WO2023209088A1 - Composés hétéroaromatiques bicycliques et leur utilisation dans le traitement du cancer - Google Patents

Composés hétéroaromatiques bicycliques et leur utilisation dans le traitement du cancer Download PDF

Info

Publication number
WO2023209088A1
WO2023209088A1 PCT/EP2023/061109 EP2023061109W WO2023209088A1 WO 2023209088 A1 WO2023209088 A1 WO 2023209088A1 EP 2023061109 W EP2023061109 W EP 2023061109W WO 2023209088 A1 WO2023209088 A1 WO 2023209088A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
formula
acceptable salt
mmol
Prior art date
Application number
PCT/EP2023/061109
Other languages
English (en)
Inventor
Scott Nathan MLYNARSKI
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2023209088A1 publication Critical patent/WO2023209088A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links

Definitions

  • This specification relates to certain heteroaromatic compounds and pharmaceutically acceptable salts thereof that inhibit TEAD, and their use in treating cancer. This specification also relates to processes and intermediate compounds involved in the preparation of the heteroaromatic compounds and to pharmaceutical compositions containing them.
  • the Hippo pathway is a highly conserved signaling pathway that controls organ size and tissue maintenance through the regulation of gene expression programs involved in cell proliferation, survival, and differentiation (Dong et al., Cell 2007, 1120-33; Ma et al., Ann Rev Biochem 2018, 577- 604 and references therein). Hippo ultimately regulates the transcription coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) which bind to DNA-bound Transcriptional Enhanced Associate Domain proteins (TEAD1-4) to form bipartite transcription complexes that activate TEAD-dependent gene expression.
  • YAP Yes-associated protein
  • TEZ transcriptional coactivator with PDZ-binding motif
  • TEAD1-4 DNA-bound Transcriptional Enhanced Associate Domain proteins
  • LATS1/2 When Hippo signaling is active, the kinases LATS1/2 phosphorylate YAP/TAZ which causes these proteins to be sequestered in the cytoplasm or degraded by the proteasome. When Hippo signaling is inactive, LATS1/2 are inactivated resulting in YAP/TAZ to be dephosphorylated and subsequently translocated into the nucleus to interact with and activate TEAD-dependent transcription (Meng et al., Genes&Dev 2016, 1-17).
  • Hippo signaling is a well-established tumor suppressor pathway and data from The Cancer Genome Atlas show that the Hippo pathway is one of eight signaling pathways that are frequently altered in human cancer (Sanchez-Vega et al., Cell 2018, 321-337). Both genetic and epigenetic alterations of Hippo components can result in aberrant activation of YAP/TAZ and TEAD-dependent transcription and have been implicated in several human malignancies (Wang et al., 2018, 1304-1317).
  • NF2 (aka Merlin) is encoded by the neurofibromatosis type 2 gene and is a key upstream regulator of the Hippo core kinase cascade consisting of STE20-like protein kinase 1 (STK3, aka MST2, and STK4, aka MST1), the large tumor suppressors (LATS1 and LATS2), and adaptor proteins Salvador homolog 1 (SAV1) and MOB kinase activators (MOB1A/MOB1B) (Tapon et al., Cell 2002, 467-478).
  • STK3, STE20-like protein kinase 1 STK3, aka MST2, and STK4, aka MST1
  • LATS1 and LATS2 large tumor suppressors
  • SAV1A/MOB1B adaptor proteins Salvador homolog 1
  • MOB1A/MOB1B MOB kinase activators
  • the compounds of the specification provide an anti-cancer effect by, as a minimum, acting as TEAD inhibitors.
  • the compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and/or greater chemical stability), and/or favourable toxicity profiles (for example a decreased activity at hERG), and/or favourable metabolic or pharmacokinetic profiles, in comparison with other known TEAD inhibitors.
  • Such compounds may therefore be especially suitable as therapeutic agents, particularly for the treatment of cancer.
  • X 1 and X 2 are independently selected from CH and N;
  • L is a covalent bond, O or CH?; either X 3 is CH and X 4 is selected from CR 5 and N, or X 3 is N and X 4 is CR 5 ;
  • R 1 is Ci-4 alkyl or C3-4 cycloalkyl
  • R 2 is selected from H and R 1 , wherein R 1 is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy;
  • R 3 , R 4 and R 5 are independently selected from H, C1-4 fluoroalkyl, C1-4 alkoxy, -S(Ci_ 4 alkyl), -O(Ci_ 4 fluoroalkyl), -S(Ci_ 4 fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R j and R k , wherein R j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C1.4 fluoroalkyl and R k is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy;
  • G is selected from
  • R 7 is H, Ci-4 alkoxy, R 10 or R 11 ; either R 8 and R 9 are independently selected from H, R 10 and R 11 ; or R 8 and R 9 , together with the carbon atom to which they are attached, form a cyclopropane or cyclobutane ring; each R 10 is independently C1.4 alkyl optionally substituted with Ci- 4 alkoxy, N(Ci. 4 alkyl) 2 or OH; each R 11 is independently C3-4 cycloalkyl optionally substituted with Ci- 4 alkoxy or OH;
  • R 12 is H or F
  • R 13 is H, CH 2 F or CH 3 ; wherein a Ci- 4 fluoroalkyl is a saturated linear or branched hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; and wherein a C3-4 fluorocycloalkyl is a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; or a pharmaceutically acceptable salt thereof.
  • a Ci- 4 fluoroalkyl is a saturated linear or branched hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom
  • a C3-4 fluorocycloalkyl is a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms.
  • C x-y indicates the numerical range of carbon atoms that are present in the group.
  • suitable C1-3 alkyl groups include methyl, ethyl, n-propyl, and i-propyl.
  • suitable C1-4 alkyl groups include methyl, ethyl, n-propyl, and i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
