 1 is CR 2 ; Y 2 is CH; Y 7 is CH; and R 2 is methyl.
  • Y 1 and Y 2 are both CH.
  • Y 1 is CR 2 , Y 2 is CH and R 2 is F. In a further alternate embodiment, Y 1 is CR 2 , Y 2 is CH and R 2 is methyl. In an embodiment, Y 4 , Y 5 , Y 6 and Y 7 are all CH. In an embodiment, Z 1 is CH or CR 3 . In an embodiment, Z 2 is CH. In an embodiment, Z 3 is CH. In an alternate embodiment, Z 3 is N. In a particular embodiment, Z 2 and Z 3 are both CH.
  • R 3 is halo; -OC 4 -C 6 heterocyclyl optionally substituted with C 1 - C 3 alkyl; or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy, OH, -NR f R g , -CONR c R d or 5- or 6- membered heteroaryl optionally substituted with C 1 -C 3 alkyl; wherein R c and R d are each independently H or C 1 -C 3 alkyl, R f is H or C 1 -C 3 alkyl, and R g is H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • R 3 is halo or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy, OH, or -NR f R g , wherein R f and R g are both CH 3 ; preferably, R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 .
  • R 3 is halo, C 1 -C 4 alkoxy or -C 1 -C 3 alkoxyC 1 -C 2 alkoxy; preferably, R 3 is F, -OCH 3 or -OCH 2 CH 2 OCH 3 .
  • R 3 is halo, C 1 -C 2 alkyl or methoxy.
  • Z 1 is CR 3 and R 3 is halo; -OC 4 -C 6 heterocyclyl optionally substituted with C 1 -C 3 alkyl; or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy, OH, -NR f R g , -CONR c R d or 5- or 6- membered heteroaryl optionally substituted with C 1 -C 3 alkyl; wherein R c and R d are each independently H or C 1 -C 3 alkyl, R f is H or C 1 -C 3 alkyl, and R g is H, C 1 -C 3 alkyl or C 1 - C 3 haloalkyl.
  • Z 1 is CR 3 and R 3 is halo or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy, OH, or -NR f R g , wherein Rf and Rg are both CH 3 ; preferably, R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 )2.
  • Z 1 is CR 3 and R 3 is F.
  • Z 1 is CH.
  • Z 1 is CR 3 and R 3 is methoxy. 5 2 t, R 5
  • R is -CO H.
  • -A- is -CH 2 CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 -, CH 2 OCH 2 CH 2 - or -CF 2 CH 2 OCH 2 -.
  • 1 3 4 ; X, X and X are CH; and X 2 is CR 1 .
  • X 1 i 2 1 3 4 s N; X is CR; and X and X are CH.
  • X 1 , X 3 and X 4 are CH; and X 2 is N.
  • X and X 4 are CH; X 2 is CR 1 ; and X 3 is N.
  • X 1 and X 3 are CH; X 2 is CR 1 ; and X 4 is N.
  • X 1 and X 3 are CH; and X 2 and X 4 are CR 1 .
  • X, X and X are CH; and X 6 is CR 1 .
  • X 5 is N; X 6 is CR 1 ; and X 7 and X 8 are CH.
  • R 1 is CN, halo, CF 3 , -CH 2 OH, ,
  • R 1 is CN, Cl, F, CF 3
  • X 1 , X 3 and X 4 are CH
  • X 2 is CR 1
  • R 1 is CN, halo, CF 3 , -CH 2 OH, ,
  • R is CN, Cl, F, CF 3
  • R 1 is CF 3 .
  • Formula VIII 1 3 ; X , X and X 4 are CH, and X 2 is N. In an alternate embodiment of Formula VIII, 1 4 ; X and X are CH; X 2 is CR 1 ; X 3 is N; and R 1 is CF 3 . In an alternate embodiment of Formula VIII, 1 3 ; X and X are CH; X 2 is CR 1 ; X 4 is N; and R 1 is CN. In an alternate embodiment of Formula VIII, 1 3 ; X and X are CH; X 2 and X 4 are CR 1 ; and each R 1 is independently selected from halo and CN. Preferably, each R 1 is independently selected from F, Cl and CN.
  • Formula VIII 5 7 ; X , X and X 8 are CH; X 6 is CR 1 ; and R 1 is CN or Cl. Particularly, R 1 is CN.
  • X 5 is N; X 6 is CR 1 ; X 7 and X 8 are CH; and R 1 is CN.
  • -B- is -CH 2 O-.
  • Y 6 is CH or CR 2 .
  • R 2 is F or methyl.
  • Y 3 is N and Y 6 is CH or CR 2 . In a further embodiment of Formula VIII, Y 3 is N and Y 6 is CH.
  • Y 3 is N and Y 6 is CR 2 , preferably R 2 is F.
  • Y 3 and Y 6 are both CH.
  • Y 3 and Y 6 are both N.
  • Z 3 is CH.
  • R 3 is halo or C 1 -C 4 alkoxy optionally substituted with one or two substituents selected from: C 1 -C 2 alkoxy, OH, or -NR f R g , wherein Rf and Rg are both CH 3 ; preferably, R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 ) 2 .
  • R 4 is . Certain compounds of Formula VIII have the following features: i.
  • -A- is -CH 2 CH 2 CH 2 O-, -CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 -, CH 2 OCH 2 CH 2 - or -CF 2 CH 2 OCH 2 -; ii.
  • X 1 , X 3 and X 4 are CH, X 2 is CR 1 , and R 1 is CN, Cl, F, CF 3 , or wherein X 1 is N, X 2 1 3 4 is CR , X and X are CH, and R 1 is CF 3 ; or wherein X 1 , X 3 and X 4 are CH, and X 2 is N; or wherein X 1 and X 4 are CH, X 2 is CR 1 , X 3 is N and R 1 is CF 3 ; or wherein X 1 and X 3 are CH, X 2 is CR 1 , X 4 is N and R 1 is CN; or wherein X 1 and X 3 are CH, X 2 and X 4 are CR 1 , and each R 1 is independently selected from F, Cl and CN; wherein X 5 , X 7 and X 8 are CH, X 6 is CR 1 , and R 1 is CN or Cl; or wherein X 1
  • -B- is -CH 2 O-; iv. Y 1 is CH or CR 2 , and R 2 is F or methyl; v. Y 6 is CH or CR 2 , and R 2 is F; vi. Z 3 is CH; vii. Z 1 is CH or CR 3 , and R 3 is F, -OCH 3 , -OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH or OCH 2 CH 2 N(CH 3 )2; and viii. R 4 is .
