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WO2024020350A1 - Inhibiteurs de tead et procédés d'utilisation - Google Patents

Inhibiteurs de tead et procédés d'utilisation Download PDF

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Publication number
WO2024020350A1
WO2024020350A1 PCT/US2023/070353 US2023070353W WO2024020350A1 WO 2024020350 A1 WO2024020350 A1 WO 2024020350A1 US 2023070353 W US2023070353 W US 2023070353W WO 2024020350 A1 WO2024020350 A1 WO 2024020350A1
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Prior art keywords
compound
alkyl
cancer
group
optionally substituted
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English (en)
Inventor
Florian Muller
Andrew Morley
Sharon Shacham
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Sporos Biodiscovery Inc
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Sporos Biodiscovery Inc
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Priority to JP2025502500A priority Critical patent/JP2025526321A/ja
Priority to EP23752144.8A priority patent/EP4558485A1/fr
Priority to AU2023308983A priority patent/AU2023308983A1/en
Priority to CN202380055158.6A priority patent/CN119497708A/zh
Priority to KR1020257005344A priority patent/KR20250038764A/ko
Publication of WO2024020350A1 publication Critical patent/WO2024020350A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/34—Ethylene-urea
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/40—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/02—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • compositions comprising a compound of formula (I), formula (I’), formula (I-1), or formula (I- 1’), e.g., a compound of formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), and/or formula (Ie), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • TAA transcriptional enhanced associate
  • TEAD domain transcription factor
  • the compounds of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), or formula (Ie) are selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • methods of treating a disease or condition mediated by TEAD activity comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein or a pharmaceutical composition disclosed herein.
  • the disease or condition is a cancer characterized by abnormal TEAD transcriptional complex activity (e.g., hyperactivation).
  • FIG.1 is a diagram showing the domain architecture of human TEAD1, TEAD2, TEAD3, and TEAD4. The percent values represent the identity of the N-terminal DNA binding domain (DNA-BD) and C-terminal YAP/TAZ binding domain (YAP/TAZ-BD) of TEAD2-4 compared to the respective binding domains of TEAD1. Post translation modifications including palmitoylation and phosphorylation as well as the p38 binding D domain of DNA-BD are also shown.
  • FIG.2A is a diagram showing the upstream signaling and downstream transcriptional outputs of TEAD in cancer biology, which regulate critical functions in tumorigenesis, stem cell maintenance, cancer immunology, and metabolism, as well as formation of signaling feedback loops.
  • FIG.2B is a diagram showing the role of TEAD in multiple stages of tumorigenesis.
  • FIG.3A is a graph showing the pre- and 7 day post-treatment tumor volume in individual mice bearing MSTO-211H tumors treated with vehicle twice daily, 3 mg/kg Compound 1-1 twice daily, or 12.5 mg/kg Compound 5 twice daily.
  • FIG.3B is a graph showing the mean change in MSTO-211H tumor volume in the treatment groups described in FIG.3A.
  • compounds and compositions e.g., compounds of formula (I), formula (I’), formula (I-1), or formula (I-1’), e.g., compounds of formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), and/or formula (Ie), or pharmaceutically acceptable salts thereof.
  • compositions comprising a compound of formula (I), formula (I’), formula (I-1), or formula (I-1’), e.g., a compound of formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), and/or formula (Ie), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a compound of formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), and/or formula (Ie) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • methods of use of compounds and compositions disclosed herein are methods of use of compounds and compositions disclosed herein.
  • TEAD transcriptional enhancer factor domain
  • the contemplated compounds and compositions disclosed herein are inhibitors of transcriptional enhancer factor domain (TEAD) activity and thus are useful in methods of treating certain diseases or disorders such as cancer characterized by abnormal TEAD transcriptional complex activity (e.g., hyperactivation).
  • TEAD transcriptional enhancer factor domain
  • Certain Terminology Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. Generally, nomenclatures utilized in connection with, and techniques of, immunology, oncology, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well-known and commonly used in the art.
  • the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • compounds described herein also comprise one or more isotopic substitutions.
  • H is in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C is any isotopic form, including 12 C, 13 C, and 14 C;
  • O is in any isotopic form, including 16 O and 18 O;
  • F is in any isotopic form, including 18 F and 19 F; and the like.
  • C 1–6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1– 6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl.
  • alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C 1– C 20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1– C 10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1– C 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1– C 8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1– C 7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C 1– C 6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1– C 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1– C 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1– C 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1- C 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • alkylene refers to a divalent radical of an alkyl group. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. In some embodiments, “alkylene” group is substituted or unsubstituted with one or more substituents as described herein.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”).
  • heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”).
  • the point of attachment is a carbon or nitrogen atom, as valency permits.
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6– membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C 3 -C 10 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3– to 10– membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–10 membered heterocyclyl”).
  • the point of attachment is a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group is either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and is saturated or is partially unsaturated.
  • heterocyclyl bicyclic ring systems include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more phenyl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”).
  • a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”).
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom.
  • hetero is applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • alkyl e.g., heteroalkyl
  • cycloalkyl e.g., heterocyclyl
  • aryl e.g., heteroaryl
  • halo and halogen refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).
  • the halo group is either fluoro or chloro.
  • haloalkyl includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.
  • hydroxyl refers to -OH.
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • substituents are described in more detail in the Detailed Description, Examples, and Claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.
  • pharmaceutically acceptable excipient refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s). Exemplary pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms “human,” “patient,” “individual” and “subject” are used interchangeably herein. None of the terms require the supervision of medical personnel.
  • the terms “disease”, “disorder”, and “condition” are used interchangeably herein.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition.