  • cycloalkyl refers to a saturated, cyclic hydrocarbon radical having the specified number of carbon atoms.
  • Examples of C3-4 cycloalkyl groups are cyclopropyl and cyclobutyl.
  • fluoroalkyl refers to saturated linear or branched hydrocarbon radicals having the specified number of carbon atoms, wherein at least one hydrogen atom is substituted for a fluorine atom.
  • suitable C1-4 fluoroalkyl groups include fluoromethyl (CFH2), difluoromethyl (CF2H), trifluoromethyl (CF3), 1,1-difluoroethyl (CF2CH3), 2,2,2-trifluoroethyl (CH2CF3) and 3-fluoropropyl (CH2CH2CH2F).
  • fluorocycloalkyl refers to saturated cyclic hydrocarbon radicals having the specified number of carbon atoms, wherein at least one hydrogen atom is substituted for a fluorine atom.
  • suitable C3-4 fluorocycloalkyl groups include 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4- difluorocyclobutyl and 2,3,4-trifluorocyclobutyL
  • alkoxy refers to a saturated group comprising the specified number of carbon atoms and one oxygen atom.
  • the alkoxy group may be a straight chain or a branched chain.
  • suitable C1.4 alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O”Pr) and i-propoxy (O'Pr), n-butoxy (O”Bu), i-butoxy (O'Bu), s-butoxy (O s Bu) and t- butoxy (C ⁇ Bu).
  • the bonding of an atom or group may be any suitable atom of that group; for example, propyl includes prop-l-yl and prop-2-yl.
  • the selected substituents may comprise the same substituents or different substituents from within the given group.
  • HN' CH3 attachment between different groups denotes a methylamide group which is attached to a different group through the nitrogen atom.
  • this specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein X 1 is CH and X 2 is CH, X 1 is N and X 2 is CH or X 1 is CH and X 2 is N.
  • the compound of Formula (I) is a compound of Formula (II): wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 3 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (III): wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 3 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IV): wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 3 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IA): wherein:
  • X 1 is CH or N
  • X 2 is CH or N
  • the compound of Formula (I) is a compound of Formula (I IA): wherein R 1 , R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (I I IA): wherein R 1 , R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IVA): wherein R 1 , R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA) or a pharmaceutically acceptable salt thereof wherein R 4 is selected from H, C1-4 fluoroalkyl, C1-4 alkoxy, -S(Ci_ 4 alkyl), -O(Ci- 4 fluoroalkyl), -S(Ci. 4 fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R j and R k , wherein R j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C1-4 fluoroalkyl (i.e.
  • R k is C1-4 alkyl optionally substituted with - CN or C1-4 alkoxy (i.e. C1-4 alkyl, C1-4 alkyl substituted with -CN, or C1-4 alkyl substituted with C1-4 alkoxy).
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein R 4 is CF2H, CF2CH3, CF3, OCF3, OCF2H or SCF3, such as CF3.
  • R 5 is selected from H, F, Cl and C1-4 alkyl (such as CH 3 ).
  • R 3 and R 5 are independently selected from H, Cl, F and C1-4 alkyl (such as CH3), and R 4 is C1-4 fluoroalkyl (such as CF3, CF2CH3 or CF2H), -O(Ci_ 4 fluoroalkyl) (such as OCF3 or OCF2H) and -S(Ci_ 4 fluoroalkyl) (such as SCF3).
  • R 3 and R 5 are both H
  • R 4 is C1-4 fluoroalkyl (such as CF3, CF2CH3 or CF2H), -O(Ci_ 4 fluoroalkyl) (such as OCF3 or OCF2H) and -S(Ci_ 4 fluoroalkyl) (such as SCF3).
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein R 8 and R 9 are independently selected from H, R 10 and R 11 , wherein R 10 is C1-4 alkyl optionally substituted with C1-4 alkoxy or OH (i.e. C1-4 alkyl, C1-4 alkyl substituted with C1-4 alkoxy, or C1-4 alkyl substituted with OH), and wherein R 11 is C3-4 cycloalkyl optionally substituted with C1-4 alkoxy or OH (i.e. C3-4 cycloalkyl, C3-4 cycloalkyl substituted with C1-4 alkoxy, or C3-4 cycloalkyl substituted with OH).
  • the compound of Formula (I) is a compound of Formula (IB): wherein:
  • X 3 is CH or N
  • R 1 is Ci-4 alkyl
  • R 3 and R 5 are independently selected from H, F, Cl and C1-4 alkyl
  • R 4 is Ci-4 fluoroalkyl, -O(Ci_ 4 fluoroalkyl) or -S(Ci_ 4 fluoroalkyl);
  • R 11 is C3-4 cycloalkyl optionally substituted with C1-4 alkoxy or OH, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (IB) or a pharmaceutically acceptable salt thereof wherein R 3 and R 5 are H, and optionally R 4 is CF 2 H, CF3, OCF3 or SCF3.
  • a compound of Formula (IB) or a pharmaceutically acceptable salt thereof wherein R 3 and R 5 are H, and R 4 is CF3.
  • R 6 is H, OH, F, CH2OH or CH2OCH3, such as H.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof that is (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(4- (trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof selected from: (S)-4-((l-acryloylpyrrolidin-3-yl)amino)-6-methyl-l-(4-(trifluoromethyl)phenyl)pyrido[3,4- d]pyridazin-5(6H)-one, (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethyl)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one, (S)-5-((l-acryloylpyrrolidin-3-yl)amino)-3-methyl-8-(5-(trifluoromethoxy)pyridin-2-yl)pyrido[4,3- d]pyrimidin-4(3H)-one, 5-(((3R,4S)-l-acrylo
  • a further feature is any of the embodiments described in the specification with the proviso that any of the specific Examples are individually disclaimed.
  • a further feature is any of the embodiments described in the specification with the proviso that any one or more of the compounds selected from the above list of Examples of compounds of the specification are individually disclaimed.
  • the compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the chemical structure or chemical name is intended to embrace all possible stereoisomers, diastereoisomers, conformers, rotamers and tautomers of the compound depicted.