  • X 2 is CR 1 and R 1 is CN. In an alternate embodiment of Formula VII and VIIa, X 2 is CR 1 and R 1 is CF 3 . In one embodiment of Formula VII and VIIa, Y 3 is N. In an alternate embodiment, Y 3 is CH. In one embodiment of Formula VII and VIIa, Y 1 is CH. In an alternate embodiment, Y 1 is CR 2 and R 2 is methyl. In one embodiment of Formula VII and VIIa, R 5 is -CO 2 H. In an alternate embodiment, R 5 is .
  • a compound of the formula wherein -A- is -CHR a CHR a CHR b O-, -OCHR b CHR a CHR a -, -OCHR b CHR b O-, -CHR a CHR b OCHR b -, -CHR b OCHR b CHR a -, -CHR b OCHR b -, -CHR a CHR b O-, or -OCHR b CHR a -;
  • R a at each occurrence is independently H, halo, C 1 -C 2 alkyl or OH;
  • R b at each occurrence is independently H, halo or C 1 -C 2 alkyl; , wherein a is the point of attachment to linker A; b is the point of attachment of linker B;
  • X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , where
  • a compound of Formula IV wherein -A- is -CHR a CHR a CHR b O-, -OCHR b CHR a CHR a -, -OCHR b CHR b O-, -CHR a CHR b OCHR b -, -CHR b OCHR b CHR a -, -CHR b OCHR b -, -CHR a CHR b O-, or -OCHR b CHR a -;
  • R a at each occurrence is independently H, halo, C 1 -C 2 alkyl or OH;
  • R b at each occurrence is independently H, halo or C 1 -C 2 alkyl; , wherein a is the point of attachment to linker A; b is the point of attachment of linker B;
  • X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein
  • a compound of the formula wherein -A- is -CHR a CHR a CHR b O-, -OCHR b CHR a CHR a -, -OCHR b CHR b O-, -CHR a CHR b OCHR b -, -CHR b OCHR b CHR a -, -CHR b OCHR b -, -CHR a CHR b O-, or -OCHR b CHR a -;
  • R a at each occurrence is independently H, halo, C 1 -C 2 alkyl or OH;
  • R b at each occurrence is independently H, halo or C 1 -C 2 alkyl;
  • X 1 , X 2 , X 3 and X 4 are independently N, CH or CR 1 , wherein only one of X 1 , X 2 , X 3 and X 4 can be N and no more
  • a compound of the formula: or a pharmaceutically acceptable salt thereof there is provided a compound of the formula: or a pharmaceutically acceptable salt thereof.
  • a compound of the formula: or a pharmaceutically acceptable salt thereof there is provided a compound of the formula: or a pharmaceutically acceptable salt thereof.
  • -A- is -CHR a CHR a CHR b O-.
  • each R a and R b is H.
  • X 1 , X 3 and X 4 are CH and X 2 is CR 1 .
  • R 1 is CN.
  • R 1 is Cl.
  • -B- is -CH 2 O-.
  • Y 1 and Y 2 are both CH.
  • Y 1 is CR 2
  • Y 2 is CH and R 2 is F.
  • Z 2 and Z 3 are both CH.
  • Z 1 is CH or CR 3 .
  • Z 1 is CH.
  • Z 1 is CR 3 and R 3 is F.
  • linker A the left hand terminal group as written is attached to the X ring and the right hand terminal group is attached to the Y 1 , Y 2 and Y 7 containing ring.
  • the oxygen is attached to the Y 1 , Y 2 and Y 7 containing ring.
  • linker B the left hand terminal group is attached to the X ring and the right hand terminal group is attached the Y 3 containing ring.
  • halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.
  • C 1 -C n alkyl refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms.
  • Examples of a C 1 -C 4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl.
  • Examples of a C 1 -C 3 alkyl group include, but are not limited to, methyl, ethyl and propyl.
  • a C 1 -C 2 alkyl group is methyl or ethyl.
  • C 1 -C n haloalkyl refers to a C 1 -C n alkyl group, as defined herein, which is substituted with one, or more halogen.
  • Examples of C 1 -C 3 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl.
  • C 1 -C n alkoxy refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl).
  • C 1 -C 4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.
  • C 1 -C n haloalkoxy refers to a C 1 -C n alkoxy group, as defined herein, which is substituted with one, or more halogen.
  • Examples of C 1 -C 3 haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy and pentafluoroethoxy.
  • C 3 -C 5 cycloalkyl refers to a monocyclic saturated carbon ring containing between 3 and 5 carbon atoms.
  • C 4 -C 6 cycloalkyl refers to a monocyclic saturated carbon ring containing between 4 and 6 carbon atoms. Specifically, it refers to cyclobutyl, cyclopentyl or cyclohexyl.
  • heteroaryl refers to a monocyclic aromatic ring containing one or more heteroatoms, preferably selected from: N, S and O. Examples of 5-membered heteroaryls include, but are not limited to, pyrazole, triazole and thiazole.
  • 6- membered heteroaryls include, but are not limited to, pyridine and pyridazine.
  • C 4 -C 6 heterocyclyl refers to a 4, 5 or 6 membered monocyclic saturated ring containing one or more heteroatoms, for example, pyrrolidine.
  • C 4 -C 5 heterocyclyl refers to a 4 or 5 membered monocyclic saturated ring containing one or more heteroatoms, for example, oxetane.
  • Formula IX encompasses Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, V, Va, Vb, VI, VII, VIIa and VIIb and reference to Formula IX below, for example in the methods of treatment and therapeutic uses, is also to be read as a reference to each and all of these sub-formulae.
  • a pharmaceutically acceptable composition comprising a compound of Formula IX, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutically acceptable composition is formulated for oral administration.
  • a method of treating a patient for type II diabetes mellitus comprises administering to the patient in need of treatment a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutically acceptable composition is formulated for oral administration.
  • the patient is a human.