  • a “therapeutically effective amount” or an “effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount or an effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” or “effective amount” encompasses an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • X is selected from the group consisting of NR a , O, and S;
  • R 1 is a 5-10 membered heteroaryl having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-10 membered heteroaryl is optionally substituted;
  • R 2 is 3-10 membered heterocyclyl or -(C 1 -C 4 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl has one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S and is optionally substituted, wherein the C1-C4alkylene is optionally substituted;
  • one of R 3a and R 3b is selected from the group consisting of halogen, -C 1 -C 6 alkyl, -C 1
  • X is selected from the group consisting of NR a , O, and S;
  • R 1 is a 5-10 membered heteroaryl having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-10 membered heteroaryl is optionally substituted;
  • R 2 is 3-10 membered heterocyclyl or -(C 1 -C 4 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl contains at least 2 carbon atoms and one, two, three, or four heteroatoms and is optionally substituted, wherein the heteroatoms are nitrogen, and wherein the C 1 -C 4 alkylene is optionally substituted;
  • one of R 3a and R 3b is selected from the group consisting of halogen, -C 1 -C 6 alkyl, -C
  • X is selected from the group consisting of NR a , O, and S;
  • R 1 is a 5-10 membered heteroaryl having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-10 membered heteroaryl is optionally substituted;
  • R 2 is 3-10 membered heterocyclyl or -(C 1 -C 4 alkylene)-(3-10 membered heterocyclyl); wherein the 3-10 membered heterocyclyl has one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S, and is optionally substituted, wherein the C 1 -C 4 alkylene is optionally substituted;
  • R 3 is selected from the group consisting of halogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl,
  • X is selected from the group consisting of NR a , O, and S;
  • R 1 is a 5-10 membered heteroaryl having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-10 membered heteroaryl is optionally substituted;
  • R 2 is 3-10 membered heterocyclyl or -(C 1 -C 4 alkylene)-(3-10 membered heterocyclyl); wherein the 3-10 membered heterocyclyl contains at least 2 carbon atoms and one, two, three, or four heteroatoms and is optionally substituted, wherein the heteroatoms are nitrogen, and wherein the C 1 -C 4 alkylene is optionally substituted;
  • R 3 is selected from the group consisting of halogen, -C 1 -C 6 alkyl, -C 1 -C 6 halo
  • X is NR a .
  • the compounds are compounds of formula (Ia): r pharmaceutically acceptable salts thereof, wherein: R 3 is -C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl; and the rest of the variables are as defined in formula (I).
  • the compounds are compounds of formula (Ia’): r pharmaceutically acceptable salts thereof, wherein: R 3 is -C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl; and the rest of the variables are as defined in formula (I’).
  • R 1 is 5-6 membered heteroaryl that is optionally substituted.
  • R 1 is 5-6 membered heteroaryl that is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), and -N(R b ) 2 , wherein each R b is independently selected from hydrogen and C 1 -C 6 alkyl.
  • R 1 is 5-6 membered heteroaryl selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine, and pyridazine, wherein the 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of C 1 -C 6 alkyl, halogen, C 1 - C 6 haloalkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), and -N(R b ) 2 , wherein each R b is independently selected from hydrogen and C1-C6 alkyl.
  • R 1 is 5-6 membered heteroaryl that is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from halogen and -C 1 -C 6 alkyl.
  • R 1 is 5-6 membered heteroaryl selected from the group consisting of oxadiazole, imidazole, pyrazole, oxazole, triazole, tetrazole, pyridine, pyrazine, and pyridazine, wherein the 5-6 membered heteroaryl is optionally substituted with C 1 -C 6 alkyl.
  • R 1 is imidazole optionally substituted with methyl.
  • R 1 is oxazole.
  • R 1 is tetrazole optionally substituted with methyl.
  • R 1 is oxadiazole, e.g., 1,3,4-oxadiazole, optionally substituted with methyl.
  • the compounds are compounds of formula (Ib): r pharmaceutically acceptable salts thereof, wherein: R d is selected from hydrogen and -C 1 -C 6 alkyl; and the rest of the variables are as defined in formula (Ia).
  • the compounds are compounds of formula (Ib’): r pharmaceutically acceptable salts thereof, wherein: R d is selected from hydrogen and -C 1 -C 6 alkyl; and the rest of the variables are as defined in formula (Ia’).
  • the compounds are compounds of formula (Ic): r pharmaceutically acceptable salts thereof, wherein the variables are as defined in formula (Ib).
  • the compounds are compounds of formula (Ic’): r pharmaceutically acceptable salts thereof, wherein the variables are as defined in formula (Ib’).
  • R 2 is 3-7 membered monocyclic heterocyclyl or -(C 1 - C 4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl has one, two, three, or four heteroatoms each independently selected from N, O, and S, wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted, and wherein the C 1 -C 4 alkylene is optionally substituted (e.g., optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, or two geminal hydrogens on a carbon of the C 1-4 alkylene can be taken together with the carbon atom to which they are attached to form a 3-7 membered cycloalkyl ring).
  • the 3-7 membered monocyclic heterocyclyl has one, two, three, or four heteroatoms each independently selected from N, O, and S, wherein the 3-7 membered monocyclic heterocyclyl is optional
  • R 2 is 3-7 membered monocyclic heterocyclyl or -(C 1 - C 4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl contains at least 2 carbon atoms and one, two, three, or four heteroatoms, wherein the heteroatoms are nitrogen and wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted, and wherein the C 1 -C 4 alkylene is optionally substituted (e.g., optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, or two geminal hydrogens on a carbon of the C 1- 4 alkylene can be taken together with the carbon atom to which they are attached to form a 3-7 membered cycloalkyl ring).
  • the 3-7 membered monocyclic heterocyclyl contains at least 2 carbon atoms and one, two, three, or four heteroatoms, wherein the heteroatoms are nitrogen and wherein the
  • R 2 is 3-7 membered monocyclic heterocyclyl or -(C 1 - C 4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl has one, two, three, or four heteroatoms each independently selected from N, O, and S, and is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of C 1 -C 6 alkyl, oxo, halogen, C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), -O- (C 1 -C 6 haloalkyl), -N(R b ) 2 , -C(O)OR g , -C(O)N(R f ) 2 , -S(O) 2 N(R f ) 2 , -OC(O)N(R f ) 2 , - -
  • R 2 is 3-7 membered monocyclic heterocyclyl or -(C 1 - C 4 alkylene)-(3-7 membered monocyclic heterocyclyl), wherein the 3-7 membered monocyclic heterocyclyl contains at least 2 carbon atoms and one, two, three, or four heteroatoms, wherein the heteroatoms are nitrogen and wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of C 1 -C 6 alkyl, oxo, hydroxyl, halogen, C 1 -C 6 haloalkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 haloalkyl), -N(R b ) 2 , -C(O)OR g , -C(O)N(R f ) 2 , -S(O) 2 N(R
  • R 2 is 3-7 membered monocyclic heterocyclyl, wherein the 3-7 membered monocyclic heterocyclyl contains at least 2 carbon atoms and one, two, three, or four heteroatoms, wherein the heteroatoms are nitrogen and wherein the 3-7 membered monocyclic heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, -C 1 -C 6 alkyl, oxo, and hydroxyl.
  • R 2 is 5-membered heterocyclyl having one or two nitrogen atoms, wherein the 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from C 1 -C 6 alkyl and oxo.
