WO2024091511A1 - Inhibiteurs de tead heterocycliques - Google Patents

Inhibiteurs de tead heterocycliques Download PDF

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Publication number
WO2024091511A1
WO2024091511A1 PCT/US2023/035818 US2023035818W WO2024091511A1 WO 2024091511 A1 WO2024091511 A1 WO 2024091511A1 US 2023035818 W US2023035818 W US 2023035818W WO 2024091511 A1 WO2024091511 A1 WO 2024091511A1
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Prior art keywords
tead
cancer
compound
trifluoromethyl
μmol
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PCT/US2023/035818
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English (en)
Inventor
Qihui Jin
Paul Keitz
Tom Yao-Hsiang Wu
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Light Horse Therapeutics, Inc.
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Publication of WO2024091511A1 publication Critical patent/WO2024091511A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • 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
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • HETEROCYCLIC TEAD INHIBITORS TECHNICAL FIELD [0001] The present application relates to TEAD inhibitor compounds that are useful for treating proliferative disorders such as cancer.
  • BACKGROUND OF THE INVENTION [0002]
  • the Hippo signaling pathway plays key roles in organ size control and tumor suppression.
  • YAP and transcriptional enhanced associate domain (TEAD) are major effectors of the Hippo signaling pathway.
  • Signal transduction involves a core kinase cascade, leading to YAP (Yes1-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif) phosphorylation.
  • Physiological or pathological inactivation leads to dephosphorylation and nuclear accumulation.
  • Nuclear YAP/TAZ binds to TEADs to mediate target gene expression.
  • the TEAD-YAP complex regulates organ development and amplification of oncogenic factors in many cancers (e.g., sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer).
  • cancers e.g., sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer.
  • Several genes in the Hippo signaling pathway have been identified as tumor suppressors, and mutations in these genes have been associated with different human cancers. Additionally, elevated YAP levels have been associated with certain human cancers.
  • TEAD transcription factors serve as canonical partners for the Hippo pathway effector YAP, which has been associated with resistance to targeted therapy in several contexts, including resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI’s) in EGFR-mutant NSCLC.
  • EGFR epidermal growth factor receptor
  • TKI tyrosine kinase inhibitors
  • the EGFR (osimertinib) and MEK (selumetinib) inhibitor combination has been studied in patients resistant to prior EGFR tyrosine kinase inhibitors and is also under evaluation as an initial therapy for advanced EGFR-mutant NSCLC in a phase II clinical trial (NCT03392246).
  • One aspect of the present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , X, Y, z1 and z2 are as defined herein.
  • Another aspect of the present invention relates to a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
  • Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claim.
  • DETAILED DESCRIPTION OF THE INVENTION I. GENERAL The present application provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit transcriptional enhanced associate domain (TEAD, e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD transcriptional enhanced associate domain
  • n 2 is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values.
  • the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units.
  • the range “from 1 to 3 ⁇ M (micromolar),” which is intended to include 1 ⁇ M, 3 ⁇ M, and everything in between to any number of significant figures (e.g., 1.255 ⁇ M, 2.1 ⁇ M, 2.9999 ⁇ M, etc.).
  • the alkyl may comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Alkyl can include any number of carbons, such as C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 110 , C 23 , C 24 , C 25 , C 26 , C 34 , C 35 , C 36 , C 45 , C 46 and C 56 .
  • C 16 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (--CH 2 --). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as CH 3 , Me, or just a single bond terminating with no end group substitution. [0017]
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below. Alkoxy groups may have the general formula: alkyl-O-.
  • alkoxy groups can have any suitable number of carbon atoms, such as C 16 .
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, and the like.
  • the alkoxy groups can be further optionally substituted as defined herein.
  • cyano as used herein, alone or in combination, refers to --CN.
  • halo or halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Haloalkylene refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (--CFH--), difluoromethylene (--CF 2 --), chloromethylene (--CHCl--) and the like.
  • any one of the positions that is understood to have a hydrogen may also exist or understood to be isotopically enriched.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Obtaining 100% deuteration at any relevant site of a compound in an amount of milligram or greater can be difficult.
  • a benzene ring may be optionally exist as –C 6 D 5 , - C 6 DH 4 , -C 6 D 2 H 3 , -C 6 D 3 H 2 , and -C 6 D 4 H.
  • a cyclohexyl group may optionally exist as –C 6 D 11 .
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • the various optional substitutions need not be the same and any combination of optional substituent groups may be combined.
  • a carbon chain may be substituted with an alkyl group, a halo group, and an alkoxy group.
  • substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed.
  • substituent is qualified as “substituted,” the substituted form is specifically intended.
  • compounds may exist as tautomers, including keto-enol tautomers; all tautomeric isomers are embraced by the embodiments disclosed herein.
  • the compounds of the various embodiments disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the various embodiments disclosed herein.
  • Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • an atom in particular when mentioned in relation to a compound described herein, includes all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • hydrogen when hydrogen is mentioned, it is understood to refer to 1 H, 2 H, 3 H or mixtures thereof; when carbon is mentioned, it is understood to refer to 11 C, 12 C, 13 C, 14 C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to 13 N, 14 N, 15 N or mixtures thereof; when oxygen is mentioned, it is understood to refer to 14 O, 15 O, 16 O, 17 O, 18 O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18 F, 19 F or mixtures thereof; unless expressly noted otherwise.
  • the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes.
  • Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents.
  • any reference to a compound of the present invention e.g., a compound of Formula (I) in connection with the invention should be understood to include the tautomers, racemates, enantiomers and diastereomers thereof, if any, the mixtures thereof as well as the pharmacologically acceptable acid addition salts, solvates, hydrates, polymorphs, physiologically functional derivatives or metabolites, or prodrugs thereof.
  • the compounds disclosed herein can exist as pharmaceutically acceptable salts, including acid addition salts.
  • Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). It is understood that each of the compounds disclosed herein, and each embodiment of the compounds set forth herein, include pharmaceutically acceptable salts of such compounds. [0032]
  • the compounds of the present invention e.g., a compound of Formula (I)
  • the compounds of Formula (I) also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I).
  • the compounds of the present invention e.g., compounds of Formula (I)
  • their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
  • compounds of Formula (I) and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the compounds of the present invention include the compounds of Examples 1-26 and stereoisomers and pharmaceutically acceptable salts and solvates thereof.
  • the compounds of Examples 1-26 are in the free base form.
  • the compounds of Examples 1-26 are in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl
  • basic groups in the compounds of the various embodiments disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the various embodiments disclosed herein contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • prodrug refers to a compound that is made active in vivo through chemical reaction in vivo thereby releasing an active compound.
  • Compounds disclosed herein can be modified to exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Additionally, prodrugs can be converted to the active compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the active compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug is a compound which is administered as an ester (the “prodrug”), which is then metabolically hydrolyzed to the carboxylic acid, as the active entity. Additional examples include peptidyl derivatives of a compound.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of subjects without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use B.
  • test compounds may be demonstrated by the biological assays described herein. IC50 values for inhibiting the activity of TEAD are shown in Tables 1 and 2.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
  • cancer is to be understood in a most general sense as a disease characterized by inappropriate cellular proliferation, migration, apoptosis or angiogenesis, preferably by inappropriate cellular proliferation.
  • Inappropriate cell proliferation means cellular proliferation resulting from inappropriate cell growth, from excessive cell division, from cell division at an accelerated rate and/or from inappropriate cell survival.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., but not limited to, humans), including leukemia, lymphomas, carcinomas and sarcomas.
  • An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. [0041]
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically 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 condition.