  • a method of treating a patient for type II diabetes mellitus comprises administering to the patient in need of treatment an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of lowering blood glucose levels in a patient comprises administering to the patient in need of treatment an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of treating hyperglycemia in a patient comprises administering to the patient in need of treatment an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of treating obesity in a mammal comprises administering to the patient in need of treatment an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a method of treating nonalcoholic steatohepatitis (NASH) in a patient comprises administering to the patient in need of treatment an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof.
  • the patient is a human.
  • a compound of Formula IX or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes mellitus.
  • a compound of Formula IX or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes mellitus.
  • a compound of Formula IX for the manufacture of a medicament for the treatment of NASH.
  • the compounds of Formula IX may be used in simultaneous, separate, or sequential combination with one or more therapeutic agents.
  • additional therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, and ketohexokinase inhibitors.
  • the compound of Formula IX is administered orally.
  • the compound of Formula IX is administered once daily.
  • the therapeutic use is in a human.
  • pharmaceutically acceptable salt refers a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use.
  • pharmaceutically acceptable salts and common methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, etal. , 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al. , "Pharmaceutical Salts” , Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
  • the term “effective amount” refers to the amount or dose of a compound of Formula IX, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.
  • the attending physician can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the size, age, and general health of the patient; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances.
  • the compounds of the present invention are effective at a dosage per day that falls within the range of about 0.01 to about 15 mg/kg of body weight.
  • treating refers to lowering, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, such as hyperglycemia, which can include increasing insulin secretion.
  • the term “patient” includes mammals.
  • the patient is preferably human.
  • the compounds of Formula IX can be formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable.
  • such compositions are for oral administration.
  • the pharmaceutical compositions are formulated as a tablet, capsule, or a solution.
  • the tablet, capsule, or solution can include a compound of Formula IX in an amount effective for treating a patient in need of treatment.
  • Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., “Remington: The Science and Practice of Pharmacy”, A. Adejare Editor, 23 rd Ed., 2020, Elsevier Science).
  • Compounds of the present invention include:
  • a pharmaceutically acceptable salt of the compounds of the invention can be formed, for example, by reaction of a compound of Formula IX and an appropriate pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R.J., et al.; Org. Process. Res. Dev., 4, 427- 435, 2000 and Berge, S.M., et al.; J. Pharm. Sci., 66, 1-19, 1977).
  • the compounds of the present invention may be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof.
  • the product of each step below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers may be separated or resolved at any convenient point in the synthesis, by methods such as, selective crystallization techniques or chiral chromatography (See for example, J.
  • Scheme 1 shows the synthesis of intermediates 7, 8, and 9 which are used in the preparation of compounds of the present invention.
  • Step 1 the hydroxyl group of intermediate 1 is methylated with iodomethane and a carbonate base at elevated temperature to give methoxy intermediate 2.
  • Step 2 the ester group of intermediate 2 is then reduced to alcohol intermediate 3 using NaBH 4 .
  • intermediate 3 is converted to bromide intermediate 4 in Step 3 using PBr 3 , which is then reacted with TMSCN and TBAF in Step 4 to give intermediate 5.
  • the cyano group of intermediate 5 is treated with sulfuric acid in an alcohol solution at elevated temperature in Step 5 to give ester intermediate 6, then the methoxy group is demethylated with BBr 3 in Step 6 to give intermediate 7.
  • intermediate 7 can be converted to a boronate in Step 7 using KOAc, and Pd(dppf)Cl 2 , and either bis(pinacolato)diboron or bis(neopentyl glycoloato)diboron at elevated temperature to give boronate 8 or 9, respectively.
  • Scheme 2 shows the synthesis of intermediates 15, 18, 22, and 23 which are also used in the preparation of compounds of the present invention.
  • Bromide 10 is converted to nitrile 11 in Step 1 using zinc cyanide and a palladium catalyst at elevated temperature.
  • Nitrile intermediate 11 is converted to ester intermediate 12 in Step 2a using thionyl chloride in an alcohol solution at elevated temperature, then the fluorine is displaced in a SNAr reaction in Step 3a with amine 13 and a carbonate base at elevated temperature to give intermediate 14.
  • the nitro group is then reduced in Step 4a under an atmosphere of hydrogen using Lindlar catalyst (5% Pd) in methanol to give intermediate 15.
  • Intermediate 15 can be reacted with 2-chloroacetyl chloride using a tertiary amine base to give 2-chloromethylimidazole intermediate 23.
  • intermediate 11 undergoes S N Ar reaction with amine 13 in Step 2b using an amine base to give intermediate 16, which then is converted to tetrazole intermediate 17 using tributyltin azide at elevated temperature in Step 3b.
  • the nitro group is then reduced in Step 4b under hydrogen pressure (4 bar) using a palladium on carbon catalyst to give intermediate 18.
  • intermediate 11 is reacted with tributyltin azide at elevated temperature in Step 2c to give tetrazole intermediate 19, which is then protected in Step 3c on the tetrazole nitrogen with a group such as SEM (trimethylsilylethoxymethyl) giving intermediate 20.
  • the fluorine is displaced in a SNAr reaction in Step 4c with amine 13 and a tertiary amine base to give intermediate 21, then reduction of the nitro group in Step 5c using iron in acetic acid at elevated temperature gives protected tetrazole intermediate 22.
  • Scheme 3 shows three routes for synthesizing intermediate 32 which is used in the preparation of compounds of the present invention.
  • Step 1a in the first route halide intermediate 24 undergoes a Heck coupling with ethyl acrylate using palladium acetate and a carbonate base at elevated temperature to give intermediate 25, which then undergoes olefin reduction under hydrogen (40 psi) in Step 2a to give intermediate 26.
  • Step 3a the alcohol group of intermediate 26 is converted to the bromide using PBr 3 , then reacted with intermediate 27 and Ag 2 CO 3 at elevated temperature to give intermediate 29. Reduction of the ester group with LiBH 4 in Step 4a gives intermediate 32.
  • intermediate 33 (which can be prepared from intermediate 24 using PBr 3 ) is first reacted in Step 1c with intermediate 27 using Ag 2 CO 3 at elevated temperature to give intermediate 34, which then undergoes a Negishi coupling in Step 2c with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and a palladium catalyst at elevated temperature to give intermediate 35. Deprotection using TBAF in Step 3c then gives intermediate 32.