  • R 2 is 5-membered heterocyclyl having one or two heteroatoms, wherein the heteroatoms are nitrogen atoms, and wherein the 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from C 1 -C 6 alkyl, oxo, and hydroxyl.
  • R 2 is -(C 1 -C 4 alkylene)-(5-membered heterocyclyl having one or two nitrogen atoms), wherein the 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from C 1 -C 6 alkyl and oxo.
  • R 2 is -(C 1 -C 4 alkylene)-(5-membered heterocyclyl having one or two heteroatoms), wherein the heteroatoms are nitrogen atoms, and wherein the 5-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from C 1 -C 6 alkyl, oxo, and hydroxyl.
  • R 2 is: , wherein t is selected from the group consisting of 0, 1, 2, and 3.
  • R 2 is: , wherein t is selected from the group consisting of 0, 1, 2, and 3.
  • t is 1.
  • R 2 is: , wherein s is selected from the group consisting of 0, 1, 2, and 3, and R e is selected from hydrogen and C 1 -C 6 alkyl. [0087] In some embodiments, s is 0 and R e is methyl. [0088] In some embodiments, R 2 is: , wherein u is selected from the group consisting of 0, 1, 2, and 3, and R e is selected from hydrogen and C 1 -C 6 alkyl. [0089] In some embodiments, R 2 is: , wherein u is selected from the group consisting of 0, 1, 2, and 3, and R e is selected from hydrogen and C 1 -C 6 alkyl.
  • R 2 is: , wherein u is selected from the group consisting of 0, 1, 2, and 3, and R e is selected from hydrogen and C 1 -C 6 alkyl. [0091] In some embodiments, u is 0 and R e is methyl. [0092] In some embodiments, the compounds are compounds of formula (Id): or pharmaceutically acceptable salts thereof, wherein R 3 is -C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl; and the rest of the variables are as defined in formula (Ia). [0093] In some embodiments, the compounds are compounds of formula (Ie): r pharmaceutically acceptable salts thereof, wherein the variables are as defined in formula (Id).
  • R 3 is C 1 -C 6 alkyl or -C 1 -C 6 haloalkyl. [0095] In some embodiments, R 3 is halogen. [0096] In some embodiments, R 3 is trifluoromethyl. [0097] In some embodiments, m and n are both 0. [0098] In some embodiments, R a is hydrogen. [0099] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof. Table 1. List of compounds.
  • compositions comprising: (a) a compound disclosed herein (e.g., a compound of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’) formula (Ic), formula (Ic’), formula (Id), or formula (Ie)) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.
  • a compound disclosed herein e.g., a compound of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’) formula (Ic), formula (Ic’), formula (Id), or formula (Ie)
  • a pharmaceutically acceptable excipient e.g., a compound of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’
  • the excipient is selected from: inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the pharmaceutical compositions are administered alone or in combination with other therapeutic agents. Such compositions are prepared in any suitable manner.
  • the pharmaceutical compositions are administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intransal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer.
  • One mode for administration is parenteral, particularly by injection.
  • the forms in which the novel compositions of the present disclosure are incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also used for injection.
  • ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils are employed.
  • the proper fluidity is maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms is brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral administration is another route for administration of the compounds disclosed herein. In some embodiments, administration is via capsule or enteric coated tablets, or the like.
  • the active ingredient in making the pharmaceutical compositions that include at least one compound described herein, is usually diluted by an excipient and/or enclosed within such a carrier that is in the form of a capsule, sachet, paper or other container.
  • a carrier that is in the form of a capsule, sachet, paper or other container.
  • the excipient when it serves as a diluent, it is in the form of a solid, semi- solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions are e in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the disclosure are formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations.
  • Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches").
  • patches are used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. In some embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions are preferably formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
  • the compounds are generally administered in a pharmaceutically effective amount.
  • each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein.
  • the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure.
  • the tablets or pills of the present disclosure are coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill comprises an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components are separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents are nebulized by use of inert gases.
  • nebulized solutions are inhaled directly from the nebulizing device or the nebulizing device is attached to a facemask tent, or intermittent positive pressure breathing machine.
  • solution, suspension, or powder compositions are administered, orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • a disease or disorder modulated by abnormal activity of a TEAD isoform e.g., TEAD1 and/or TEAD4
  • a TEAD isoform e.g., TEAD1 and/or TEAD4
  • administering to the individual a compound of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), or formula (Ie), or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of a compound of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), or formula (Ie), or a pharmaceutically acceptable salt thereof).
  • TEADs TEA domain transcription factors
  • TEADs are downstream effectors of the Hippo signaling pathway.
  • four isoforms of TEAD have been identified – TEAD1, TEAD2, TEAD3, and TEAD4.
  • the TEAD isoforms share highly similar structures.
  • the N-terminus of the four isoforms share a highly conserved 68-amino acid TEA/ATTS DNA-binding domain, which binds to the MCAT element (50 -CATTCCA/T-30).
  • the C-terminus contains the transactivation domain which recruits transcriptional coactivators YAP/TAZ.
  • the expression of TEAD proteins is up-regulated in many cancer types including gastric, colorectal, breast, and prostate cancers.
  • TEAD hyperactivation plays a role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance and is correlated with poor survival in patients.
  • Selective binding of TEAD1 and/or TEAD4 is beneficial for optimizing anti-tumor efficacy while minimizing undesired effects.
  • Inhibition of TEAD3 has been associated with off- target toxicity (e.g., kidney toxicity), while inhibition of TEAD2 may be pro-proliferative.
  • the TEAD isoform selectivity demonstrated by compounds disclosed herein is an advantage over TEAD inhibitors known in the art. For example, as demonstrated by Tang and Post using thermal shift assays, TEAD inhibitor VT3989 primarily interacts with TEAD1-3.
  • TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models,” Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr.8-13. Philadelphia (PA): AACR; Poster #5364).
  • the data provided in Table 2 shows that VT3989 provides minimal selectivity over TEAD2 and 3, TEAD isoforms for which inhibition is undesirable. Furthermore, VT3989 shows lower levels of binding to TEAD4, a TEAD isoform for which inhibition is desirable.
  • each change in ⁇ Tm (°C) of 2.5 °C may be associated with an approximately 10-fold difference in binding affinity (Bhayani et al.; “Determination of dissociation constants of protein ligands by thermal shift assay,” Biochemical and Biophysical Research Communications, 2022, 560:1-6.) Table 2. Thermal shift assay of TEAD isoforms 1-4 treated with TEAD inhibitor VT3989 compared to inactive analog control. [00117]
  • the compounds disclosed herein selectively bind one or more TEAD isoforms. In certain embodiments, the compounds disclosed herein selectively bind TEAD1. In certain embodiments, the compounds disclosed herein selectively bind TEAD4. In certain embodiments, the compounds disclosed herein selectively bind TEAD1 and TEAD4.