  • a therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for inhibition of a TEAD transcription factor.
  • a therapeutically effective amount is an amount sufficient for treating a proliferative disease.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease or condition.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the term refers to a reduction of the level of enzyme activity, e.g., TEAD1, TEAD2, TEAD3, or TEAD4 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of transcription factor activity.
  • TEAD1, TEAD2, TEAD3, or TEAD4 activity e.g., TEAD1, TEAD2, TEAD3, or TEAD4 activity
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • X is NH or O
  • Y is –CHR 3 –
  • R 1 and R 2 are independently selected from hydrogen, halogen, cyano, C 1 -C 3 alkyl and –(CH 2 ) m O-(C 1 -C 3 alkyl)
  • R 3 is independently selected at each occurrence from hydrogen andC 1 -C 3 alkyl
  • m is 1 or 2
  • z1 is 0 or 1
  • z2 is 0, 1 or 2
  • each alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of: halo, oxo, cyano, hydroxy, C 1 -C 3 alkyl,
  • the compound of Formula (I) is a compound of Formula (II): wherein: X is NH or O; Y is –CHR 3 –; R 1 and R 2 are independently selected from hydrogen, halogen, cyano, C 1 -C 3 alkyl and –(CH 2 ) m O-(C 1 -C 3 alkyl); R 3 is independently selected at each occurrence from hydrogen and C 1 -C 3 alkyl; m is 1 or 2; z1 is 0 or 1; and z2 is 0, 1 or 2; wherein each alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of: halo, oxo, cyano, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, and -OCD 3 .
  • R 1 and R 2 are hydrogen.
  • R 1 or R 2 is selected from methyl, cyano, and halogen.
  • R 1 is selected from methyl, cyano, and halogen; and R 2 is hydrogen.
  • R 1 is hydrogen; and R 2 is selected from methyl, cyano, and halogen.
  • Y is –CH 2 –.
  • Y is —CH(C 1 -C 3 alkyl)–.
  • the C 1 -C 3 alkyl is methyl, ethyl, n-propyl or i-propyl.
  • Y is —CH(CH 3 )–. In some embodiments, Y is –CH(CH 2 CH 3 )–. In some embodiments, Y is —CH(CH 2 CH 2 CH 3 )–. In some embodiments, Y is –CH(CH(CH 3 ) 2 )–.
  • X is NH. [0053] In some embodiments, X is O. [0054] In some embodiments, m is 1. In other embodiments, m is 2. [0055] In some embodiments, z1 is 0. In other embodiments z1 is 1. [0056] In some embodiments, z2 is 0. In other embodiments z2 is 1. In some embodiments, z2 is 2. [0057] In some embodiments, the compound of the present invention is selected from , , , ,
  • the compound of Formula (I) is .
  • the compound of Formula (I) is .
  • the compound is a compound selected from Examples 1-26. IV. MODES OF ADMINISTRATION A .
  • Pharmaceutical Compositions While it may be possible for the compounds disclosed herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition (i.e., as a formulation).
  • compositions which comprise one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients.
  • the carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of Formula (I), or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • the pharmaceutical compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition including, for example, a compound and a pharmaceutically acceptable carrier and/or excipient.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophiles for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • a pharmaceutically acceptable carrier including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol; ( 11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; ( 12) esters, such as ethyl oleate and
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • compositions suitable for same can be found in, for example, U.S. Pat. Nos.6, 110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • Formulations of the compounds disclosed herein suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient
  • Solid dosage forms for oral administration may include the active ingredient mixed with one or more pharmaceutically acceptable earners, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as.
  • glycerol for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; ( 50) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents.
  • compositions may also include buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), and/or surface- active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions such as dragees, capsules, pills and granules, may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredients) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents .
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents .
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbon s and volatile unsubstituted hydrocarbons, such as butane and propane.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intraderm al, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof) the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the additional therapeutic agent of the pharmaceutical compositions described herein include an anti-cancer agent.
  • the anti-cancer agent may be a chemotherapeutic, radiation, or surgical removal of the cancer.
  • the treatment method includes the co-administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent.
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • radioactive isotopes e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu
  • chemotherapeutic agents e.g., At 211 , I 131 , I 125
  • Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signalling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
  • “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA ® , Genentech/OSI Pharm.), bortezomib (VELCADE ® , Millennium Pharm.), disulfiram , epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ® , AstraZeneca), sunitib (SUTENT ® , Pfizer/Sugen), letrozole (FEMARA ® , Novartis), imatinib mesylate (GLEEVEC ® ., Novartis), finasunate (VATALANIB ® , Novartis), oxaliplatin (ELOXATIN ® , Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirol),
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, e
  • Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ® ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON ® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE ® (megestrol acetate), AROMASIN ® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR ® (
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No.4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX ⁇ ) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No.
  • EMD7200 a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding
  • human EGFR antibody HuMax-EGFR (GenMab)
  • Fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem.279(29):30375-30384 (2004)).
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037.
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA ® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]- 7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX- 1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl
  • Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR- targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprel
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone- 17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene a
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifarnib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone farnesyltransferase inhibitors
  • SCH 6636 farnesyltransferase inhibitors
  • pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN TM ) combined with 5-FU and leucovorin.
  • Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects.
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumirac
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin,
  • a compound disclosed herein is administered in combination with a biologic agent, such as bevacizumab or panitumumab.
  • a biologic agent such as bevacizumab or panitumumab.
  • compounds disclosed herein, or a pharmaceutically acceptable composition thereof are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine,
  • the additional therapeutic agent of the pharmaceutical compositions described herein includes a RAS pathway inhibitor.
  • a RAS Pathway inhibitor as used herein includes any compound exhibiting inactivation activity (e.g., active site (e.g., competitive) inhibition, allosteric inhibition, inhibition of dimerization, inhibition of expression, inhibition of protein-protein interaction, and induction of degradation) of any protein in a Ras pathway.
  • Non-limiting examples of a protein in a Ras pathway include any one of the proteins in the Ras-RAF-MAPK pathway or PI3K/AKT pathway such as Ras (e.g., KRas, HRas, and/or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof.
  • Ras e.g., KRas, HRas, and/or NRas
  • EGFR ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FG
  • a Ras pathway inhibitor can be selective for a particular Ras protein (e.g., KRas, HRas, or NRas)
  • the RAS pathway inhibitor is a KRas inhibitor including, for example, AMG 510, ARS-3248, ARS1620, SML-8-73-1, SML-10-70-1, VSA9, AA12, MRTX-849, MRTX849, LY3499446, JNJ-74699157, ARS853, AZD4785, and JNJ- 74699157.
  • the RAS pathway inhibitor is an EGFR inhibitor, some examples of which are described supra.
  • the EGFR inhibitor is selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, and olmutinib.
  • the RAS pathway inhibitor is a MEK inhibitor, including for example, trametinib, cobimetinib, binimetinib, selumetinib and refametinib. C.
  • compositions including a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient.
  • the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient. [0102] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. [0103]
  • the daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein.
  • compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein.
  • the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein.
  • the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein.
  • Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art.
  • the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition.
  • factors associated with the particular subject being treated including subject response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages.
  • the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg.
  • the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg.
  • such administration can be once-daily or twice-daily (BID) administration.
  • BID twice-daily
  • kits useful for example, in the treatment of a Hippo pathway-associated disease or disorder (e.g., a TEAD-associated cancer), which include one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • kits indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • a gene e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD)
  • One aspect of the present invention relates to a method of treating a proliferative disease (e.g., cancer (e.g., a cancer associated with a dysregulation of a transcription factor (e.g, TEAD)) in a subject in need of such treatment.