  • intermediate 24 undergoes Sonogashira coupling with tert- butyildimethyl(2-propynyloxy)silane using a palladium catalyst and tertiary amine base in Step 1b to give intermediate 28, which then undergoes a Mitsunobu reaction with intermediate 27 to give intermediate 30.
  • Deprotection using TBAF in Step 3b and then hydrogenation of the alkyne using platinum oxide under an atmosphere of hydrogen in Step 4b gives Intermediate 32.
  • Scheme 4 W Cl, Br; X 1 , X 2 , X 3 , X 4 , Y 3 , Y 4 , Y 5 , and Y 6 are as defined in Formula IX wherein at least one of Y 3 and Y 4 is N
  • Scheme 4 shows the synthesis of intermediate 42 which is used in the preparation of compounds of the present invention.
  • bromide intermediate 36 is reacted with potassium phthalimide at elevated temperature to give intermediate 37.
  • a Sonogashira coupling with propargyl alcohol gives alkyne intermediate 38.
  • the alkyne of intermediate 38 is reduced with a rhodium catalyst at elevated temperature under hydrogen pressure (90 psi) to give intermediate 39.
  • the phthalimide group is reacted with hydrazine at elevated temperature to give amine 40 in Step 4, which then undergoes a S N Ar reaction with intermediate 41 using DIPEA at elevated temperature in Step 5 to give intermediate 42.
  • X 1 , X 2 , X 3 , X 4 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are as defined in Formula IX
  • Scheme 5 shows the synthesis of intermediate 47 which is used in the preparation of compounds of the present invention.
  • intermediate 43 is reacted with (2- bromoethoxy)-tert-butyldimethylsilane using a carbonate base at elevated temperature.
  • the aldehyde of intermediate 44 is reduced in Step 2 using sodium borohydride to give alcohol 45, which then undergoes a Mitsunobu reaction with intermediate 27 in Step 3 to give intermediate 46.
  • Step 4 gives intermediate 47.
  • Intermediate 32 as described in Scheme 3, can be prepared by the alternative routes shown in Scheme 6.
  • Step 1a intermediate 48 undergoes a Negishi coupling with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and a palladium catalyst at elevated temperature to give intermediate 49, which is then reduced to alcohol intermediate 50 in Step 2a using lithium aluminum hydride.
  • Step 3a intermediate 50 is reacted with intermediate 27 under Mitsunobu conditions to give intermediate 32.
  • intermediate 24 is reacted with either intermediate 27 under Mitsunobu conditions, or with potassium tert-butoxide and aryl fluoride intermediate 41 to give intermediate 34 in Step 1b.
  • Steps 2b and 3b are as described in Scheme 3 (Negishi coupling with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc, followed by deprotection to give intermediate 32).
  • Step 2a intermediate 52 then undergoes an intramolecular cross-coupling with a palladium catalyst to form macrocyclic intermediate 54.
  • intermediate 51 undergoes a Mitsunobu reaction with intermediate 7 to give intermediate 53 in Step lb, then palladium-catalyzed intramolecular Stille coupling at elevated temperature in Step 2b gives intermediate 54.
  • the ester group of intermediate 54 is hydrolyzed in Step 3 using either aqueous LiOH or a guanidine base in ACN/water to give intermediate 55.
  • Scheme 8 shows the synthesis of intermediate 64 which is used in the preparation of compounds of the present invention.
  • intermediate 56 undergoes a reductive coupling with 3 -bromo-1 -propanol at elevated temperature to give intermediate 57, which then is protected with a TBS group in Step 2 to give intermediate 58.
  • Reduction of the ester with lithium borohydride then gives alcohol intermediate 59 in Step 3, which then undergoes a Mitsunobu reaction with intermediate 27 in Step 4 to give intermediate 60.
  • Removal of the TBS protecting group with TBAF gives intermediate 61 in Step 5, which then undergoes a Mitsutnobu reaction with intermediate 8 in Step 6 to give intermediate 62.
  • Step 7 intermediate 62 is cyclized using a palladium catalyst and potassium phosphate to give intermediate 63, which is then hydrolyzed in Step 8 using a using either aqueous LiOH or a guanidine base in ACN/water to give acid intermediate 64.
  • X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are as defined in Formula IX Scheme 9 shows the synthesis of intermediate 77 which is used in the preparation of compounds of the present invention, and two synthetic routes to the common intermediate 74 are shown.
  • Step la acid intermediate 65 is reduced using borane-dimethylsulfide complex to give alcohol intermediate 66, which then undergoes a reaction with sodium hydride and bromide intermediate 67 in Step 2a to give intermediate 68.
  • Step 3a ester reduction with lithium borohydride gives intermediate 73, which then undergoes a Mitsunobu reaction with intermediate 27 to give intermediate 74 in Step 4a.
  • Step lb alkyl bromide intermediate 69 is reacted with intermediate 27 using silver carbonate at elevated temperature to give intermediate 70.
  • Step 2b the ester of intermediate 70 is reduced with lithium borohydride to give alcohol 71, which is then reacted with alkyl bromide 72 using potassium tert-butoxide to give intermediate 74 in Step 3b.
  • intermediate 74 is coupled with ethyl diazoacetate using a palladium catalyst at elevated temperature to give intermediate 75.
  • an intramolecular Stille coupling with a palladium catalyst at elevated temperature gives intermediate 76.
  • Step 6 is accomplished by one-pot coupling with bis(neopentyl glycolato)diboron using a palladium catalyst and potassium pivalate and intramolecular cross-coupling to give cyclic intermediate 76.
  • Intermediate 76 is then hydrolyzed using either aqueous LiOH or a guanidine base in ACN/water in Step 7 to give acid intermediate 77.
  • Step 2a the ester is treated with a reducing agent such as diisobutylaluminum hydride to give alcohol 80, then reacted with aryl fluoride 41 using a strong organic base such as potassium tert-butoxide to give intermediate 81.
  • intermediate 34 (see Scheme 3) is first coupled with (E)-1-ethoxyethene-2-boronic acid pinacol ester using a palladium catalyst and an inorganic base at elevated temperature to give intermediate 81 in Step 1b.