  • a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R).
  • a pharmaceutical composition which comprises a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.
  • the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or other stoichiometry of hydrate) and/or solvated forms.
  • hydrated e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or other stoichiometry of hydrate
  • isotopes will be understood to include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include 13 C and 14 C.
  • Isotopes of nitrogen include 15 N.
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB) is, for example, an acid addition salt.
  • An acid addition salt of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • a further suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA), (II), (I IA), (III), ( 11 IA), (IV), (IVA) or (IB) is, for example, a salt formed within a patient's body after administration of a compound of Formula (I), (IA), (II), ( I IA), (III), ( II IA), (IV), (IVA) or (IB) to the patient.
  • the compound of Formula (I), (IA), (II), (HA), (III), (I II A), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof may be prepared as a co-crystal solid form. It is to be understood that a pharmaceutically acceptable co-crystal of an compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or pharmaceutically acceptable salts thereof, form an aspect of the present specification.
  • a pharmaceutical composition comprising a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile.
  • a pharmaceutical composition according to the present specification will comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • compositions An effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, will normally be present in the composition.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible.
  • the compositions may be administered at varying doses.
  • the pharmaceutical formulations of the compound of Formula (I) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.
  • compositions of the compound of Formula (I) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
  • compositions suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifying agents; and preservatives Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of Formula (I) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.
  • SEG soft elastic gelatin
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by TEAD, including cancer.
  • cancer includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases.
  • therapy is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • therapy also includes “prophylaxis” unless there are specific indications to the contrary.
  • therapeutic and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer (HCC),
  • the cancer that exhibits an elevated TEAD transcriptional signature is hepatocellular cancer (HCC), gastric cancer or prostate cancer.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof for use in the treatment of EGFR mutationpositive cancer such as non-small cell lung cancer.
  • the EGFR mutationpositive cancer comprises at least one activating mutation in EGFR selected from exon 19 deletions and L858R substitution mutations.
  • the EGFR mutation-positive cancer comprises an EGFR T790M resistance mutation.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (ll) 7 ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.
  • Terms such as “treating” or “treatment” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • a patient is successfully "treated” for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.
  • an effective amount means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • patient refers to any animal (e.g., a mammal), including, but not limited to humans, nonhuman primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • patient refers to a human subject.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumour (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, melanoma and mesothelioma (such as malignant pleural mesothelioma).
  • the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer,
  • a method of treating hippo mutation-positive cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.
  • the hippo mutation-positive cancer is hippo mutation-positive mesothelioma.
  • a method of treating lung cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( 11 IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.
  • a method of treating non-small cell lung cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), ( 11 A), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (IA), (II), ( I IA), (III), ( II IA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof is for use in combination with conventional surgery, radiotherapy, chemotherapy and/or immunotherapy.
  • Such chemotherapy could be administered concurrently, simultaneously, sequentially or separately to treatment with the TEAD inhibitor of the present disclosure.
  • a combination for use in the treatment of cancer comprising a compound of the Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and an additional anti-tumour agent.
  • the additional anti-tumour argent is a selected from an EGFR inhibitor, KRAS inhibitor, BRAF inhibitor, CDK4/6 inhibitor, MEK inhibitor, MET inhibitor, PI3K inhibitor, AKT inhibitor or ALK inhibitor.
  • the additional anti-tumour agent may be a third generation EGFR TKL
  • Third-generation EGFR TKIs are inhibitors of EGFR bearing activating mutations that also significantly inhibit EGFR bearing the T790M mutation and do not significantly inhibit wild-type EGFR.
  • Examples of third-generation TKIs include compounds of Formula (I), osimertinib, AZD3759, lazertinib, fasciartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, PF-06747775 (mavelertinib), avitinib (abivertinib), alflutinib (AST2818) and CXCK-101 (RX-518), HS-10296 and BPI-7711.