  • the method includes administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the cancer is a TEAD- associated cancer.
  • a cancer is associated with a dysregulation of the Hippo pathway (e.g., dysregulation in the regulatory functions of transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex).
  • a TEAD-associated cancer an EGFR-associated cancer, a RAS-associated cancer, an ErbB2-associated cancer, an ErbB3- associated cancer, an ErbB4-associated cancer, a NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, a FGFR1-associated cancer, FGFR2-associated cancer, FGFR3-associated cancer, a IGF1 R-associated cancer, a INSR-associated cancer, a ALK- associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1- associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL- associated cancer, a SHP2-associated cancer, a RAF-associated cancer (e.g., RAF-associated cancer, e.g
  • the method includes a) detecting a dysregulation of the transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • embodiments herein relate to methods of treating a subject with cancer (e.g., a cancer associated with a dysregulation in the regulatory functions of transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex) including administering to the subject a compound of the present invention (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof).
  • a compound of the present invention e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • TEAD transcription enhancing factors
  • YAP/TAZ nuclear localization and levels are elevated in many tumors such as lung, thyroid, skin, ovarian, colorectal, prostate, pancreatic, esophageal, liver and breast cancers (Harvey et al, Nat Rev Cancer, 13: 246-257 (2013).
  • Aberrant Hippo pathway regulation is observed at a large scale in many cancers, leading to YAP/TAZ nuclear translocation.
  • disruption of the YAP/TAZ-TEAD (and/or YAP-TEAD) interaction downstream is thought to eliminate the carcinogenic properties of YAP/TAZ.
  • a “TEAD-associated cancer” is a cancer associated with dysregulation of the function of a transcription factor gene or protein (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, and/or TEAD4; YAP, and/or the TEAD-YAP complex) as well as the coactivators and/or corepressors that modulate the expression of genes that regulate organogenesis and cell growth within the Hippo signaling pathway.
  • TEAD such as TEAD1, TEAD2, TEAD3, and/or TEAD4
  • YAP and/or the TEAD-YAP complex
  • the cancer is cancer is associated with the overexpression and/or aberrant activity of the TEAD transcription factor.
  • Exemplary TEAD-associated cancers include, but are not limited to sarcoma, lung cancer including non- small cell lung cancer (NSCLC), thyroid cancer, skin cancer, epithelioid hemangioendothelioma, ependymoma and meningioma, glioblastoma, hepatocellular carcinoma and cholangiocarcinoma, mesothelioma, osteosarcoma ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), esophageal cancer, liver cancer, breast cancer.
  • NSCLC non- small cell lung cancer
  • the cancer is a sarcoma (e.g., Kaposi’s sarcoma). In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer, mesothelioma). In certain embodiments, the cancer has a mutation in a gene of the Hippo signaling pathway. In certain embodiments, the cancer has a mutation in EGFR. In certain embodiments, the cancer has a mutation in MEK. In certain embodiments, the cancer is an EGFR-mutant non-small cell lung cancer. In certain embodiments, the cancer is resistant to certain anti-proliferative agents (e.g., cancers resistant to inhibitors of EGFR and/or MEK).
  • certain anti-proliferative agents e.g., cancers resistant to inhibitors of EGFR and/or MEK.
  • the cancer is resistant to inhibitors of EGFR (e.g., osimertinib) and/or inhibitors of MEK (e.g., trametinib).
  • the cancer is resistant to tyrosine kinase inhibitors (TKI’s).
  • the phrase “dysregulation of the transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex” refers to a genetic mutation that results in the expression of a mutation in a TEAD, YAP and/or TAZ gene that results in the expression of a TEAD, YAP and/or TAZ protein that includes a deletion of at least one amino acid as compared to a wild type protein, a mutation in a TEAD, YAP and/or TAZ gene that results in the expression of a protein with one or more point mutations as compared to a wild type protein, a mutation in a TEAD, YAP and/or TAZ gene that results in the expression of TEAD, YAP and/or TAZ protein with at least one inserted amino acid as compared to a wild type protein, a gene duplication that results in an increased level of TEAD, YAP and/or TAZ protein in a cell, a mutation in a regulatory sequence (e.g.,
  • any of the above dysfunctions may result in an increase in activity of the TEAD-YAP and/or TEAD-TAZ complex and/or an increased cellular level of the TEAD-YAP and/or TEAD- TAZ complex.
  • the method includes administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the method includes detecting a dysregulation of the transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex, or the expression or activity or level of any of the same in a sample from the subject.
  • the detecting may be done prior to administration, or after having administered the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • another aspect of the present invention relates to a method of treating a TEAD-associated cancer in a subject, including administering to a subject identified or diagnosed as having TEAD-associated cancer an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to the subject.
  • Another aspect of the present invention relates to a method for treating cancer in a subject in need thereof, including: (a) determining that the cancer is associated with a dysregulation of the transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, to the subject.
  • methods for treating cancer in a subject in need thereof includes: (a) detecting a TEAD-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a small molecule or an immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have a TEAD- associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying a dysregulation of the transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • the method includes: administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject.
  • the subject is determined to have a cancer associated with a dysregulation of the transcription factors TEAD, YAP, TAZ and/or the TEAD-YAP or TEAD-TAZ complex, or expression or activity or level of any of the same.
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a small molecule or an immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
  • the subject is determined to have a TEAD-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
  • the test or assay is provided as a kit.
  • Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • administering e.g., specifically or selectively administering
  • Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a small molecule or immunotherapy).
  • the subject was previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy.
  • the subject is a subject suspected of having a TEAD-associated cancer, a subject presenting with one or more symptoms of a TEAD- associated cancer, or a subject having an elevated risk of developing a TEAD-associated cancer.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating a TEAD-associated cancer in a subject identified or diagnosed as having a TEAD-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, where the presence of a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, identifies that the subject has a TEAD-associated cancer.
  • an assay e
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a TEAD-associated cancer in a subject identified or diagnosed as having a TEAD-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD- TAZ complex, or expression or activity or level of any of the same where the presence of dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, identifies that the subject has a TEAD-associated cancer.
  • Some embodiments of any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. [0124] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • the subject has a tumor that is positive for a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • the subject can be a subject whose tumors have a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • the subject is suspected of having a TEAD-associated cancer.
  • provided herein are methods for treating a TEAD-associated cancer in a subject in need of such treatment.
  • the method includes a) detecting a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or the expression or activity or level of any of the same in a sample from the subject; and b) administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or the expression or activity or level of any of the same includes one or more TEAD and/or YAP protein point mutations/insertions/deletions.
  • the cancer having dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the tumor with a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • Also provided are methods of treating a subject that include administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same.
  • the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or level of any of the same.
  • the method also includes administering to a subject determined to have a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity, or level of any of the same an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method includes determining that a subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or level of any of the same via an assay performed on a sample obtained from the subject.
  • the method also includes administering to a subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the cancer is a hematological cancer.
  • hematological cancers include, for example, leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, specify juvenile myelomonocytic leukemia (JMML), and hairy cell leukemia) and lymphomas (e.g., non-Hodgkin’s lymphoma, Hodgkin’s disease cutaneous T-cell lymphoma, and Burkitt lymphoma).