  • Step 4 intermediate 81 is treated with HCl in an organic solvent to give aldehyde 82, which is then reduced with NaBH 4 in Step 3 to give alcohol intermediate 83.
  • intermediate 81 can be converted to intermediate 83 in one step using mercuric acetate and NaBH 4 .
  • Scheme 11 shows the preparation of intermediate 86, which is used in the preparation of compounds of the present invention.
  • aryl iodide 84 undergoes Negishi coupling with (2-ethoxy-2-oxoethyl)zinc(II) bromide and a palladium catalyst at elevated temperature.
  • Step 2 intermediate 85 undergoes photochemical bromination with N-bromosuccinimide in a flow reactor to give bromide intermediate 86.
  • Step 1a intermediate 83 is reacted with intermediate 86 using 2,6-di-tert-butylpyridine and silver triflluoromethanesulfonate to give intermediate 89.
  • intermediate 83 can be first reacted in Step 1b with alkyl bromide 87 under similar conditions to Step 1a to give intermediate 88, which then undergoes Negishi coupling in Step 1c with (2-ethoxy-2- oxoethyl))zinc bromide and a palladium catalyst at elevated temperature to give intermediate 89.
  • Step 2a intermediate 89 undergoes a palladium-catalyzed intramolecular Stille coupling at elevated temperature to give intermediate 91.
  • Step 2b the bromide 89 is converted to the boronic ester intermediate 90 by cross-coupling with bis(pinacolato)diboron, Pd(dppf)Cl 2 and potassium acetate at elevated temperature, which then in Step 2c is cyclized via intramolecular cross-coupling with a palladium catalyst to form macrocyclic intermediate 91 (Steps 2b and 2c can be performed as a single reaction step).
  • Step 3 the ester is hydrolyzed using either aqueous LiOH or a guanidine base in ACN/water to give acid intermediate 92.
  • Intermediate 93 is first coupled to intermediate 27 using Mitsunobu conditions to give intermediate 94 in Step 1.
  • Step 2 intermediate 94 is coupled with bromoethanol using nickel and iridium catalysts and irradiating the reaction under blue light (456 nm) to give intermediate 95.
  • intermediate 95 is prepared in a manner analogous to the synthetic routes shown in the preparation of intermediate 83 in Scheme 10, starting with intermediate 93 in place of intermediate 78.
  • intermediate 95 is reacted with intermediate 96 using 2,6-di- tert-butylpyridine and silver triflluoromethanesulfonate to give intermediate 97.
  • bromide intermediate 97 is converted to the boronic ester intermediate 98 by cross- coupling with bis(pinacolato)diboron, Pd(dppf)Cl 2 and potassium acetate at elevated temperature.
  • Step 5 intermediate 98 then undergoes an intramolecular cross-coupling with a palladium catalyst to form macrocyclic intermediate 99.
  • intermediate 97 is converted in one step to intermediate 99 via intramolecular Stille coupling using hexamethylditin and a palladium catalyst at elevated temperature.
  • Intermediate 99 is then hydrolyzed using either aqueous LiOH or a guanidine base in ACN/water in Step 6 to give acid intermediate 100.
  • X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are as defined in Formula IX
  • Scheme 14 shows the preparation of intermediate 109, which is used to prepare compounds of the present invention.
  • intermediate 101 undergoes radical bromination with N-bromosuccinimide at elevated temperature, then reacted with trimethyl silyl cyanide and TBAF, then treated with sulfuric acid in aqueous EtOH at elevated temperature to give ester intermediate 102.
  • intermediate 102 is coupled with (E)-l -ethoxy ethene-2-boronic acid pinacol ester using a palladium catalyst and a carbonate base to give intermediate 103, which is then converted to alcohol 104 in Step 3 using mercuric acetate and sodium borohydride.
  • aldehyde intermediate 43 is first protected e.g.
  • Step 5 intermediate 105 undergoes a Mitsunobu reaction with intermediate 27 to give intermediate 106.
  • Intermediates 104 and 106 are coupled via Mitsunobu reaction to give intermediate 107, which then undergoes intramolecular cyclization in Step 7 in a manner analogous to Step 2a (one-pot Stille coupling) or Steps 2b and 2c (borylation followed by Pd-catalyzed cross-coupling) in Scheme 12 to give intermediate 108.
  • Ester hydrolysis using either aqueous LiOH or a guanidine base in ACN/water in Step 8 then gives intermediate 109.
  • intermediate 34 is carbonylated in Step 1b using potassium formate and a palladium catalyst to give intermediate 111, followed by reduction of the aldehyde in Step 2b using NaBH 4 to give intermediate 112.
  • the alcohol of intermediate 112 is converted to the alkyl bromide using CBr 4 and triphenylphosphine to give intermediate 113.
  • Step 4 intermediates 113 and 104 are reacted with silver trifluoromethanesulfonate to give intermediate 114.
  • Step 5 then undergoes intramolecular cyclization in Step 5 in a manner analogous to Step 2a (one-pot Stille coupling) in Scheme 12, or in Steps 5 and 6 in a manner similar to Steps 2b and 2c (borylation followed by Pd-catalyzed cross- coupling) in Scheme 12.
  • the resulting ester is hydrolyzed in Step 7 using either aqueous LiOH or a guanidine base in ACN/water to give intermediate 115.
  • Scheme 16 W Cl, Br; X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are as defined in Formula IX Scheme 16 shows the preparation of intermediate 123, which is used in the preparation of compounds of the present invention.
  • intermediate 116 is reacted with methyl bromodifluoroacetate and copper to give intermediate 117, which is then brominated photochemically in Step 2 using N-bromosuccinimide in a flow reactor to give alkyl bromide intermediate 118.
  • Step 3 intermediate 118 is reacted with intermediate 27 using a phosphate base at elevated temperature to give intermediate 119, which then undergoes LiBH 4 reduction in Step 4 to give alcohol intermediate 120.
  • Step 5 intermediate 120 is treated with NaH and reacted with intermediate 124 to give intermediate 121.
  • Step 6 intermediate 121 undergoes Negishi coupling with (2- ethoxy-2-oxo-ethyl)zinc bromide and a palladium catalyst at elevated temperature to give intermediate 122.