  • the binding selectivity for TEAD1 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold over TEAD2 and/or TEAD3.
  • the binding selectivity for TEAD4 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold over TEAD2 and/or TEAD3.
  • Evidence of the TEAD isoform selectivity demonstrated by compounds disclosed herein is provided in Example 26 below.
  • the compounds disclosed herein are useful as a medical therapy for treating a disease or condition mediated by hyperactivation of YAP/TAZ-TEAD (e.g, TEAD1 and/or TEAD4) transcriptional co-activator complex.
  • the compounds disclosed herein are useful as a medical therapy for treating a disease or condition characterized by the hyperactivation of TEAD (e.g., TEAD1, TEAD2, TEAD3, and TEAD4 isoforms).
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and TEAD4 isoforms
  • the disease or condition is characterized by the overexpression or genomic fusion or amplification of TEAD.
  • TEAD1 and TEAD4 experience recurrent onco- fusions; for example, TEAD1-PARVA. These fusions drive higher expression of TEADs and may result in enhanced transcription of TEAD-target genes.
  • TEAD4 Amplifications (genomic copy number gains) of TEAD4 occur in diverse cancers as part of the 12p13 locus in, e.g., ovarian and uterine carcinoma as well as testicular germ cell tumors. These genomic amplifications of TEAD4 are associated with strong increase in its mRNA expression and may drive high TEAD- YAP/TAZ transcriptional activity.
  • the TEAD isoform is TEAD1.
  • the TEAD isoform is TEAD4.
  • the disease, disorder or condition is a cancer characterized by abnormal TEAD transcriptional complex activity (e.g., hyperactivation).
  • Such cancers include but are not limited to breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular cancer, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastomas.
  • the cancer is selected from pancreatic adenocarcinoma, hepatocellular cancer, breast cancer, and malignant mesothelioma.
  • the pancreatic cancer is pancreatic adenocarcinoma.
  • the cancer is malignant mesothelioma.
  • a compound or pharmaceutically acceptable salt disclosed herein, or a pharmaceutical composition disclosed herein for use in treating a disease or disorder mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.
  • a compound or pharmaceutically acceptable salt disclosed herein, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a disease or disorder mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.
  • the cancer is a breast cancer. In some embodiments, the cancer is a lung cancer.
  • the cancer is a gastric cancer. In some embodiments, the cancer is a colorectal cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a head and neck cancer. In some embodiments, the cancer is a renal cell carcinoma. In some embodiments, the cancer is a medulloblastoma. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a hepatocellular cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a metastatic breast cancer. In some embodiments, the cancer is a metastatic lung cancer. In some embodiments, the cancer is a metastatic gastric cancer.
  • the cancer is a metastatic colorectal cancer. In some embodiments, the cancer is a metastatic prostate cancer. In some embodiments, the cancer is a metastatic head and neck cancer. In some embodiments, the cancer is a metastatic renal cell carcinoma. In some embodiments, the cancer is a metastatic mesothelioma. In some embodiments, the cancer is a metastatic pancreatic cancer. In some embodiments, the cancer is a metastatic hepatocellular cancer.
  • the disclosure provides for compounds of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), or formula (Ie) for modulating TEAD activity.
  • the disclosure provides for pharmaceutically acceptable salts of compounds of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ia’), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), or formula (Ie) for modulating TEAD activity.
  • the disclosure provides for compounds of formula (I), formula (I’), formula (I-1), formula (I-1’), formula (Ia), formula (Ia’), formula (Ib), formula (Ib’), formula (Ic), formula (Ic’), formula (Id), or formula (Ie) or pharmaceutically acceptable salts thereof for use in medical therapy.
  • the compounds and pharmaceutically acceptable salts thereof or pharmaceutical compositions disclosed herein are administered alone or in combination with one or more other therapeutic agents.
  • the other therapeutic agent is any suitable chemotherapeutic agent.
  • the one or more other therapeutic agents are selected from modulators of other transcription factors.
  • the modulators of other transcription factors are selected from modulators of YAP, modulators of EGFR, or modulators of MEK.
  • the one or more other therapeutic agents are administered concurrently with the compounds or pharmaceutically salts thereof or pharmaceutical compositions disclosed herein.
  • the one or more other therapeutic agents are administered sequentially with the compounds or pharmaceutically salts thereof or pharmaceutical compositions disclosed herein.
  • the one or more other therapeutic agents are administered before the compounds or pharmaceutically salts thereof or pharmaceutical compositions disclosed herein.
  • the one or more other therapeutic agents are administered after the compounds or pharmaceutically salts thereof or pharmaceutical compositions described disclosed.
  • NMR Nuclear magnetic resonance
  • Step-8 [00144] To a stirred solution of 5-(3-methyl-2-oxopyrrolidin-3-yl)-2-((4-(trifluoromethyl) phenyl) amino) benzohydrazide (A7) (0.15 g, 0.382 mmol, 1.0 eq), in dichloromethane (1.5 mL) was added triethylamine (0.115 g, 1.146 mmol, 3.0 eq) at 0 °C. Then acetyl chloride (0.029 g, 0.382 mmol, 1.0 eq) was added at 0 °C and stirred at RT for 4 h.
  • Step-2 [00147] To a stirred solution of 4-bromo-1-methyl-1H-imidazole (CAS: 25676-75-9) (0.25 g, 1.552 mmol, 1.0 eq), in 1,4-dioxane:H 2 O (7:3) (10 mL) was added 3-methyl-3-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl) phenyl) amino) phenyl) pyrrolidin- 2-one (A9) (0.85 g, 1.863 mmol, 1.2 eq) at rt then potassium carbonate (0.64 g, 4.658 mmol, 3.0 eq) was added and purged with N 2 (g) for 30 min at RT.
  • 4-bromo-1-methyl-1H-imidazole CAS: 25676-75-9
  • the resulting mixture was allowed to warm to RT and stirring maintained for 16 h.
  • the reaction was monitored by TLC (using EtOAc: Hex; 7:3 as mobile phase) which confirmed that the reaction was completed.
  • the resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL) dried over Na 2 SO 4 and concentrated under reduced pressure to afford 1.0 g crude.
  • reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was completed after 16 h of stirring at RT.
  • the resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3x20 mL). Dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.4 g crude.