  • leukemias e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, specify juvenile myelomonocytic leukemia (JMML), and hairy cell leukemia
  • lymphomas e.g., non-Hodgkin’s lymphoma, Hodgkin’s disease cutaneous T-cell lymphoma, and Burkitt
  • solid tumors include, for example, thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer (e.g., non-small cell lung cancer, small-cell lung carcinoma, bronchial adenoma, and pleuropulmonary blastoma), pancreatic cancer, pancreatic ductal carcinoma, biliary tract cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ), stomach cancer, small intestinal cancer, colon cancer, colorectal cancer, peritoneal cancer, ovarian cancer, uterine cancer, liver cancer, endometrial cancer, prostate cancer (including benign prostatic hyperplasia), testicular cancer, bladder cancer, urinary tract cancer, cervical cancer, head and neck cancer, brain cancer (e.g., glioblastoma, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, and
  • the subject is a human.
  • a method for treating a subject diagnosed with or identified as having a TEAD-associated cancer e.g., any of the exemplary TEAD-associated cancers disclosed herein, including administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the compound of Formula (I) is selected from Examples 1-26, or a pharmaceutically acceptable salt thereof.
  • the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance.
  • Such compounds are capable of crossing the blood brain barrier and inhibiting the Hippo pathway (e.g., a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same) activity in the brain and/or other CNS structures.
  • the compounds provided herein are capable of crossing the blood brain barrier in an effective amount.
  • treatment of a subject with cancer e.g., a TEAD-associated brain or CNS cancer
  • administration e.g., oral administration
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, the tumors listed in Louis, D.N. et al., Acta Neuropathol 131(6), 803-820 (June 2016)).
  • gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas,
  • the brain tumor is a primary brain tumor.
  • the subject has previously been treated with another anticancer agent, e.g., an inhibitor of another tumorgenic pathway gene or protein (e.g., Ras (e.g., KRas, HRas, and/or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof).
  • Ras e.g., KRas, HRas, and/or NRas
  • EGFR ErbB2, ErbB3, ErbB4, NF1, PDGFR-A,
  • the brain tumor is a metastatic brain tumor.
  • assays known in the art.
  • Such assays include BBB models such as the transwell system, the hollow fiber (dynamic in vitro BBB) model, other microfluidic BBB systems, the BBB spheroid platform, and other cell aggregate-based BBB models. See, e.g., Cho et al. Nat Commun. 2017; 8: 15623; Bagchi, et al. Drug Des Devel Ther. 2019; 13: 3591–3605; Gastfriend et al., Curr Opin Biomed Eng. 2018 Mar; 5: 6–12; and Wang et al.
  • the compounds described herein are fluorescently labeled, and the fluorescent label can be detected using microscopy (e.g., confocal microscopy).
  • microscopy e.g., confocal microscopy
  • the ability of the compound to penetrate the surface barrier of the model can be represented by the fluorescence intensity at a given depth below the surface.
  • the fluorescent label is non-fluorescent until it permeates live cells and is hydrolyzed by intracellular esterases to produce a fluorescent compound that is retained in the cell and can be quantified with a spectrophotometer.
  • Non-limiting examples of fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared IRDye® CW-800 (LICOR #929-71012), far-red IRDye® 650 (LICOR #929-70020), sodium fluorescein (Na-F), lucifer yellow (LY), 5’carboxyfluorescein, and calcein- acetoxymethylester (calcein-AM).
  • the BBB model e.g., the tissue or cell aggregate
  • a compound described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analyses).
  • the ability of a compound described herein to cross the BBB through a transcellular transport system can be demonstrated by assays known in the art. See, e.g., Wang, et al. Drug Deliv. 2019; 26(1): 551–565.
  • assays to determine if compounds can be effluxed by the P-glycoprotein (Pgp) include monolayer efflux assays in which movement of compounds through Pgp is quantified by measuring movement of digoxin, a model Pgp substrate (see, e.g., Doan et al.2002. J Pharmacol Exp Ther.
  • binding of the compounds described herein to brain tissue is quantified.
  • a brain tissue binding assay can be performed using equilibrium dialysis, and the fraction of a compound described herein unbound to brain tissue can be detected using LC-MS/MS (Cyprotex: Brain Tissue Binding Assay www.cyprotex.com/admepk/protein_binding/brain-tissue-binding/).
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • a regulatory agency-approved e.g., FDA-approved, assay or kit.
  • the subject has a tumor that is positive for a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • a regulatory agency-approved e.g., FDA-approved, assay or kit.
  • the subject can be a subject whose tumors have a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a TEAD-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • an assay used to determine whether the subject has a dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT- PCR).
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
  • Assays can utilize other detection methods known in the art for detecting dysregulation of a TEAD gene, a TEAD protein, a YAP gene, a YAP protein, a TAZ gene, a TAZ protein, the TEAD-YAP complex or the TEAD-TAZ complex, or expression or activity or levels of any of the same.
  • the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject.
  • the subject is a subject suspected of having a TEAD-associated cancer, a subject having one or more symptoms of a TEAD-associated cancer, and/or a subject that has an increased risk of developing a TEAD- associated cancer.
  • the TEAD- associated cancer has developed a resistance to inhibition to a previous cancer therapeutic (e.g., a tyrosine kinase inhibitor (e.g., gefitinib, erlotinib and/or lapatinib)).
  • a previous cancer therapeutic e.g., a tyrosine kinase inhibitor (e.g., gefitinib, erlotinib and/or lapatinib)
  • the cancer is a relapsed or refractory cancer.
  • the Hippo signaling pathway is also active in modulating the immune response in different acute and chronic inflammatory diseases as well as injury- and pathogen-induced inflammation (Mia et al., The FEBS Journal 289: 4061–4081 (2022)).
  • a method of treating a Hippo pathway-associated disease or disorder in a subject in need of such treatment including administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the Hippo pathway-associated disease or disorder is proliferative disease (e.g., cancer, benign neoplasm, for example, a cancer resistant to a modulator of another transcription factor (e.g., YAP, EGFR, MEK)), an inflammatory disease (e.g., fibrosis), and/or an autoimmune disease (e.g., sclerosis)).
  • the disease is an inflammatory disease (e.g., fibrosis).
  • the disease is an autoimmune disease (e.g., sclerosis).
  • the term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation.
  • inflammatory disease may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non- infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, per
  • An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.
  • the inflammatory disorder is fibrosis, and the fibrosis is idiopathic pulmonary fibrosis, liver cirrhosis, cystic fibrosis, systemic sclerosis, progressive kidney disease, or cardiovascular fibrosis.
  • An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells.
  • autoimmune thyroiditis This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney).
  • the treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response.
  • Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardio
  • the autoimmune disorder is sclerosis.
  • the sclerosis is systemic sclerosis (scleroderma) or multiple sclerosis.
  • the compounds provided herein are selective TEAD inhibitors.
  • selective TEAD inhibitor means a compound which selectively inhibits certain mutant TEAD transcription factors over wild-type TEAD transcription factors. Said another way, a selective TEAD inhibitor has no or low activity against wild-type TEAD.
  • a selective TEAD inhibitor s inhibitory activity against certain mutant TEAD transcription factors is more potent in terms of IC50 value (i.e., a nanomolar IC50 value) when compared with its inhibitory activity against wild-type TEAD and other transcription factors.
  • TEAD transcription factors are palmitated at cysteine residues that are evolutionarily conserved. It has been found that three cysteine residues are evolutionarily conserved and mutations into serine (C53S, C327S, and C359S) in human TEAD1 were utilized to determine the effects on TEAD1 palmitoylation. C359S mutants showed the greatest loss of palmitization, and C327S and C53S also showed reduced palmitization. These results indicate that C 3 59 plays an important role in TEAD1 palm acylation.
  • the compound of Formula (I) is selective for a mutant TEAD transcription factor.