  • Intermediate 122 then undergoes intramolecular cyclization in Step 7 in a manner analogous to Step 2a (one-pot Stille coupling) or Steps 2b and 2c (borylation followed by Pd-catalyzed cross-coupling) in Scheme 12.
  • Step 1 intermediate 83 is reacted with alkyl bromide intermediate 125 using silver trifluoromethanesulfonate to give intermediate 126, which then undergoes intramolecular cyclization in Step 2 in a manner analogous to Step 2a (one-pot Stille coupling) or Steps 2b and 2c (borylation followed by Pd-catalyzed cross-coupling) in Scheme 12.
  • Step 3 intermediate 127 is coupled with bis(pinacolato)diboron using a palladium catalyst and potassium acetate at elevated temperature to give boronate intermediate 128.
  • intermediate 129 is coupled with chloromethylimidazole intermediate 23 in Step 1a using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 143, then in Step 3a the ester is hydrolyzed using either aqueous LiOH or a guanidine base in ACN/water at elevated temperature to give acid of Formula IX’.
  • acid intermediate 130 is coupled with intermediate 15 in Step 1c with an amide coupling reagent such as EDC or HATU to give intermediate 132.
  • Intermediate 132 is then cyclized in Step 2a using acetic acid at elevated temperature to give intermediate 143, then the ester is hydrolyzed as described in Step 3a.
  • Compounds of the Formula IX are prepared in Step 4a by coupling an acid of the Formula IX’ with cyclopropylmethanesulfonamide using EDC and 4- dimethylaminopyridine.
  • Compounds of the Formula IX’ are prepared by coupling intermediate 130 with intermediate 18 (without a tetrazole nitrogen protecting group such as SEM) or 22 (with a tetrazole nitrogen protecting group) using HATU in Step 1b to give intermediate 131, then in Step 2b cyclization with acetic acid at elevated temperature (then if needed, Step 3b – tetrazole deprotection e.g. using TBAF to remove a SEM group) gives the tetrazole compound of Formula IX’”.
  • difluoro aryl intermediate 134 first undergoes S N Ar reaction in Step 1b with alcohol 136, which is first treated with NaH and then reacted with intermediate 134 at elevated temperature to give intermediate 135.
  • a second alternative gives intermediate 138 in Step 1c by SNAr reaction with intermediate 137 and 136 in a manner similar to Step 1b.
  • the nitro group of intermediate 138 is reduced e.g. with hydrogen gas and palladium on carbon to give aniline intermediate 139 in Step 3.
  • compounds of Formula IX” are prepared in three steps from intermediates 139 and 130. If the “-O-R” group depicted in Scheme 19 bears a protecting group, e.g.
  • Boc group on a nitrogen or tert- butyldimethylsilyl group on an oxygen that protecting group can be removed as a last step (e.g. using TFA to remove a Boc group or TBAF to remove a tert-butyldimethylsilyl group).
  • Scheme 20 shows the preparation of compounds of the present invention from halide intermediate 140. Intermediate 140 undergoes a cross-coupling reaction (e.g.
  • Suzuki with an optionally substituted 5- or 6-membered aryl or heteroaryl boronic acid or boronic ester using a palladium catalyst and an inorganic base at elevated temperature to give 141.
  • 140 can be converted to boronate 142, for example using tetrahydroxydiboron and a palladium catalyst at elevated temperature giving 142 as a boronic acid, which then undergoes a cross-couping reaction (e.g. Suzuki) with an optionally substituted 5- or 6-membered aryl or heteroaryl halide to give 141.
  • a cross-couping reaction e.g. Suzuki
  • Preparation 41 4-[(1,3-Dioxoisoindolin-2-yl)methyl]-3-(3-hydroxypropyl)benzonitrile
  • a 250 mL Buchi® Miniclave reactor to a suspension of 4-[(1,3- dioxoisoindolin-2-yl)methyl]-3-(3-hydroxyprop-1-ynyl)benzonitrile (3 g, 9.48 mmol) in MeOH (60 mL), add 1,1'-bis(di-i-propylphosphino)ferrocene(1,5- cyclooctadiene)rhodium(I) tetrafluoroborate (0.34 g, 0.47 mmol).
  • Preparation 52 3-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propoxy-tert-butyl- dimethyl-silane Prepare the title compound essentially as described in Preparation 28 using 2- bromo-6-[[2-iodo-4-(trifluoromethyl)phenyl]methoxy]pyridine. Purify the title compound via silica gel flash chromatography eluting with a gradient of 0 to 10% EtOAc in hexanes. Use directly in Preparation 53 without further characterization.
  • Preparation 72 Ethyl 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclooctaphane-1 4 -yl)acetate Prepare the title compound essentially as described in Preparation 65 using ethyl 2-(4-bromo-2-(((2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy)methyl)-5- fluorophenyl)acetate, using 1.1 eq of hexamethylditin and with Pd(dppf)Cl 2 -DCM as catalyst, and stirring the reaction at 100 °C for 3.5 h.
  • Preparation 80 2-(5 4 -Cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 4 - yl)acetic acid Prepare the title compound essentially as described in Preparation 78 using ethyl 2-(5 4 -cyano-1 6 -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 4 - yl)acetate.
  • Preparation 81 2-(5 4 -Cyano-1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 75 using ethyl 2-(5 4 -cyano-1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)acetate, stirring the reaction at 45 °C for 3 h. Quench the reaction with formic acid to pH 7 and dilute with water.
  • Preparation 82 2-(5 4 -Cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane- 1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 75 using ethyl 2-(5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane- 1 4 -yl), stirring the reaction at 45 °C for 1 h.
  • Preparation 84 2-(1 6 -Methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 75 using methyl 2-(1 6 -methyl-5 4 -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)acetate, stirring the reaction at 50 °C for 1 h. Use the title compound in crude form in Preparation 100.
  • Preparation 130 4-[(6-Chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile Charge a vial with nickel(II) chloride ethylene glycol dimethyl ether complex (34 mg, 0.15 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (48 mg, 0.17 mmol). Purge the vial with nitrogen and add anhydrous 1,2-dimethoxyethane (3 mL). Stir mixture for 15min.