  • oritinib SH-1028
  • Befotertinib D-0316
  • ASK-120067 ZN-e4
  • YZJ-0318 TL007
  • XZP kenaitinib
  • YK-029A SLC005-I
  • TY-9591 TY-9591
  • XZP-5809-TT1 ZSP0391
  • TQB3456 TQB3456
  • the third- generation EGFR TKI is selected from osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alf I utinib or a pharmaceutically acceptable salt thereof, CXCK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and BPI-7711 or a pharmaceutically acceptable salt thereof.
  • the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.
  • Osimertinib The free base of osimertinib is known by the chemical name: /V-(2- ⁇ 2-dimethylamino ethyl-methylamino ⁇ -4-methoxy-5- ⁇ [4-(l-methylindol-3-yl)pyrimidin-2-yl]amino ⁇ phenyl) prop-2- enamide.
  • Osimertinib is described in WO 2013/014448, the contents of which is incorporated by reference.
  • Osimertinib is also known as AZD9291.
  • Osimertinib may be found in the form of the mesylate salt: /V-(2- ⁇ 2-dimethylamino ethyl-methylamino ⁇ -4-methoxy-5- ⁇ [4-(l-methylindol-3- yl)pyrimidin-2-yl]amino ⁇ phenyl) prop-2-enamide mesylate salt.
  • Osimertinib mesylate is also known as TAGRISSOTM.
  • Osimertinib mesylate is currently approved as an oral once daily tablet formulation, at a dose of 80 mg (expressed as free base, equivalent to 95.4 mg osimertinib mesylate), for the treatment of metastatic EGFR T790M mutation positive NSCLC patients.
  • a 40 mg oral once daily tablet formulation (expressed as free base, equivalent to 47.7 mg osimertinib mesylate) is available should dose modification be required.
  • the tablet core comprises pharmaceutical diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropyl cellulose) and lubricants (such as sodium stearyl fumarate).
  • the tablet formulation is described in WO 2015/101791, the contents of which is incorporated by reference.
  • AZD3759 The free base of AZD3759 is known by the chemical name: 4-[(3-chloro-2- fluorophenyl)amino]-7-methoxy-6-quinazolinyl (2R)-2,4-dimethyl-l-piperazinecarboxylate. AZD3759 is described in WO 2014/135876, the contents of which is incorporated by reference.
  • Lazertinib The free base of lazertinib is known by the chemical name /V- ⁇ 5-[(4- ⁇ 4- [(dimethylamino)methyl]-3-phenyl-lH-pyrazol-l-yl ⁇ -2-pyrimidinyl)amino]-4-methoxy-2-(4- morpholinyl)phenyl ⁇ acrylamide.
  • Lazertinib is described in WO 2016/060443, the contents of which is incorporated by reference.
  • Lazertinib is also known by the names YH25448 and GNS-1480.
  • Nazartinib The free base of Nazartinib is known by the chemical name: N-(7-chloro-l-(l-(4- (dimethylamino)but-2-enoyl)azepan-3-yl)-lH- benzordlimidazol-2-yl)-2-methylisonicotinamide. Nazartinib is disclosed in WO 2013/184757, the contents of which is incorporated by reference.
  • Avitinib (abivertinib): The free base of avitinib is known by the chemical name: N-(3-((2-((3-fluoro-4- (4-methylpiperazin-l-yl)phenyl)amino)-7H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)phenyl)prop-2-enamide.
  • Avitinib is disclosed in US2014038940, the contents of which is incorporated by reference.
  • Avitinib is also known as abivertinib.
  • Alf I utinib (furmonertinib): The free base of alf I utinib is known by the chemical name: N - ⁇ 2- ⁇ [2- (dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxyl)-5- ⁇ [4-(l-methyl-lH -indol-3- yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide.
  • Alfl utinib is disclosed in WO 2016/15453, the contents of which is incorporated by reference.
  • Alflutinib is also known as AST2818.
  • Afatinib The free base of afatinib is known by the chemical name: /V-[4-(3-chloro-4-fluoroanilino)-7- [(3S)-oxolan-3-yl] oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide.
  • Afatinib is disclosed in WO 02/50043, the contents of which is incorporated by reference.
  • Afatinib is also known as Gilotrif.
  • CK-101 The free base of CK-101 is known by the chemical name: /V-(3-(2-((2,3-difluoro-4-(4-(2- hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.
  • CK-101 is disclosed in WO 2015/027222, the contents of which is incorporated by reference.
  • CK-101 is also known as RX- 518.
  • HS-10296 (aumolertinib): The free base of HS-10296 is known by the chemical name: /V-[5-[[4-(l- cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy- phenyl]prop-2-enamide.
  • HS-10296 is disclosed in WO 2016/054987, the contents of which is incorporated by reference.
  • BPI-7711 The free base of BPI-7711 is known by the chemical name: /V-[2-[2- (dimethylamino)ethoxy]-4-methoxy-5-[[4-(l-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2- enamide.
  • BPI-7711 is disclosed in WO 2016/94821, the contents of which is incorporated by reference.
  • Dacomitinib The free form of dacomitinib is known by the chemical name: (2Ej-/V- ⁇ 4-[(3-chloro-4- fluorophenyl)amino]-7-methoxyquinazolin-6-yl ⁇ -4-(piperidin-l-yl)but-2-enamide. Dacomitinib is described in WO 2005/107758, the contents of which is incorporated by reference. Dacomitinib is also known by the name PF-00299804.
  • a combination for use in the treatment of cancer comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and a third generation EGFR TKI.
  • a combination for use in the treatment of cancer comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof and osimertinib, or a pharmaceutically acceptable salt thereof.
  • joint treatment refers to simultaneous, separate or sequential administration.
  • conjoint treatment refers to simultaneous administration.
  • conjoint treatment refers to separate administration.
  • conjoint treatment refers to sequential administration.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said patient, where the amounts of the compound of Formula (I), (IA), (II), (HA), (III), (I I IA), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering a third generation EGFR TKI to said patient, where the amounts of the compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or pharmaceutically acceptable salt thereof, and the third generation EGFR TKI are jointly effective in producing an anti-cancer effect.