  • the compounds disclosed herein e.g., a compound of Formula (I)
  • the compounds described herein reversibly inhibit TEAD transcription factors.
  • the transcription factor is TEAD1.
  • the transcription factor is TEAD2.
  • the transcription factor is TEAD3.
  • the transcription factor is TEAD4.
  • the compounds described herein reversibly inhibit the activity of TEAD transcription factors (eg, TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD transcription factors eg, TEAD1, TEAD2, TEAD3, and/or TEAD4.
  • the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1 or TAZ and TEAD1.
  • the compounds disclosed herein bind to TEAD2 and disrupt or inhibit the interaction between YAP and TEAD2 or TAZ and TEAD2.
  • the compounds disclosed herein bind to TEAD3 and disrupt or inhibit the interaction between YAP and TEAD3 or TAZ and TEAD3.
  • the compounds disclosed herein bind to TEAD4 and disrupt or inhibit the interaction between YAP and TEAD4 or TAZ and TEAD4.
  • a method for inhibiting TEAD activity in a mammalian cell including contacting the mammalian cell with a compound of Formula (I).
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell having TEAD activity.
  • the mammalian cell is a mammalian cancer cell.
  • the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a TEAD-associated cancer cell. [0145] Also provided is a method for disrupting the TEAD-YAP or TEAD-TAZ interaction in a cell. The method includes contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a mammalian cell. [0146] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound provided herein to a subject, such as a human, having a TEAD protein, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing the TEAD protein.
  • a method of inhibiting mammalian cell proliferation This method may be carried out in vitro or in vivo. The method includes contacting a mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as Ras pathway inhibitors, kinase inhibitors (e.g., EGFR and MEK inhibitors), signal transduction inhibitors, and/or monoclonal antibodies.
  • a surgery may be open surgery or minimally invasive surgery.
  • the compounds of Formula (I) described herein, or a pharmaceutically acceptable salt thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • Compounds of Formula (I), or pharmaceutically acceptable salts or thereof can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor.
  • the treatment with one or more doses of a compound of Formula (I) , or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.
  • a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy.
  • the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
  • the one or more additional therapies or therapeutic agents are independently selected from those therapeutic agents described supra.
  • the compound of Formula (I) and the one or more additional therapies or therapeutic agents are both administered to a subject simultaneously in the form of a single composition or dosage.
  • the compound of Formula (I) and the one or more additional therapies or therapeutic agents are both administered to a subject sequentially with variable intervening time limits.
  • a method of treating a cancer including administering to a subject in need thereof a pharmaceutical combination for treating cancer which includes (a) a compound of Formula (I), or pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of Formula (I) described herein and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly effective amounts, e.g., in daily or intermittently dosages.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.
  • the cancer is a Hippo pathway-associated cancer (e.g., a TEAD-associated cancer).
  • the method includes administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • Such methods can be used in the treatment of one or more of the cancers described herein. See, e.g., US Publication No.2013/0029925; International Publication No. WO 2014/083567; and US Patent No.8,568,998.
  • the cancer is a Hippo pathway-associated cancer (e.g., a TEAD-associated cancer).
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent, such as those described herein.
  • metastasis is an art known term and means the formation of an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject, where the additional tumor includes the same or similar cancer cells as the primary tumor.
  • methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a TEAD-associated cancer include: selecting, identifying, or diagnosing a subject as having a TEAD-associated cancer, and administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a TEAD-associated cancer.
  • Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a subject having a TEAD-associated cancer that includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a TEAD-associated cancer.
  • the decrease in the risk of developing a metastasis or an additional metastasis in a subject having a TEAD-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the subject prior to treatment, or as compared to a subject or a population of subjects having a similar or the same TEAD-associated cancer that has received no treatment or a different treatment.
  • the additional therapeutic agent is selected from any of the therapeutic agents identified herein.
  • the subject has been administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, prior to administration of the pharmaceutical composition.
  • risk of developing a metastasis means the risk that a subject having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor.
  • the phrase “risk of developing additional metastases” means the risk that a subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors include the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastasis are described herein. VI. GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS [0158] The following schemes can be used to practice the various embodiments disclosed herein. It will be understood that these schemes are merely exemplary and that they provide ready access to core structures with variable functionality.
  • the reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Common Intermediate 1 5-fluoro-N-((3R,4R)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)pyrimidin-2-amine
  • Scheme 1 Synthetic route for the formation of 5-fluoro-N-((3R,4R)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)pyrimidin-2-amine.
  • Step 1 tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-hydroxypyrrolidine-1- carboxylate
  • tert-butyl (3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate 8.0 g, 39.55 mmol, 1 eq
  • 2-chloro-5-fluoropyrimidine 6.3 g, 47.47 mmol, 5.88 mL, 1.2 eq
  • DMF 8.0.0 mL
  • Step 2 tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy) pyrrolidine-1-carboxylate
  • tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4- hydroxypyrrolidine-1-carboxylate (300.0 mg, 1.01 mmol, 1 eq) in DMF (3.0 mL) was added NaH (44.5 mg, 1.11 mmol, 60% purity, 1.1 eq) at 0 °C, and the mixture was stirred for 10 min.
  • Step 3 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine
  • tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl) benzyl)oxy)pyrrolidine-1-carboxylate (120.0 mg, 262.91 ⁇ mol, 1 eq) in DCM (4.0 mL) was added HCl/EtOAc (4 M, 4.0 mL, 60.86 eq). The mixture was stirred at 25 °C for 1 hour.
  • Step 1 tert-butyl-trans-3-((5-fluoropyrimidin-2-yl)amino)-4-hydroxypyrrolidine-1- carboxylate
  • NHF 129.56 mg, 3.24 mmol, 60% purity, 1.2 eq
  • tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3- carboxylate (0.5 g, 2.70 mmol, 1 eq) was added, and the reaction mixture was stirred at 80 °C for 12 h. The reaction was then quenched with aqueous NH 4 Cl solution (2 mL) at 0 °C.
  • reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Boston Prime C18150*30mm*5 ⁇ m; mobile phase: [water (ammonia hydroxide v/v)- ACN]; B%: 13%-53%, 9min) to give the title compound (0.15 g, 452.55 ⁇ mol, 16.76% yield, 90% purity) as a white solid.
  • Step 2 tert-butyl-trans-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate [0171] To a solution of tert-butyl-trans-3-((5-fluoropyrimidin-2-yl)amino)-4- hydroxypyrrolidine-1-carboxylate (0.15 g, 452.55 ⁇ mol, 90% purity, 1 eq) in THF (8 mL) at 20 °C was added NaH (21.72 mg, 543.05 ⁇ mol, 60% purity, 1.2 eq), and the reaction mixture was stirred at 65 °C for 15 min.1-(Bromomethyl)-4-(trifluoromethyl)benzene (118.99 mg, 497.80 ⁇ mol, 76.77 ⁇ L, 1.1 eq) was then added to the reaction mixture at 65 °C, and the mixture stirred
  • reaction mixture was quenched with a saturated aqueous NH 4 Cl solution (0.2 mL) at 0 °C, and concentrated under reduced pressure to give a residue.
  • Step 3 5-fluoro-N-(trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)pyrimidin- 2-amine
  • tert-butyl-trans-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 90 mg, 177.46 ⁇ mol, 90% purity, 1 eq
  • DCM 3 mL
  • HCl/dioxane 4 M, 1 mL, 22.54 eq
  • Step 4 (Z)-3-chloro-1-(trans-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0173] To a solution of 5-fluoro-N-(trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine (32.64 mg, 306.50 ⁇ mol, 1.3 eq) and DIEA (152.36 mg, 1.18 mmol, 205.33 ⁇ L, 5 eq) in DMF (2 mL) was added HATU (179.29 mg, 471.54 ⁇ mol, 1.5 eq) at 20 °C, and the resulting mixture was stirred at 20 °C for 15 min.