  • the resulting mixture was heated to 50 o C and stirring maintained for 8 h.
  • the reaction was monitored by TLC (using DCM: MeOH; 9:1 as mobile phase) which confirmed that the reaction was completed after 8 h of stirring at 50 o C.
  • the resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x20 mL) dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.3 g crude.
  • reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was completed after 2 h of stirring at RT.
  • the resulting reaction mixture was basified with sat. NaHCO 3 (5 mL) and extracted with EtOAc (3x10 mL) dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.09 g crude.
  • Step-2 [00158] To a solution of tert-butyl (4-(chloromethyl)-2-(1-methyl-1H-imidazol-4-yl) phenyl) (4-(trifluoromethyl) phenyl) carbamate (A15) (0.3 g, 0.645 mmol, 1.0 eq) and 3-(4- methoxybenzyl) imidazolidine-2,4-dione (A18) (0.212 g, 0.967 mmol, 1.5 eq) in ACN (3 mL) was added Cs 2 CO 3 (0.524 g, 1.612 mmol, 2.5 eq). The reaction mixture was heated to 80 °C and stirring maintained for 3 h.
  • reaction was monitored on TLC (using EA:HEX; 8:2 as mobile phase) which confirmed that the reaction was completed after 3 h.
  • the resulting reaction mixture was quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.3 g crude.
  • the resulting mixture was stirred for 3 h at room temperature.
  • the reaction was monitored on TLC (using EA:HEX; 9:1 as mobile phase) which confirmed that the reaction was completed after 3 h.
  • the resulting reaction mixture was quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.2 g crude.
  • reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was completed after 2 h of stirring at RT.
  • the resulting reaction mixture was basified with sat. NaHCO 3 (5 mL) and extracted with EtOAc (3 x 25 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.09 g.
  • RM was heated to 40 °C and was maintained for 16 h at 40 °C.
  • the reaction was monitored by TLC (using 70% EtOAc in hexane as mobile phase) which confirmed that the reaction was completed after 16 h of stirring at 40 °C.
  • reaction mixture was allowed to RT and stirred for 4 h.
  • the reaction was monitored by TLC (using 70% EtOAc in hexane as mobile phase) which confirmed that the reaction was completed after 4 h of stirring at RT.
  • the resulting reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 1.5 g crude.
  • Step-3 [00165] To a stirred solution of N-methoxy-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl) phenyl) amino) benzamide (A22) (1.0 g, 2.47 mmol, 1.0 eq) in DCM at RT was added (BOC) 2 O (0.80 g, 3.70 mmol, 1.5 eq) and DMAP (0.12 g, 0.98 mmol, 0.4 eq), under a nitrogen atmosphere. The reaction mixture was stirred for 16 h. TLC shows completion of reaction (70% EtOAc in hexane as mobile phase).
  • reaction mixture was allowed to warm to RT and was stirred for 3 h.
  • the reaction was monitored on TLC (using 50% EtOAc in hexane as mobile phase).
  • EtOAc 50% EtOAc in hexane as mobile phase.
  • EA 3 x 100 mL.
  • the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.7 g crude.
  • reaction mixture was heated up to 100 °C and was stirred for 16 h.
  • the reaction was monitored on TLC (using 70 % EtOAc in hexane as mobile phase).
  • the resulting reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.7 g crude.
  • Step-2 [00170] In a 30 mL reactor, a stirred solution of 2-iodooxazole (A26) (0.25 g, 0.54 mmol, 1.0 eq) in dioxane (2 mL) was added (A9) (0.126 g, 0.65 mmol, 1.2 eq) followed by K 2 CO 3 (0.22 g, 1.62 mmol, 3 eq) and water under N 2 atm. PdCl 2 (dppf) (0.019 g, 0.02 mmol, 0.05 eq) was added. The reactor was sealed and the reaction stirred at 90 °C for 2 h.
  • reaction was monitored by TLC (using EA:Hexane; 7.0:3.0 as mobile phase) which confirmed that the reaction got completed.
  • the resulting reaction mixture was quenched with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.3 g crude.
  • PdCl 2 (dppf) (0.0038 g, 0.050 mmol, 0.05 eq) was added at RT and the vial was then sealed and heated to 110 °C with stirring maintained for 2 h.
  • the reaction was monitored by TLC (100% ethyl acetate in hexane as mobile phase) which confirmed that the reaction was completed after 2 h of stirring at 110 °C.
  • the resulting reaction mixture was cooled at RT then poured in cold water (50 mL) and extracted with ethyl acetate (30 x 2) organic layer was dried over Na 2 SO 4 and concentrated under reduce pressure to obtain crude material which was purified by column chromatography using hexane and ethyl acetate.
  • reaction mixture was heated at 90 °C with stirring for 2 h.
  • the reaction was monitored on TLC (using DCM:MeOH; 9:1 as mobile phase).
  • the resulting reaction mixture was quenched with ice-cold water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.15 g crude.
  • Step-2 [00179] To a solution of 2-(4-nitrophenyl)acetic acid (A30) (144 g, 794.92 mmol, 1.0 eq) in DMF was added methyl (4-methoxybenzyl)glycinate (A29) (216.0 g, 1033 mmol, 1.3 eq) and DIPEA (112.7 g, 874 mmol, 1.1 eq), and the reaction mixture was stirred at RT followed by addition of HATU (453.3 g, 1192.3 mmol 1.5 eq), and the mixture was stirred for 16 h. The reaction was monitored on TLC (using EtOAc: Hex; 5:5 as mobile phase).
  • reaction mixture was heated to 100 °C, then stirred for 5 h.
  • the reaction was monitored by TLC (using: MeOH:DCM 1:9 as mobile phase) which confirmed that the reaction was complete after 5 h.
  • the resulting reaction mixture was filtered then washed with 10% MeOH in DCM (400 ml), then the aqueous layer was extracted with 10% MeOH in DCM (400 ml). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 24 g crude.
  • reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was complete after 24 h of stirring at 80 o C.
  • the resulting reaction mixture was stirred and then settled.
  • Toluene was decanted and then water (200 ml) was added, and the resulting mixture was washed with ethyl acetate (4 x 300 mL).
  • the aqueous layer was basified with NaHCO 3 then extracted with ethyl acetate (4 x 300 mL).
  • NBS (2.44 g, 13.61 mmol, 0.7 eq) was added portionwise, and the resulting mixture was stirred for 10 min.
  • the reaction was monitored by TLC (using DCM: MeOH; 7:3 as mobile phase) which confirmed that the reaction was complete.