  • a method of treating cancer such as non-small cell lung cancer, in a patient comprising administering to the patient an effective amount of a compound of Formula (I),
  • the third-generation EGFR TKI is selected from osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alf I utinib or a pharmaceutically acceptable salt thereof, CXCK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and BPI-7711 or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (HA), (III), ( I II A), (IV), (IVA) or (IB), or a pharmaceutically acceptable salt thereof, wherein the cancer is resistant to treatment with an EGFR TKI.
  • the compounds of the Formula (I) are primarily of value as therapeutic agents for use in patients, they are also useful whenever it is required to inhibit TEAD. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • Certain compounds of Formula (I) may be prepared through the reaction of a suitable aromatic electrophile (for example a compound of Formula (Al), (All) or (AHI) as defined below) and a suitable nucleophile, optionally in the presence of a catalyst.
  • a suitable aromatic electrophile for example a compound of Formula (Al), (All) or (AHI) as defined below
  • a suitable nucleophile optionally in the presence of a catalyst.
  • a non-limiting example of such a reaction is the reaction of Intermediate 1 and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate as part of the synthesis of Example 1.
  • X 1 and X 2 are independently selected from CH and N; either X 3 is CH and X 4 is selected from CR 5 and N, or X 3 is N and X 4 is CR 5 ;
  • L is a covalent bond, O or CH2;
  • R 1 is Ci-4 alkyl or C3-4 cycloalkyl
  • R 2 is selected from H and R 1 , wherein R 1 is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy;
  • R 3 , R 4 and R 5 are independently selected from H, C1-4 fluoroalkyl, C1-4 alkoxy, -S(Ci. 4 alkyl), -O(Ci. 4 fluoroalkyl), -S(Ci. 4 fluoroalkyl), F, Cl, C3-4 fluorocycloalkyl, R j and R k , wherein R j is C3-4 cycloalkyl optionally substituted with -CN, C1-4 alkoxy or C w fluoroalkyl and R k is C1-4 alkyl optionally substituted with -CN or C1-4 alkoxy; and
  • X A is selected from F, Cl, Br, I, OSO2CF3, OSC Ph and O(4-toluenesulfonyl), or a salt thereof.
  • the compound of Formula (Al) is a compound of Formula (All), wherein L, R 1 , R 2 , R 3 , R 4 , X 3 , X 4 and X A are as defined for a compound of Formula (Al), or a salt thereof.
  • the compound of Formula (Al) is a compound of Formula (Alli), wherein L, R 1 , R 2 , R 3 , R 4 , X 3 , X 4 and X A are as defined for a compound of Formula (Al), or a salt thereof.
  • a compound of Formula (Al), (All) or (Alli), or a salt thereof wherein R 3 and R 5 are independently selected from H, Cl, F and C1-4 alkyl, and optionally R 4 is C1-4 fluoroalkyl, -O(Ci. 4 fluoroalkyl) or -S(Ci. 4 fluoroalkyl).
  • a compound of Formula (Al), (All) or (Alli), or a salt thereof wherein R 3 and R 5 are, and optionally R 4 is CF?H, CF3, OCF3, OCF2H or SCF3.
  • evaporations were carried out by rotary evaporation or utilising GENEVAC equipment or BIOTAGE vlO evaporator or ROTA VAPOR BUCHI and FREEZEMOBILE 35EL from SP SCIENTIFIC in vacuo and workup procedures were carried out after removal of residual solids by filtration and quenching with appropriate solvent;
  • 3-Chlorobenzoperoxoic acid (70% purity, 9.4 g, 38 mmol) was added to a mixture of 8-bromo-3- methylpyrido[4,3-d]pyrimidin-4(3H)-one (4.6 g, 19 mmol) in DCM (150 mL) and the reaction mixture was stirred at rt for 16 hrs. The reaction mixture was then diluted with a solution of 7:1 CHCU/isopropanol (250 mL) and water (50 mL). The phases were separated and the organic layer was washed with saturated aq. NajSzOs (70 mL), saturated aq. K2CO3 and water (2 x 100 mL).
  • reaction mixture was diluted with DCM (50 mL) and water (30 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over NajSC , filtered, and concentrated to dryness.
  • reaction mixture was heated to 95 °C and stirred for 3 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (200 mL).
  • the organic phase was washed with saturated aq. NH 4 CI (80 mL) and water (80 mL), dried over Na2SO 4 , filtered, and concentrated to dryness.
  • 3-Chlorobenzoperoxoic acid (70% purity, 9.4 g, 38 mmol) was added to a mixture of 8-bromo-3- methylpyrido[4,3-d]pyrimidin-4(3H)-one (4.6 g, 19 mmol) in DCM (150 mL) and the reaction mixture was stirred at rt for 16 hrs. The reaction mixture was then diluted with a solution of 7:1 CHCU/isopropanol (250 mL) and water (50 mL). The phases were separated and the organic layer was washed with saturated aq. NajSzOs (70 mL), saturated aq. K2CO3 (70 mL) and water (2 x 100 mL).
  • DIPEA (1.1 mL, 6.2 mmol) was added to a mixture of 8-bromo-5-chloro-3-methylpyrido[4,3- d]pyrimidin-4(3H)-one (0.28 g, 1.0 mmol) and tert-butyl (S)-3-aminopyrrolidine-l-carboxylate (0.38 g, 2.1 mmol) in DMSO (2 mL). The reaction mixture was heated to 90 °C and stirred for 16.5 hrs.
  • the reaction mixture was heated to 105 °C and stirred for 65 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (60 mL) and saturated aq. NH 4 CI (30 mL).
  • the phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na2SO 4 , filtered, and concentrated to dryness.
  • Pd(0Ac)2 (69.8 mg, 0.311 mmol), tert-butyl (S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidin-5-yl)amino)pyrrolidine-l-carboxylate (Intermediate 2, 0.660 g, 1.56 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.975 g, 7.777 mmol), di((ls,3S)- adamantan-l-yl)(butyl)phosphane (112 mg, 0.312 mmol), and potassium acetate (153 mg, 1.56 mmol) were diluted in 1,4-dioxane (15 mL) under an atmosphere of N2.