  • Step 1 1-(tert-butyl) 3-ethyl 4-(((S)-1-phenylethyl)amino)pyrrolidine-1,3-dicarboxylate
  • Step 2 1-(tert-butyl) 3-ethyl (3R,4S)-4-(((S)-1-phenylethyl)amino)pyrrolidine-1,3- dicarboxylate hydrochloride [0175] To a solution of 1-(tert-butyl) 3-ethyl 4-(((S)-1-phenylethyl)amino)pyrrolidine-1,3- dicarboxylate (44.0 g, 121.39 mmol, 1 eq) in EtOAc (500.0 mL) was added HCl/dioxane (4 M, 35.0 mL, 1.15 eq) dropwise at 25 °C, and the mixture was then cooled to 0 °C.
  • Step 3 1-(tert-butyl) 3-ethyl (3R,4S)-4-(((S)-1-phenylethyl)amino)pyrrolidine-1,3- dicarboxylate [0176] To a sat. NaHCO 3 (200.0 mL) aqueous solution was added 1-(tert-butyl) 3-ethyl (3R,4S)-4-(((S)-1-phenylethyl)amino)pyrrolidine-1,3-dicarboxylate hydrochloride (13.5 g, 33.84 mmol), and the mixture was extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with brine (100.0 mL) and concentrated under vacuum.
  • Step 4 1-(tert-butyl) 3-ethyl (3R,4S)-4-aminopyrrolidine-1,3-dicarboxylate [0177] To a solution of 1-(tert-butyl) 3-ethyl (3R,4S)-4-(((S)-1-phenylethyl)amino)pyrrolidine- 1,3-dicarboxylate (12.1 g, 33.38 mmol, 1 eq) in EtOH (120.0 mL) was added Pd/C (7.11 g, 6.68 mmol, 10% purity, 0.20 eq), and the mixture was stirred at 25 °C for 20 h under 15 psi H2.
  • Step 6 tert-butyl (3S,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4- (hydroxymethyl)pyrrolidine-1-carboxylate [0179] To a solution of tert-butyl (3S,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1- carboxylate (5.2 g, 24.04 mmol, 1 eq), 2-chloro-5-fluoropyrimidine (3.82 g, 28.85 mmol, 3.57 mL, 1.2 eq) in DMF (50.0 mL) was added DIEA (9.32 g, 72.13 mmol, 12.56 mL, 3 eq).
  • Step 7 tert-butyl (3S,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate
  • 4- (trifluoromethyl)phenol 311.5 mg, 1.92 mmol, 1.2 eq
  • cyanomethylenetributylphosphorane (1.93 g, 8.00 mmol, 5 eq) in toluene (5.0 mL) was stirred at 110 °C under N 2 in a microwave for 1.5 hours.
  • Step 8 5-fluoro-N-((3S,4R)-4-((4-(trifluoromethyl)phenoxy)methyl)pyrrolidin-3- yl)pyrimidin-2-amine
  • tert-butyl (3S,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate 400.0 mg, 876.36 umol, 1 eq
  • DCM 3.0 mL
  • HCl/dioxane 4 M, 219.09 ⁇ L, 1 eq
  • Step 9 1-((3S,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)phenoxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one [0182] To a solution of 5-fluoro-N-((3S,4R)-4-((4- (trifluoromethyl)phenoxy)methyl)pyrrolidin-3-yl)pyrimidin-2-amine (310.0 mg, 870.01 ⁇ mol, 1 eq) and TEA (440.2 mg, 4.35 mmol, 605.47 ⁇ L, 5 eq) in DCM (4.0 mL) was added acryloyl chloride (78.8 mg, 870.01 ⁇ mol, 70.94 ⁇ L, 1 eq) at 0 °C.
  • reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (30 mL x 3), brine (30 mL x 3) and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 ⁇ m; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 32%-72%, 9min) to give the title compound (60.9 mg, 133.44 ⁇ mol, 52.83% yield, 99.6% purity) as an off-white solid.
  • Step 1 4-(trifluoromethyl)benzothioyl chloride
  • n-BuLi 2.5 M, 2.90 mL, 1.63 eq
  • Carbon disulfide (3.15 g, 41.37 mmol, 2.50 mL, 9.31 eq) was added to the reaction mixture at -40 °C, and the reaction mixture was stirred at -40 °C for 0.25 h.
  • the reaction mixture was quenched with water (10 mL) at -10 °C.
  • the aqueous phase was washed with DCM (2 x 10 mL).
  • the mixture was neutralized with 12 N HCl (0.5 mL) and extracted with EtOAc (10 mL x 3).
  • the combined organic layers were washed with brine (20 mL), and dried over Na2SO4.
  • the solid was filtered off, and the filtrate was concentrated to give the residue.
  • the residue was treated with SOCl 2 (1.64 g, 13.78 mmol, 1 mL, 3.10 eq), and the mixture was stirred at 80 °C for 12 h.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash chromatography on silica gel (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 30% Ethylacetate/Petroleum ether gradient at 35 mL/min) to give the title compound (60 mg, 111.00 ⁇ mol, 33.45% yield, 90% purity) as a white solid.
  • Step 3 tert-butyl (3R,4R)-3-(difluoro(4-(trifluoromethyl)phenyl)methoxy)-4-((5- fluoropyrimidin-2-yl)amino)pyrrolidine-1-carboxylate [0186] To a solution of tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)phenylcarbonothioyl)oxy)pyrrolidine-1-carboxylate (15 mg, 27.75 ⁇ mol, 90% purity, 1 eq) and SbCl 3 (1.90 mg, 8.33 ⁇ mol, 0.3 eq) in DCM (2 mL) at 20 °C was added BAST (13.51 mg, 61.05 ⁇ mol, 13.37 ⁇ L, 2.2 eq), and the reaction mixture was stirred at 20°C for 2 h.
  • Step 4 N-((3R,4R)-4-(difluoro(4-(trifluoromethyl)phenyl)methoxy)pyrrolidin-3-yl)-5- fluoropyrimidin-2-amine [0187] To a solution of tert-butyl (3R,4R)-3-(difluoro(4-(trifluoromethyl)phenyl)methoxy)-4- ((5-fluoropyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (47 mg, 71.59 ⁇ mol, 75% purity, 1 eq) in DCM (3 mL) at 20 °C was added HCl/dioxane (4 M, 357.93 ⁇ L, 20 eq), and the reaction mixture was stirred at 20 °C for 0.5 h.
  • Step 5 1-((3R,4R)-3-(difluoro(4-(trifluoromethyl)phenyl)methoxy)-4-((5- fluoropyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one [0188] To a solution of N-((3R,4R)-4-(difluoro(4-(trifluoromethyl)phenyl)methoxy)pyrrolidin- 3-yl)-5-fluoropyrimidin-2-amine (33 mg, 63.84 ⁇ mol, 90% purity, 1 eq, 2 HCl) and TEA (32.30 mg, 319.20 ⁇ mol, 44.43 ⁇ L, 5 eq) in DCM (3 mL) at 0 °C was added acryloyl chloride (6.36 mg, 70.22 ⁇ mol, 5.73 ⁇ L, 1.1 eq), the reaction mixture was stirred at 0 °C for
  • reaction mixture was quenched with water (1 mL) at 0 °C.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: C18-1150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 31%-71%, 9 min) to give the title compound (21.00 mg, 45.30 ⁇ mol, 70.96% yield, 96.3% purity) as a white solid.