  • the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (3 x 250 mL). The organic layer was separated and washed with ice cold water and brine, then dried over Na 2 SO 4 and concentrated under reduced pressure to afford 3.2 g crude.
  • the resulting mixture was stirred at RT and purged with N 2 (g) for 15 min, followed by addition of PdCl 2 (dppf) 2 (2.324 g, 3.18 mmol, 0.2 eq) .
  • the resulting mixture was stirred at RT and purged with N 2 (g) for 15 min, then reaction was heated in microwave to 130 o C for 30 min.
  • the reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was complete after 30 min.
  • the reaction mixture was extracted with EtOAc (2 x 200 mL). The organic layer was separated and washed with brine (200 ml), then dried over Na 2 SO 4 and concentrated under reduced pressure to afford 2.0 g crude.
  • the resulting mixture was stirred at RT in open atmosphere for 3 h.
  • the reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was complete after 3h .
  • the reaction mixture was quenched with water (200 ml) and extracted with DCM (3 x 100 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.850 g crude.
  • COLUMN ID YMC CELLULOSE SC (250 X 20 mm 5 um)
  • MOBILE PHASE A Liq.CO 2
  • MOBILE PHASE B M.NH3-HEP-IPA (70-30)
  • FLOW RATE ML/MIN
  • Input Quantity 0.1 g.
  • reaction was monitored by TLC (using DCM:MeOH; 9:1 as mobile phase) which confirmed that the reaction was complete after 30 min of stirring at RT.
  • the reaction mixture was diluted with CHCl 3 , and then NH 4 Cl solution in water (5 mL) was added.
  • the mixture was extracted with DCM (3 x 20 mL), and organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to afford 0.06 g crude.
  • TEAD1-genetically dependent cell line NCI-H226 responder cell line
  • TEAD-independent cell lines NCI-H23, HEK293T
  • TEAD inhibitor stocks were made at a 1000X fold excess in DMSO, and a dose response test compound dose range of 10,000 to 0.1 nM was used. Each treatment was carried out in triplicate. After 144hrs of treatment, relative cell viability numbers were determined using the CellTiter-Glo 2.0 assay following the manufacturer’s instructions. Test plates and CellTiter-Glo 2.0 reagent were allowed to equilibrate to room temperature. CellTiter-Glo 2.0 reagent was added at 1:1 reagent to media ratio to the 96-well cell plates, plates were placed on a plate shaker for 2 minutes and then incubated at room temperature for a further 10 minutes to allow complete cell lysis to occur.
  • TEAD inhibitors disclosed herein were evaluated for the effects on cell proliferation responder (H226) and non-responder negative control cancer cell lines (CAMA1, H28), as well as non-transformed normal human cells (HUVEC, NHDF). Dissociated cells were resuspend in media (depending on cell line, either in DMEM, RPMI, or EMEM all with 10% FBS, with gentamicin as an antibiotic). Cells were seeded at 100 ⁇ L/well at 750 cells per well in 96-well plates and allowed to settle and attach.
  • test compound-containing media After an incubation of 24 hrs (370C, 5% CO 2 , humidified incubator), 100 ⁇ L of test compound-containing media was added. A dilution series of 2000X concentrated stock of test compounds was prepared in DMSO, for final concentrations from 0.1 to 10,000 nM. After addition of test compound-containing media, cells were incubated for 6 days at 370C, 5% CO 2 , humidified incubators). To measure cell density, 20 ⁇ L of Promega Substrate Cell Titer 96 Aqueous One Solution Reagent (Promega, # G3582) to each well was added according to the manufacturer's instructions.
  • the plated cells were incubated overnight at 37 °C, 5% CO 2 before being treated with compounds in triplicate for each assay point.50 ⁇ l of the serially diluted compound was added to each well giving a final DMSO concentration of 0.5% per well and a total volume of 250 ⁇ l per well. The treated cells were incubated for 144 hours (6 days) at 37 °C, 5% CO2. Following compound treatment the remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 ⁇ l of media was removed from each of the wells to be assayed and 100 ⁇ l of room temperature CellTiter-Glo 2.0 reagent was added.
  • the plate was placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, and then incubated without shaking for a further 10 minutes at room temperature.150 ⁇ l of cell lysate was removed from each well and dispensed into a single well of a white opaque 96 well plate. Luminescence at 545 nm was read using a BMG CLARIOstar plate reader. The luminescent signal was directly proportional to number of viable cells, the percent of viable cells relative to the DMSO control was then calculated for each assay point. Percent viability relative to DMSO control is plotted against compound concentration and a curve fitted with non-linear regression in GraphPad Prism software.
  • Area Under the Curve (AUC) Prism computed area-under-the-curve by the trapezoidal method. The analysis sees a fitted curve as simply a series of connected XY points. Prism simply computes the area under the "curve” defined by connecting the points by straight lines. The units of the AUC are the units of the Y axis times units of the X axis.
  • the plated cells were incubated overnight at 37 °C, 5% CO 2 before being treated with compounds in triplicate for each assay point.50 ⁇ l of the serially diluted compound was added to each well giving a final DMSO concentration of 0.5% per well and a total volume of 250 ⁇ l per well. The treated cells were incubated for 144 hours (6 days) at 37 °C, 5% CO 2 . Following compound treatment, the remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 ⁇ l of media was removed from each of the wells to be assayed and 100 ⁇ l of room temperature CellTiter-Glo 2.0 reagent was added.
  • the plate was placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, and then incubated without shaking for a further 10 minutes at room temperature.150 ⁇ l of cell lysate was removed from each well and dispensed into a single well of a white opaque 96 well plate. Luminescence at 545 nm was read using a BMG CLARIOstar plate reader. The luminescent signal was directly proportional to number of viable cells, the percent of viable cells relative to the DMSO control was then calculated for each assay point. Percent viability relative to DMSO control was plotted against compound concentration and a curve fitted with non-linear regression in GraphPad Prism software.
  • Area Under the Curve (AUC) Prism computes area-under-the-curve by the trapezoidal method. The analysis sees a fitted curve as simply a series of connected XY points. Prism simply computes the area under the "curve” defined by connecting the points by straight lines. The units of the AUC are the units of the Y axis times units of the X axis.
  • the symbol “A” indicates a value of less than 0.2 ⁇ M; the symbol “B” indicates a value in the range of from 0.2 ⁇ M up to 1 ⁇ M; and the symbol “C” indicates a value of greater than 1 ⁇ M.