  • Triethylamine (0.11 mL, 0.81 mmol) was added to a solution of (S)-3-methyl-5-(pyrrolidin-3- ylamino)-8-(5-(trifluoromethoxy)pyridin-2-yl)pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (120 mg, 0.27 mmol) and acryloyl chloride (32.9 pL, 0.407 mmol) in DCM (0.6 mL) at 0 °C over a period of 2 min. The resulting mixture was stirred at 0 °C for 1 hr.
  • Oxalyl chloride (8.20 mL, 93.6 mmol) and DMF (58 pL, 0.75 mmol) were added to a suspension of 2- fluoro-4-iodonicotinic acid (20.0 g, 74.9 mmol) in DCM (150 mL) at 0 °C.
  • the resulting mixture was stirred at 0 °C for 30 min, then rt for 1 hr.
  • the reaction mixture was concentrated to dryness to afford 2-fluoro-4-iodonicotinoyl chloride as an orange solid, which was dissolved in THF (150 mL) and cooled to 0 °C.
  • Triethylamine (0.239 mL, 1.71 mmol) in MeCN (3.5 mL) was added to the reaction, and the resulting mixture was heated to 80 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt, diluted with MeCN (10 mL), and washed with saturated aq. NH 4 CI (3 x 5 mL).
  • the organic layer was dried over NajSC , filtered, and concentrated to dryness.
  • reaction mixture was cooled to rt, diluted with MeOH (5 mL), and directly subjected to reverse phase chromatography (C18: 5 to 100% MeCN in water w/ 0.1% NH4HCO3) to afford tert- butyl (S)-3-((4-bromo-7-methyl-8-oxo-7,8-dihydro-2,7-naphthyridin-l-yl)amino)pyrrolidine-l- carboxylate (160 mg, 94% yield) as a white solid.
  • reaction mixture was heated to 80 °C and stirred for 6 hrs.
  • the reaction mixture was cooled to rt, diluted with DCM (10 mL), and washed with saturated KF (2 mL) and brine (2 mL).
  • the organic layer was dried over NajSC , filtered, and concentrated to dryness.
  • Compounds were dosed with a final DMSO concentration of 1% (v/v). Compound IC 5 o values were assessed following a 10-point, half-logio dilution schema starting at 100 pM compound concentration.
  • human TEAD protein from TEAD4(217-434) was cloned into an overexpression vector, expressed as an /V-terminal HIS-TEV-Avi-tagged fusion protein in E coli, and subsequently purified, then protein was chemically depalmitoylated & biotinylated. The assay was performed in 384-well LV plates (384-well black, medium binding, PS, HIBASE, GREINER #784076) and run in the presence and absence of the compound of interest.
  • Each well of 5 pL assay mixture contained 10 mM Tris-HCI (pH 7.5), 100 mM NaCI, 0.05 mM EDTA, 1 mM TECP, 1% DMSO, 0.03% Pluronic acid F127, 20 nM dePai Avi TEAD4 (217-434) -depalmitoylated & biotinylated protein, 0.8 nM Streptavidin Terbium cryptate (CisBio#610SATLB), 625 nM FAM labelled Probe A. Reactions were incubated at 25°C for 120 min before reading on a PHERASTAR FSX Plate Reader (337 520 490 HTRF module required) (Supplier BMP).
  • the ratio of the donor and acceptor (Channel A / Channel B) is calculated within Genedata Assay Analyzer. Subsequently, the dose-response of the ratio to testing compound concentration was fitted to a select fit model that will provide the best fit quality using automatic parameter (SMARTFIT) to derive IC 5 o values for each testing compound.
  • SMARTFIT automatic parameter
  • Probe A is 3',6'-dihydroxy-3-oxo-N- ⁇ 8-[2-(5- ⁇ 2-[4-(trifluoromethyl)anilino]phenyl ⁇ -2H-tetrazol-2- yl)acetamido]octyl ⁇ -3H-spiro[[2]benzofuran-l,9'-xanthene]-5-carboxamide;
  • MCF7-Tead cell line was obtained from BPS BIOSCIENCE (catalog number 60618) and was maintained in DMEM containing 10% fetal calf serum, 2mM glutamine, and 400pg/ml G418. Cells were grown in a humidified incubator at 37 °C with 5% CO2. Cells were distributed to flat bottom white polystyrene TC treated 384 well plates at a density of 3,500 cells/well in 30pL. Cells were incubated for 24 hours at 37 °C with 5% CO2. Cells were acoustically dosed using an Echo 555, with compounds serially diluted in 100% DMSO. Plates were incubated for an additional 24 hours.
  • MCF7-Luciferase cell line was obtained from GENTARGET (catalog number SC050-L) and was maintained in DMEM containing 10% fetal calf serum, 2mM glutamine. Cells were grown in a humidified incubator at 37°C with 5% CO2. Cells were distributed to flat bottom white polystyrene TC treated 384 well plates at a density of 3,500 cells/well in 30pL. Cells were incubated for 24 hours at 37 °C with 5% CO2. Cells were acoustically dosed using an Echo 555, with compounds serially diluted in 100% DMSO. Plates were incubated for an additional 24 hours.
  • the crude reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aq. NaHCOs (2 x 20 mL), saturated aq. NH 4 CI (2 x 20 mL) and brine (20 mL). The organic layer was dried over NajSC , filtered and concentrated to dryness.
  • the crude material was purified by flash silica chromatography (0-50% EtOAc in Hex) to afford tert-butyl (8-(2- (5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamido)octyl)carbamate (53.7 mg, 47% yield) as a white solid.
  • HATU 61 mg, 0.16 mmol
  • DIPEA 86 pL, 0.49 mmol
  • 5- carboxyfluorescein 60 mg, 0.16 mmol
  • /V-(8-aminooctyl)-2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamide 60 mg, 0.12 mmol
  • DMF 1.1 mL
  • the reaction mixture was stirred at 0 °C for 2 hrs before warming to rt with stirring for an additional 1 h.
  • reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aq. NH 4 (2 x 30 mL) and brine (30 mL). The organic layer was dried over NajSC , filtered and concentrated to dryness.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La description concerne des composés de formule (I) : (I) et leurs sels pharmaceutiquement acceptables, des procédés et des intermédiaires utilisés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement du cancer.
PCT/EP2023/061109 2022-04-28 2023-04-27 Composés hétéroaromatiques bicycliques et leur utilisation dans le traitement du cancer WO2023209088A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263363746P 2022-04-28 2022-04-28
US63/363,746 2022-04-28