  • Preparation 132 3-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-fluoro-phenyl]propoxy-tert-butyl-dimethyl- silane Prepare the title compound essentially as described in Preparation 28 using 2- bromo-6-[(4-fluoro-2-iodo-phenyl)methoxy]pyridine. Purify the title compound via silica gel flash chromatography eluting with a gradient of 0 to 10% EtOAc in hexanes to give an oil that does not ionize by ES-MS, which is used directly in Preparation 133 without further identification.
  • Preparation 138 (3-Iodo-4-pyridyl)methanol Cool a mixture of methyl 3-iodopyridine-4-carboxylate (5.0 g, 19 mmol) in THF (40 mL) and MeOH (10 mL) to -10 °C using an ice/salt bath, then add sodium borohydride (1.52 g, 40.2 mmol) and stir with cooling for 1 h. Quench the reaction by dropwise addition of water (1 mL) then dilute with EtOAc (50 mL). Filter the resulting mixture through Celite ® and rinse w/ EtOAc (100 mL).
  • Preparation 140 3-[4-[(6-Bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy-tert-butyl-dimethyl-silane Prepare the title compound essentially as described in Preparation 28 using 2- bromo-6-[(3-iodo-4-pyridyl)methoxy]pyridine. Purify the title compound via silica gel chromatography using a gradient of 0 to 80% EtOAc in hexanes, and use it in Preparation 141 without further characterization.
  • Preparation 141 3-[4-[(6-Bromo-2-pyridyl)oxymethyl]-3-pyridyl]propan-1-ol
  • Purify the title compound via silica gel chromatography eluting with a gradient of 5 to 75% (1:4 MeOH : EtOAc) in DCM.
  • Preparation 158 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane- 1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 78 using ethyl 2-(5 4 -cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane- 1 4 -yl)acetate. ES-MS m/z 418 (M+H).
  • Preparation 159 2-(5 4 -Cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 4 -yl)acetic acid
  • Preparation 160 2-(1 6 -Methyl-5 4 -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 75 using methyl 2-(1 6 -methyl-5 4 -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)acetate, stirring the reaction at 50 °C for 1 h. The title compound is used without purification in Preparation 168.
  • Preparation 204 2-(5 4 -Cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane- 1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 75 using ethyl 2-(5 4 -cyano-1 6 -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane- 1 4 -yl)acetate, heating the reaction at 45 °C for 3 h.
  • Preparation 246 6-[(6-Chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)pyridine-3-carbonitrile Prepare the title compound essentially as described in Preparation 235 using 6-[(6- chloro-2-pyridyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carbonitrile. Upon completion of the reaction, filter off a solid and wash with EtOAc. From the filtrate, separate the organic layer and extract the aqueous layer with EtOAc three times. Combine the organic layers, dry over anhydrous Na 2 SO 4 , then filter and concentrate under reduced pressure.
  • Preparation 249 2-(5 5 -Cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)acetic acid Prepare the title compound essentially as described in Preparation 78 using methyl 2-(5 5 -cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)acetate. When the reaction is complete, remove the organic solvents and water and aqueous citric acid (1 M) to bring the pH to 5-6. Filter the resulting solid and wash with water to provide the title compound as a white solid.
  • Preparation 254 2-((3-(Bromomethyl)-4-chlorobenzyl)oxy)-6-chloropyridine Cool a solution of (2-chloro-5-(((6-chloropyridin-2- yl)oxy)methyl)phenyl)methanol (from Preparation 253, 1.5 g, 5.3 mmoL) and triphenylphosphine (2.0 g, 7.5 mmoL) in DCM (35 mL) to 0 °C. Add carbon tetrabromide (1.9 g, 5.7 mmoL), stir the reaction mixture at 0 °C for 10 min then at RT for 30 min. Filter the reaction solution through a pad of silica gel and rinse with DCM.
  • Preparation 258 2-(5 4 -Chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 4 - yl)acetic acid Prepare the title compound essentially as described in Preparation 75 using ethyl 2-(5 4 -chloro-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 4 - yl)acetate, using 3:3:1 ACN : 1,4-dioxane : water as solvent and heating the reaction at 50 °C for 1 h 20 min.
  • Preparation 272 2-[2-[(6-Bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetic acid Dissolve methyl 2-[2-(bromomethyl)-5-cyano-phenyl]-2,2-difluoro-acetate (6.2 g, 20 mmol) and 2-bromo-6-hydroxypyridine (4.5 g, 25 mmol) in DMSO (50 mL). Add potassium phosphate tribasic (6.6 g, 30 mmol) to this solution and heat to 60 °C for 2 h. After this time, quench the reaction with 1N HCl (to pH ⁇ 6) and extract with EtOAc.
  • Preparation 274 4-[(6-Bromo-2-pyridyl)oxymethyl]-3-(1,1-difluoro-2-hydroxy-ethyl)benzonitrile Dissolve methyl 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2- difluoro-acetate (8 g, 20.14 mmol) in THF (100 mL). To this solution add lithium borohydride (0.88 g, 40.4 mmol) and stir at ambient temperature under nitrogen for 2 h. After this time, quench the reaction with saturated NH 4 Cl solution, and extract with EtOAc. Dry the organics over MgSO 4 , filter, and concentrate.
  • Preparation 293 1 4 -Chloro-5 6 -(trifluoromethyl)-3,8-dioxa-2(2,6),5(3,4)-dipyridina-1(1,3)- benzenacyclononaphane
  • dichlorobis(tricyclohexylphosphine)palladium (II) (1.02 g, 1.35 mmol) and heat to 90 °C for 20 h.
  • dichlorobis(tricyclohexylphosphine)palladium (II) (0.10 g, 0.13 mmol)
  • KOAc (0.410g, 4.1 mmol). Heat the mixture to 90 °C for 4 h.