  • Table 7. Cytotoxic potency measured by CTG assay for Mero82 cell line EXAMPLE 22 – BHY Proliferation and Cell Viability Assay [00204] BHY cells were trypsinised, counted and plated at 2500 cells/well in 200 ⁇ l of growth media in 96 well flat bottom tissue culture treated plates.
  • the plated cells were incubated overnight at 37 0C, 5% CO2 before being treated with compounds in triplicate for each assay point.50 ⁇ l of the serially diluted compound was added to each well giving a final DMSO concentration of 0.5% per well and a total volume of 250 ⁇ l per well. The treated cells were incubated for 144 hours (6 days) at 37 0C, 5% CO 2 . Following compound treatment, the remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 ⁇ l of media was removed from each of the wells to be assayed and 100 ⁇ l of room temperature CellTiter-Glo 2.0 reagent was added.
  • the plate was placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, and then incubated without shaking for a further 10 minutes at room temperature.150 ⁇ l of cell lysate was removed from each well and dispensed into a single well of a white opaque 96 well plate. Luminescence at 545 nm was read using a BMG CLARIOstar plate reader. The luminescent signal was directly proportional to number of viable cells, the percent of viable cells relative to the DMSO control was then calculated for each assay point. Percent viability relative to DMSO control was plotted against compound concentration and a curve fitted with non-linear regression in GraphPad Prism software.
  • the symbol “A” indicates a value of less than 0.2 ⁇ M; the symbol “B” indicates a value in the range of from 0.2 ⁇ M up to 1 ⁇ M; and the symbol “C” indicates a value of greater than 1 ⁇ M.
  • Table 8. Cytotoxic potency measured by CTG assay for BHY cell line EXAMPLE 23 – LOU-NH91 Proliferation and Cell Viability Assay [00206] LOU-NH91 cells were trypsinised, counted and plated at 1000 cells/well in 200 ⁇ l of growth media in 96 well flat bottom tissue culture treated plates.
  • the plated cells were incubated overnight at 37 0C, 5% CO 2 before being treated with compounds in triplicate for each assay point.50 ⁇ l of the serially diluted compound was added to each well giving a final DMSO concentration of 0.5% per well and a total volume of 250 ⁇ l per well. The treated cells were incubated for 216 hours (9 days) at 37 0C, 5% CO 2 . Following compound treatment, the remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 ⁇ l of media was removed from each of the wells to be assayed and 100 ⁇ l of room temperature CellTiter-Glo 2.0 reagent was added.
  • the plate was placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, and then incubated without shaking for a further 10 minutes at room temperature.150 ⁇ l of cell lysate was removed from each well and dispensed into a single well of a white opaque 96 well plate. Luminescence at 545 nm was read using a BMG CLARIOstar plate reader. The luminescent signal was directly proportional to number of viable cells, the percent of viable cells relative to the DMSO control was then calculated for each assay point. Percent viability relative to DMSO control was plotted against compound concentration and a curve fitted with non-linear regression in GraphPad Prism software.
  • Area Under the Curve (AUC) Prism computes area-under-the-curve by the trapezoidal method. The analysis sees a fitted curve as simply a series of connected XY points. Prism simply computes the area under the "curve" defined by connecting the points by straight lines. The units of the AUC are the units of the Y axis times units of the X axis.
  • the symbol “A” indicates a value of less than 0.2 ⁇ M; the symbol “B” indicates a value in the range of from 0.2 ⁇ M up to 1 ⁇ M; and the symbol “C” indicates a value of greater than 1 ⁇ M.
  • Table 9. Cytotoxic potency measured by CTG assay for LOU-NH91 cell line EXAMPLE 24 – MSTO-211H Proliferation and Cell Viability Assay [00208] MSTO-211H cells were trypsinised, counted and plated at 1500 cells/well in 200 ⁇ l of growth media in 96 well flat bottom tissue culture treated plates.
  • the plated cells were incubated overnight at 37 0C, 5% CO 2 before being treated with compounds in triplicate for each assay point.50 ⁇ l of the serially diluted compound was added to each well giving a final DMSO concentration of 0.5% per well and a total volume of 250 ⁇ l per well. The treated cells were incubated for 144 hours (6 days) at 37 0C, 5% CO 2 . Following compound treatment, the remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 ⁇ l of media was removed from each of the wells to be assayed and 100 ⁇ l of room temperature CellTiter-Glo 2.0 reagent was added.
  • the plate was placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, and then incubated without shaking for a further 10 minutes at room temperature.150 ⁇ l of cell lysate was removed from each well and dispensed into a single well of a white opaque 96 well plate. Luminescence at 545 nm was read using a BMG CLARIOstar plate reader. The luminescent signal was directly proportional to number of viable cells, the percent of viable cells relative to the DMSO control was then calculated for each assay point. Percent viability relative to DMSO control was plotted against compound concentration and a curve fitted with non-linear regression in GraphPad Prism software.
  • Area Under the Curve (AUC) Prism computes area-under-the-curve by the trapezoidal method. The analysis sees a fitted curve as simply a series of connected XY points. Prism simply computes the area under the "curve" defined by connecting the points by straight lines. The units of the AUC are the units of the Y axis times units of the X axis.
  • the plated cells were incubated overnight at 37 0C, 5% CO 2 before being treated with compounds in triplicate for each assay point.50 ⁇ l of the serially diluted compound was added to each well giving a final DMSO concentration of 0.5% per well and a total volume of 250 ⁇ l per well. The treated cells were incubated for 144 hours (6 days) at 37 0C, 5% CO 2 . Following compound treatment the remaining viable cells were detected using the Promega CellTiter-Glo 2.0 assay as follows: 150 ⁇ l of media was removed from each of the wells to be assayed and 100 ⁇ l of room temperature CellTiter-Glo 2.0 reagent was added.
  • the plate was placed on an orbital shaker at 500 rpm at room temperature for 2 minutes, and then incubated without shaking for a further 10 minutes at room temperature.150 ⁇ l of cell lysate was removed from each well and dispensed into a single well of a white opaque 96 well plate. Luminescence at 545nm was read using a BMG CLARIOstar plate reader. The luminescent signal was directly proportional to number of viable cells, the percent of viable cells relative to the DMSO control was then calculated for each assay point. Percent viability relative to DMSO control was plotted against compound concentration and a curve fitted with non-linear regression in GraphPad Prism software.
  • Area Under the Curve (AUC) Prism computes area-under-the-curve by the trapezoidal method. The analysis sees a fitted curve as simply a series of connected XY points. Prism simply computes the area under the "curve" defined by connecting the points by straight lines. The units of the AUC are the units of the Y axis times units of the X axis.