Publications (1)

Publication Number Publication Date
WO2023209088A1 true WO2023209088A1 (fr) 2023-11-02

Family

ID=86382905

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/061109 WO2023209088A1 (fr) 2022-04-28 2023-04-27 Composés hétéroaromatiques bicycliques et leur utilisation dans le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2023209088A1 (fr)

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002050043A1 (fr) 2000-12-20 2002-06-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives de la quinazoline, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
WO2005107758A1 (fr) 2004-05-06 2005-11-17 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
WO2009097287A1 (fr) * 2008-02-01 2009-08-06 Irm Llc Composés et compositions comme inhibiteurs de kinases
WO2013014448A1 (fr) 2011-07-27 2013-01-31 Astrazeneca Ab Dérivés de 2-(anilino 2,4,5-substitué)pyrimidine utilisés comme modulateurs de l'egfr utiles pour le traitement d'un cancer
WO2013184757A1 (fr) 2012-06-06 2013-12-12 Irm Llc Composés et compositions destinés à la modulation de l'activité de l'egfr
US20140038940A1 (en) 2012-01-13 2014-02-06 Acea Biosciences Inc. Novel egfr modulators and uses thereof
WO2014135876A1 (fr) 2013-03-06 2014-09-12 Astrazeneca Ab Inhibiteurs quinazoline de l'activation des formes mutantes du récepteur de croissance épidermique (egfr)
WO2015027222A2 (fr) 2013-08-23 2015-02-26 Neupharma, Inc. Entités chimiques, compositions et méthodes particulières
WO2015101791A1 (fr) 2014-01-02 2015-07-09 Astrazeneca Ab Compositions pharmaceutiques comprenant azd9291
WO2016015453A1 (fr) 2014-07-29 2016-02-04 上海艾力斯医药科技有限公司 Dérivé de pyridine amidopyrimidine, son procédé de préparation et utilisation
WO2016054987A1 (fr) 2014-10-11 2016-04-14 上海翰森生物医药科技有限公司 Inhibiteur d'egfr, et préparation et application associées
WO2016060443A2 (fr) 2014-10-13 2016-04-21 Yuhan Corporation Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
WO2016094821A2 (fr) 2014-12-11 2016-06-16 Beta Pharma, Inc. Dérivés de 2-anilinopyrimidine substitués utilisés comme modulateurs de l'egfr
WO2018204532A1 (fr) 2017-05-03 2018-11-08 Vivace Therapeutics, Inc. Composés tricycliques non fusionnés