  • tetrahydroxydiboron 139 mg, 1.47 mmol
  • tricyclohexylphosphine 5 mg, 0.018 mmol
  • Example 7 (S)-2-((5 4 -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 - yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Example 13 (S)-2-((5 4 -Cyano-1 6 -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid
  • Example 17 (S)-2-((5 4 -cyano-1 6 -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid
  • Example 18 (S)-2-((5 4 -Bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 - yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Example 20 (S)-2-((5 4 -Cyano-1 6 -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid
  • Example 22 (S)-4-Methoxy-2-((1 6 -methyl-5 4 -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid
  • Example 23 2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 - yl)methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
  • Example 40 (S)-2-((5 4 -(1-Methyl-1H-pyrazol-4-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid
  • Example 54 (S)-2-((5 4 -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 - yl)methyl)-1-(oxetan-2-ylmethyl)-4-(2-((2,2,2-trifluoroethyl)amino)ethoxy)-1H- benzo[d]imidazole-6-carboxylic acid
  • Example 70 (S)-2-((5 4 -Cyano-1 6 ,5 6 -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)- 1H-benzo[d]imidazole-6-carboxylic acid
  • Example 72 (S)-2-((5 4 -(4-Methyl-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- dibenzenacyclononaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid Add anhydrous DMSO (0.06 mL) to a mixture of (S)-2-((5 4 -bromo-3,9-dioxa- 2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 -yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, 0.031 mmol), 4- methylimidazole (10 mg, 0.119 mmol), trip
  • the hGLP-1R receptor expressing cells are treated with compound (20 point concentration-response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384 well plate Corning Cat# 3570) in DMEM (Gibco Cat# 31053) supplemented with 1X GlutaMAX TM (Gibco Cat# 35050), 0.1% bovine casein (Sigma C4765-10ML), 250 ⁇ M IBMX (3-Isobutyl-1-methylxanthine, Acros Cat# 228420010) and 20 mM HEPES (Gibco Cat# 15630) in a 20 ⁇ L assay volume (final DMSO concentration is 0.5%).
  • cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer (10 ⁇ L) followed by the antibody anti-cAMP-Eu 3+ -Cryptate, also in cell lysis buffer (10 ⁇ L).
  • the resulting competitive assay is incubated for at least 60 min at RT, then detected using a PerkinElmer Envision ® instrument with excitation at 320 nm and emission at 665 nm and 620 nm.
  • Envision units (emission at 665nm/620nm*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve.
  • the amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed with human GLP-1(7-36)NH 2 .
  • a relative EC 50 value and percent top (E max ) are derived by non-linear regression analysis using the percent maximal response vs. the concentration of compound added, fitted to a four-parameter logistic equation.
  • the EC 50 and E max data when the compounds of Examples 1 to 80 are tested in the cAMP assay described above using HEK293 cells expressing 581 and 104 fmol/mg GLP-1R are shown in Tables 1 and 2, respectively. These data indicate that the compounds of Examples 1 to 80 are agonists of the human GLP-1 receptor. Table 1. HEK293 cell line with 581 fmol/mg expression density of GLP-1R, intracellular cAMP response, relative EC 50 and E max
  • GLP-1R CHO Cell ⁇ -Arrestin Recruitment Assay
  • Activated G-protein coupled receptors can interact with the ⁇ -arrestin family of signaling proteins.
  • the potency of compounds for GLP-1R induced arrestin recruitment is determined using the PathHunter Enzyme Fragment Complementation approach substantially as described (von Degenfeld et al., FASEB J., 2007 (14):3819-26 and Hamdouchi et al., J. Med Chem., 201659(24):10891-10916).
  • CHO-K1 cells expressing Pro-Link-tagged Human GLP-1R and enzyme-acceptor-tagged ⁇ -arrestin-2 may be obtained from DiscoveRx and prepared as assay-ready frozen cells.
  • Test compounds are solubilized in DMSO and serial dilutions are performed using the Echo acoustic dispenser (LabCyte).
  • Assay media is the PathHunter Cell Assay Buffer (DiscoveRx) containing 0.1% w/v hydrolyzed Casein (Sigma).100 nL of test compound solution is dispensed into 10 ⁇ L of assay media in a 384 well plate and then 10 ⁇ L of cells in assay media are added to give 5000 cells per well. Plates are incubated for 90 min in a 37 °C/5% CO 2 incubator and 10 ⁇ L of PathHunter detection reagent is added (DiscoveRx) and plates are incubated at RT for 60 min. Luminescence signal is measured.

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Abstract

Dans un mode de réalisation, la présente invention concerne un composé de formule : ou un sel pharmaceutiquement acceptable de celui-ci, et des méthodes d'utilisation de ce composé pour le traitement du diabète sucré de type II.
PCT/US2022/029958 2021-05-20 2022-05-19 Agonistes macrocycliques du récepteur du peptide 1 de type glucagon Ceased WO2022246019A1 (fr)

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KR1020237039778A KR20230173166A (ko) 2021-05-20 2022-05-19 마크로시클릭 글루카곤-유사 펩티드 1 수용체 효능제
IL308397A IL308397A (en) 2021-05-20 2022-05-19 Macrocyclic glucagon-like peptide 1 receptor agonists
AU2022275931A AU2022275931B2 (en) 2021-05-20 2022-05-19 Macrocyclic glucagon-like peptide 1 receptor agonists
CA3218345A CA3218345A1 (fr) 2021-05-20 2022-05-19 Agonistes macrocycliques du recepteur du peptide 1 de type glucagon
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WO2024102625A1 (fr) * 2022-11-11 2024-05-16 Eli Lilly And Company Agonistes de récepteur du peptide 1 de type glucagon
US12024507B2 (en) 2021-10-25 2024-07-02 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
CN119219759A (zh) * 2024-10-22 2024-12-31 浙江工业大学 一种双水相萃取耦合反相柱层析分离纯化发酵液中glp-1类似物的方法
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025158275A1 (fr) 2024-01-24 2025-07-31 Pfizer Inc. Polythérapie utilisant des composés antagonistes du récepteur du polypeptide insulinotrope glucose-dépendant et des composés agonistes du récepteur glp-1
US12378237B2 (en) 2021-09-27 2025-08-05 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
US12410163B2 (en) 2022-02-23 2025-09-09 Terns Pharmaceuticals, Inc. Compounds as GLP-IR agonists
WO2025189141A1 (fr) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Méthodes de traitement de l'obésité et d'augmentation de la perte de poids
US12485118B2 (en) 2023-04-07 2025-12-02 Terns Pharmaceuticals, Inc. Combinations of GLP-1R and THRβ agonists and methods of use thereof

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