  • Example 7a 1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidin-1-yl)prop-2-en-1-one and Example 7b: 1-((3S,4S)-3-((5- fluoropyrimidin-2-yl)amino)-4-(4-(trifluoromethyl)phenethoxy)pyrrolidin-1-yl)prop-2-en-1-one
  • Step 1 trans-tert-butyl-3-hydroxy-4-((4-methylphenyl)sulfonamido)pyrrolidine-1- carboxylate
  • Step 2 trans-tert-butyl-3-((4-methylphenyl)sulfonamido)-4- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate [0191] To a solution of trans-tert-butyl-3-hydroxy-4-((4- methylphenyl)sulfonamido)pyrrolidine-1-carboxylate (5.00 g, 14.03 mmol, 100% purity, 1 eq) and pyridine (5.55 g, 70.14 mmol, 5.66 mL, 5 eq) in DCM (120 mL) was added MsCl (3.39 g, 29.59 mmol, 2.29 mL, 2.11 eq) at 0 °C.
  • Step 3 tert-butyl 6-tosyl-3,6-diazabicyclo[3.1.0]hexane-3-carboxylate [0192] To a solution of trans-tert-butyl-3-((4-methylphenyl)sulfonamido)-4- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (7.5 g, 13.81 mmol, 80% purity, 1 eq) in CH 3 CN (80 mL) was added K 2 CO 3 (7.63 g, 55.23 mmol, 4 eq). The reaction mixture was stirred at 45 °C for 16 h.
  • Step 4 trans-4-methyl-N-(4-(4-(trifluoromethyl)phenethoxy)pyrrolidin-3- yl)benzenesulfonamide
  • tert-butyl 6-tosyl-3,6-diazabicyclo[3.1.0]hexane-3-carboxylate (0.42 g, 1.12 mmol, 90% purity, 1 eq)
  • 2-(4-(trifluoromethyl)phenyl)ethan-1-ol (1.70 g, 8.94 mmol, 8 eq) was added bis(trifluoromethylsulfonyloxy)copper (201.99 mg, 558.48 ⁇ mol, 0.5 eq).
  • Step 5 trans-tert-butyl-3-((4-methylphenyl)sulfonamido)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidine-1-carboxylate
  • reaction solution was diluted with DCM (20 mL), washed with water (20 mL ⁇ 2) and brine (20 mL), dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was purified with flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 30 ⁇ 70% Ethyl acetate/Petroleum ether gradient at 45 mL/min) to give the title compound (0.44 g, 749.17 ⁇ mol, 71.33% yield, 90% purity) as an off-white solid.
  • Step 6 trans-tert-butyl-3-amino-4-(4-(trifluoromethyl)phenethoxy)pyrrolidine-1- carboxylate
  • a solution of trans-tert-butyl-3-((4-methylphenyl)sulfonamido)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidine-1-carboxylate (0.3 g, 510.80 ⁇ mol, 90% purity, 1 eq) in MeOH (10 mL) was added Mg (1.61 g, 66.40 mmol, 130 eq) at 25 °C under N 2 , and the mixture was heated at 80 °C for 63 h.
  • the mixture was diluted with dichloromethane (60 mL) and filtered through a pad of Celite, and the cake was rinsed with dichloromethane (30 mL ⁇ 5).
  • the filtrate was concentrated under reduced pressure, and the residue was purified with flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 2-6% methanol / dichloromethane gradient at 50 mL/min) to give the title compound (0.14 g, 336.54 ⁇ mol, 65.88% yield, 90% purity) as a colorless oil.
  • Step 7 trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)amino)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidine-1-carboxylate
  • trans-tert-butyl-3-amino-4-(4- (trifluoromethyl)phenethoxy)pyrrolidine-1-carboxylate (0.18 g, 432.70 ⁇ mol, 90% purity, 1 eq) and 2-chloro-5-fluoropyrimidine (86.01 mg, 649.04 ⁇ mol, 80.39 ⁇ L, 1.5 eq) in THF (8 mL) was added Pd(OAc)2 (19.43 mg, 86.54 ⁇ mol, 0.2 eq), BINAP (107.77 mg, 173.08 ⁇ mol, 0.4 eq) and Cs 2 CO 3 (281.96 mg, 865.39 ⁇ mol, 2 eq).
  • the reaction was stirred at 85 °C for 15 h under N 2 as color turned to red.
  • the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20% Ethylacetate/Petroleum ether gradient at 40 mL/min) to give the title compound (0.1 g, 148.79 ⁇ mol, 34.39% yield, 70% purity) as a light yellow gum.
  • Step 8 trans-5-fluoro-N-(4-(4-(trifluoromethyl)phenethoxy)pyrrolidin-3-yl)pyrimidin- 2-amine
  • trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)amino)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidine-1-carboxylate 80 mg, 119.03 ⁇ mol, 70% purity, 1 eq
  • DCM 3 mL
  • HCl/dioxane 4 M, 3 mL, 100.81 eq.
  • Step 9 trans-1-(3-((5-fluoropyrimidin-2-yl)amino)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidin-1-yl)prop-2-en-1-one [0198]
  • trans-5-fluoro-N-(4-(4-(trifluoromethyl)phenethoxy)pyrrolidin-3- yl)pyrimidin-2-amine 70 mg, 110.54 ⁇ mol, 70% purity, 1 eq, 2HCl
  • TEA 55.93 mg, 552.72 ⁇ mol, 76.93 ⁇ L, 5 eq
  • DCM 2 mL
  • acryloyl chloride 10.01 mg, 110.54 ⁇ mol, 9.01 ⁇ L, 1 eq
  • Step 9 1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidin-1-yl)prop-2-en-1-one and 1-((3S,4S)-3-((5- fluoropyrimidin-2-yl)amino)-4-(4-(trifluoromethyl)phenethoxy)pyrrolidin-1-yl)prop-2-en-1-one [0199] trans-1-(3-((5-Fluoropyrimidin-2-yl)amino)-4-(4- (trifluoromethyl)phenethoxy)pyrrolidin-1-yl)prop-2-en-1-one (31.4 mg, 73.54 ⁇ mol, 99.4% purity, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10 ⁇ m); mobile phase: [0.1% NH
  • the mixture was stirred at 25 °C for 0.5 h, and filtered a pad of Celite.
  • the filtrate was purified by prep-HPLC (column: Boston Prime C18150*30mm*5 ⁇ m; mobile phase: [water (ammonia hydroxide v/v)- ACN]; B%: 39%-69%, 8min) to give the title compound (64.4 mg, 147.82 ⁇ mol, 35.25% yield, 99.9% purity) as a white solid.
  • Step 1 trans-tert-butyl-3-hydroxy-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate 1.1 g, 5.94 mmol, 810.89 ⁇ L, 1.1 eq
  • DMF 0.1 mL
  • NaH 237.53 mg, 5.94 mmol, 60% purity, 1.1 eq
  • Step 2 trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate [0202] To a solution of trans-tert-butyl-3-hydroxy-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (600.0 mg, 1.66 mmol, 1 eq) in THF (5.0 mL) was added NaH (73.1 mg, 1.83 mmol, 60% purity, 1.1 eq) at 0 °C, and the mixture stirred for 10 min.