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002050043A1 (fr) 2000-12-20 2002-06-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives de la quinazoline, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
WO2005107758A1 (fr) 2004-05-06 2005-11-17 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
WO2009097287A1 (fr) * 2008-02-01 2009-08-06 Irm Llc Composés et compositions comme inhibiteurs de kinases
WO2013014448A1 (fr) 2011-07-27 2013-01-31 Astrazeneca Ab Dérivés de 2-(anilino 2,4,5-substitué)pyrimidine utilisés comme modulateurs de l'egfr utiles pour le traitement d'un cancer
US20140038940A1 (en) 2012-01-13 2014-02-06 Acea Biosciences Inc. Novel egfr modulators and uses thereof
WO2013184757A1 (fr) 2012-06-06 2013-12-12 Irm Llc Composés et compositions destinés à la modulation de l'activité de l'egfr
WO2014135876A1 (fr) 2013-03-06 2014-09-12 Astrazeneca Ab Inhibiteurs quinazoline de l'activation des formes mutantes du récepteur de croissance épidermique (egfr)
WO2015027222A2 (fr) 2013-08-23 2015-02-26 Neupharma, Inc. Entités chimiques, compositions et méthodes particulières
WO2015101791A1 (fr) 2014-01-02 2015-07-09 Astrazeneca Ab Compositions pharmaceutiques comprenant azd9291
WO2016015453A1 (fr) 2014-07-29 2016-02-04 上海艾力斯医药科技有限公司 Dérivé de pyridine amidopyrimidine, son procédé de préparation et utilisation
WO2016054987A1 (fr) 2014-10-11 2016-04-14 上海翰森生物医药科技有限公司 Inhibiteur d'egfr, et préparation et application associées
WO2016060443A2 (fr) 2014-10-13 2016-04-21 Yuhan Corporation Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
WO2016094821A2 (fr) 2014-12-11 2016-06-16 Beta Pharma, Inc. Dérivés de 2-anilinopyrimidine substitués utilisés comme modulateurs de l'egfr
WO2018204532A1 (fr) 2017-05-03 2018-11-08 Vivace Therapeutics, Inc. Composés tricycliques non fusionnés

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Concise Dictionary of Biomedicine and Molecular Biology", 2002, CRC PRESS
"Oxford Dictionary of Biochemistry and Molecular Biology", 2000, OXFORD UNIVERSITY PRESS
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"The Dictionary of Cell and Molecular Biology", 1999, ACADEMIC PRESS
DONG ET AL., CELL, 2007, pages 1120 - 33
MA ET AL., ANN REV BIOCHEM, 2018, pages 577 - 604
MENG ET AL., GENES&DEV, 2016, pages 1 - 17
POMA ET AL., SCIENTIFIC REPORTS, vol. 8, no. 10623, 2018
SANCHEZ-VEGA ET AL., CELL, 2018, pages 321 - 337
TAPON ET AL., CELL, 2002, pages 467 - 478
ZANCANATO ET AL., CANCER CELL, 2016, pages 783 - 803

Similar Documents

Publication Publication Date Title
EP2498607B1 (fr) Inhibiteurs de kinases
DK2880035T3 (en) Hitherto UNKNOWN PYRROLOPYRIMIDINE COMPOUNDS AS PROTEIN CHINAS INHIBITORS
ES2956642T3 (es) Compuestos y métodos para la inhibición de JAK
BR112020026748A2 (pt) Inibidores de quinases dependentes de ciclina
JP2022516469A (ja) ユビキチン特異的プロテアーゼ１を阻害するための組成物
US20210188821A1 (en) Jak1 selective inhibitors
EP3294742B1 (fr) Nouveaux (5,8-diméthyl-9-phényle-5,8-dihydro-6h-pyrazolo[3,4-h]quinazolein-2-yl)-(1h-pyrazol-3-yl)-amines et leurs dérivés comme inhibiteurs de la igf-1r/ir
BR112018008397B1 (pt) Composto, sal farmacêuticamente aceitável e formas cristalinas
AU2012310168B2 (en) 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
JP7418353B2 (ja) トリアゾロピリミジン化合物およびがんの処置におけるそれらの使用
EP3997097B1 (fr) Dérivés spirocycliques macrocycliques en tant qu'inhibiteurs de mcl-1
WO2020160180A1 (fr) Composés et leurs utilisations
CN107383013B (zh) 作为btk抑制剂的吡唑并嘧啶衍生物及其制备方法和药物组合物
AU2016361834B2 (en) 1,3,4-thiadiazole compounds and their use in treating cancer
CA2902755C (fr) Derives de 6-[4-(1 h-imidazol-2-yl)piperidin-1 -yl]pyrimidin-4-amine en tant que modulateurs de l'activite kinase
WO2021074251A1 (fr) Dérivés de pyrrolo[2,3-d]pyrimidine et leur utilisation dans le traitement du cancer
WO2021124279A1 (fr) Composés actifs vis-à-vis des récepteurs nucléaires
WO2023209088A1 (fr) Composés hétéroaromatiques bicycliques et leur utilisation dans le traitement du cancer
CN117203199A (zh) N2-苯基嘧啶-2,4-二胺化合物及其制备方法和使用方法
CA3189041A1 (fr) Immunomodulateur heterocyclique
WO2023209086A1 (fr) Composés hétéroaromatiques bicycliques pour le traitement du cancer
WO2023209090A1 (fr) Composés hétéroaromatiques bicycliques et leur application dans le traitement du cancer
WO2023209084A1 (fr) Composés hétéroaromatiques bicycliques condensés et leur utilisation dans le traitement du cancer
RU2806751C2 (ru) Соединения на основе пиразолопиридинона
RU2810113C2 (ru) Новые хинолиновые соединения

Legal Events

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

Ref document number: 23723848

Country of ref document: EP

Kind code of ref document: A1