  • TSA Thermal shift assay
  • SYPRO Orange binds non-specifically to hydrophobic surfaces, and water strongly quenches its fluorescence.
  • the exposed hydrophobic surfaces bind the dye, resulting in an increase in fluorescence by excluding water.
  • Detergent micelles also bind the dye and increase background noise dramatically. Binding of small molecules to proteins leads to a stabilization against to thermal denaturation with the degree of thermal stabilization proportional to the strength of binding.
  • ⁇ Tm melting temperature
  • Tumor Cell Information Tumor Inoculation [00219] Each mouse was inoculated subcutaneously at the right flank with MSTO-211H tumor cells (5 ⁇ 10 6 + 50% matrigel/0.2 mL) for tumor development. Animals were marked with earrings with unique 6 significant figure number for identification. The treatments of part 1 were started on day 5 after cell inoculation when the average tumor volume reached 181 mm 3 . The treatments of part 2 were started on day 16 after cell inoculation when the average tumor volume reached 254 mm 3 . The treatments of part 3 were started on day 33 after cell inoculation when the average tumor volume reached 969 mm 3 .
  • Tumor Measurement [00220] The major endpoint was to determine if the tumor growth could be delayed.
  • the tumor size was then used for calculations of T/C value.
  • the TGI value (in percent) or the T/C value (in percent) is an indication of antitumor effectiveness; T and C are the mean tumor volumes or tumor weights of the treated and control groups, respectively, on a given day.
  • TGI of part 1 was calculated based on tumor volume measurements on PG-D31 after the start of the treatment (Table 16).
  • TGI of part 2 was calculated based on tumor volume measurements on PG-D30 after the start of the treatment (Table 17).
  • TGI of part 3 was calculated based on tumor volume measurements on PG-D13 after the start of the treatment (Table 18). Table 16. Tumor size on day 31 of study part 1.
  • T/C(%) T RTV / C RTV ⁇ 100
  • TGI [1-(T i -T 0 )/ (V i -V 0 )] ⁇ 100.
  • T/C(%) T RTV / C RTV ⁇ 100
  • TGI [1-(T i -T 0 )/ (V i -V 0 )] ⁇ 100.
  • Tumor Inoculation Each mouse was inoculated subcutaneously at the right flank with MSTO-211H tumor cells (10 ⁇ 10 6 + 50% matrigel/0.2 mL) for tumor development. Test subjects received vehicle (e.g., 0.5% CMC-Na + 1% Tween80) beginning on day 7 after cell inoculation. Treatment began on day 28 after cell inoculation when the tumor volumes reached 500 mm 3 to 1200 mm 3 . Compound Preparation Tumor Measurement [00237] The major endpoint was to determine if the tumor growth could be delayed.
  • the tumor size was then used for calculations of T/C value and TGI values.
  • the T/C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volume of the treated and control groups, respectively, on a given day.
  • SEM standard error of the mean
  • FIG.3A provides tumor volume changes for individual test subjects
  • FIG.3B provides the mean tumor volume changes for each treatment group. Tumor growth was observed in the Vehicle and Compound 1-1 treatment groups, while tumor reduction was observed in the Compound 5 treatment group.
  • EXAMPLE 29 Inhibition of mouse xenograft NCI-H226 tumors with TEAD inhibitors [00243] This study evaluated the in vivo anti-tumor efficacy of test compounds in NOD SCID mice for treatment of NCI-H226 lung tumor model.
  • N animal number in each group.
  • Dose volume adjust dose volume based on body weight 10 ⁇ L/g.
  • Treatment schedule was adjusted if body weight loss > 15%.
  • Cell Culture [00244] The NCI-H226 tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% Fetal bovine serum and 1% Antibiotic-Antimycotic at 37oC in an atmosphere of 5% CO 2 in air. The tumor cells were routinely subcultured twice weekly by trypsin-EDTA. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • Tumor Cell Information Tumor Inoculation Each mouse was inoculated subcutaneously at the right flank with NCI-H226 tumor cells (10 ⁇ 10 6 + 50% matrigel/0.2 mL) for tumor development. Animals were marked with earrings with unique 6 significant figure number for identification. The treatments were started when the average tumor volume reached an average size of 154 mm 3 .
  • TGI value in percent
  • T/C value in percent
  • Tumor volume Trace [00254] The change in tumor volume over the course of the study is provided in Table 19. Table 19. Tumor size over course of study. Note: a. Mean ⁇ SEM Tumor Growth Inhibition Analysis [00255] Tumor growth inhibition rate for the test compounds was calculated based on tumor volume measurement at day 28 after the start of treatment. The T/C values calculated according to tumor volume are close to each other, and the trend is shown in Table 20. Table 20. Tumor size on day 28. b.
  • T/C(%) T RTV / C RTV ⁇ 100
  • TGI [1-(T i -T 0 )/ (V i -V 0 )] ⁇ 100.

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Abstract

La présente invention concerne, en partie, des composés de formule (I) : dans laquelle les variables sont telles que définies dans la description, des compositions pharmaceutiques comprenant les composés, et des procédés d'utilisation des composés pour traiter des troubles physiologiques, tels que des troubles prolifératifs, médiés par des facteurs de transcription de domaine TEA.
PCT/US2023/070353 2022-07-21 2023-07-17 Inhibiteurs de tead et procédés d'utilisation Ceased WO2024020350A1 (fr)

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EP23752144.8A EP4558485A1 (fr) 2022-07-21 2023-07-17 Inhibiteurs de tead et procédés d'utilisation
AU2023308983A AU2023308983A1 (en) 2022-07-21 2023-07-17 Tead inhibitors and methods of use
CN202380055158.6A CN119497708A (zh) 2022-07-21 2023-07-17 Tead抑制剂和使用方法
KR1020257005344A KR20250038764A (ko) 2022-07-21 2023-07-17 Tead 억제제 및 사용 방법

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014165143A1 (fr) * 2013-03-12 2014-10-09 Abbvie Inc. Inhibiteurs de bromodomaine dihydro-pyrrolopyridinone
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations

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Publication number Priority date Publication date Assignee Title
WO2014165143A1 (fr) * 2013-03-12 2014-10-09 Abbvie Inc. Inhibiteurs de bromodomaine dihydro-pyrrolopyridinone
WO2020243423A1 (fr) * 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations

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TANG ET AL.: "Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma", MOL. CANCER THER, vol. 20, no. 6, 2021, pages 986 - 998, XP055875212, DOI: 10.1158/1535-7163.MCT-20-0717

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