  • Step 3 trans-5-fluoro-2-((4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine
  • trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 320.0 mg, 699.58 ⁇ mol, 1 eq
  • DCM 2.0 mL
  • HCl/dioxane 4 M, 1.94 mL, 11.09 eq
  • Example 10 (Z)-4-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)-4-oxobut-2-enenitrile [0205] To a solution of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine (200 mg, 419.35 ⁇ mol, 90% purity, 1 eq, 2HCl) and (Z)-3-cyanoacrylic acid (81.41 mg, 838.69 ⁇ mol, crude purity, 2 eq) in DMF (3 mL) was added TEA (212.17 mg, 2.10 mmol, 291.84 ⁇ L, 5 eq) and HATU (318.90 mg, 838.69 ⁇ mol, 2 eq).
  • Step 1 tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-hydroxypiperidine-1- carboxylate
  • 2-chloro-5-fluoropyrimidine (183.82 mg, 1.39 mmol, 171.80 ⁇ L, 1 eq)
  • Cs 2 CO 3 (1.36 g, 4.16 mmol, 3 eq) in t-amyl alcohol (5 mL) was added tBuBrettphos-Pd-G3 (118.52 mg, 138.71 ⁇ mol, 0.1 eq) under a N 2 glove-box, and the mixture was stirred at 80 °C for 16 h.
  • Step 2 tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate
  • tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4- hydroxypiperidine-1-carboxylate 180 mg, 535.96 ⁇ mol, 93% purity, 1 eq
  • THF 10 mL
  • DMF 1 mL
  • NaH 25.72 mg, 643.15 ⁇ mol, 60% purity, 1.2 eq
  • the mixture was stirred at 25 °C for 5 min.1-(Bromomethyl)-4-(trifluoromethyl)benzene (128.11 mg, 535.96 ⁇ mol, 82.65 ⁇ L, 1 eq) was then added, and
  • the reaction mixture was quenched with aqueous NH 4 Cl solution (5 mL) at 0 °C.
  • the organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL x 3).
  • the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated.
  • the residue was purified by flash chromatography on silica gel (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 30% Ethyl acetate/Petroleum ether gradient at 25 mL/min) to give the title compound (190 mg, 363.47 ⁇ mol, 67.82% yield, 90% purity) as a yellow oil.
  • Step 3 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)piperidin-3- yl)pyrimidin-2-amine
  • tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate 190 mg, 363.47 ⁇ mol, 90% purity, 1 eq
  • DCM tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate (190 mg, 363.47 ⁇ mol, 90% purity, 1 eq) in DCM (5 mL) was added dropwise HCl/dioxane (4 M, 2 mL) at 25 °C.
  • Step 4 1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidin-1-yl)prop-2-en-1-one [0209] To a solution of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)piperidin-3- yl)pyrimidin-2-amine (170 mg, 383.52 ⁇ mol, crude, 1 eq, 2HCl) in DCM (5 mL) was added DIEA (247.83 mg, 1.92 mmol, 334.01 ⁇ L, 5 eq) and acryloyl chloride (38.18 mg, 421.87 ⁇ mol, 34.40 ⁇ L, 1.1 eq) at 0 °C.
  • reaction mixture was stirred at 0 °C for 30 min, and then quenched with water (1 mL) and extracted with DCM (3 x 5 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC (column: Boston Prime C18150*30mm*5 ⁇ m; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 42%-72%, 8min) to give the title compound (107.5 mg, 251.50 ⁇ mol, 65.58% yield, 99.3% purity) as an off-white solid.
  • Example 12 1-((3S,4S)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Step 1 trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)amino)-4-hydroxypiperidine-1- carboxylate
  • 5-fluoropyrimidin-2-amine 3.41 g, 30.11 mmol, 1.2 eq
  • DMF 50 mL
  • NaH 1.20 g, 30.11 mmol, 60% purity, 1.2 eq
  • the mixture was stirred at 25 °C for 30 mins.
  • Step 2 trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate [0211] To a solution of trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)amino)-4- hydroxypiperidine-1-carboxylate (760 mg, 2.19 mmol, 90% purity, 1 eq) in THF (10 mL) and DMF (1 mL) was added NaH (105.11 mg, 2.63 mmol, 60% purity, 1.2 eq) at 25 °C.
  • Step 3 trans-5-fluoro-N-(4-((4-(trifluoromethyl)benzyl)oxy)piperidin-3-yl)pyrimidin- 2-amine
  • trans-tert-butyl-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate 330 mg, 631.30 ⁇ mol, 90% purity, 1 eq
  • DCM 3 mL
  • HCl/dioxane 4 M, 1 mL, 6.34 eq
  • Step 4 trans-1-(3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidin-1-yl)prop-2-en-1-one [0213] To a solution of trans-5-fluoro-N-(4-((4-(trifluoromethyl)benzyl)oxy)piperidin-3- yl)pyrimidin-2-amine (250 mg, 507.60 ⁇ mol, 90% purity, 1 eq, 2HCl) and TEA (256.82 mg, 2.54 mmol, 353.25 ⁇ L, 5 eq) in DCM (5 mL) was added acryloyl chloride (45.94 mg, 507.60 ⁇ mol, 41.39 ⁇ L, 1 eq) at 0 °C under N 2 .
  • Step 5 1-((3S,4S)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidin-1-yl)prop-2-en-1-one and 1-((3R,4R)-3-((5- fluoropyrimidin-2-yl)amino)-4-((4-(trifluoromethyl)benzyl)oxy)piperidin-1-yl)prop-2-en-1-one [0214] trans-1-(3-((5-Fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)piperidin-1-yl)prop-2-en-1-one (100 mg, 235.63 ⁇ mol, 100% purity, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10 ⁇ m); mobile phase: [0.1%
  • Example 13 (Z)-1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)but-2-en-1-one [0215] To a solution of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine (4 g, 10.10 mmol, 90% purity, 1 eq) in DMF (80 mL) was added DIPEA (7.83 g, 60.62 mmol, 10.56 mL, 6 eq), (Z)-but-2-enoic acid (1.16 g, 12.12 mmol, 90% purity, 1.2 eq) and HATU (5.76 g, 15.16 mmol, 1.5 eq).
  • the reaction mixture was stirred at 30 °C for 1 hour.
  • the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL x 3).
  • the combined organic layers were washed with water (200 mL x 6), brine (200 mL x 3), and then dried over Na 2 SO 4 .
  • the mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 35% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give the crude product (4.0 g).
  • Example 14 (E)-1-((3R,4R)-3-(difluoro(4-(trifluoromethyl)phenyl)methoxy)-4-((5- fluoropyrimidin-2-yl)amino)pyrrolidin-1-yl)but-2-en-1-one [0216] To a solution of N-((3R,4R)-4-(difluoro(4-(trifluoromethyl)phenyl)methoxy)pyrrolidin- 3-yl)-5-fluoropyrimidin-2-amine (36 mg, 82.59 ⁇ mol, 90% purity, 1 eq) and (E)-but-2-enoic acid (14.22 mg, 165.18 ⁇ mol, 2 eq) in DCM (1 mL) were added propanephosphonic acid anhydride (T3P, 50% in EtOAc, 105.11 mg, 165.18 ⁇ mol, 2 eq) and TEA (25.07 mg, 247.
  • Step 1 tert-butyl trans-3-hydroxy-4-(phenylthio)pyrrolidine-1-carboxylate
  • benzenethiol 4.1 g, 36.94 mmol, 3.77 mL, 1.37 eq
  • DMF 20.0 mL
  • NaH 1.1 g, 26.99 mmol, 60% purity, 1.2 eq
  • tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate 5.0 g, 26.99 mmol, 1 eq
  • Step 2 tert-butyl trans-3-(phenylthio)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl trans-3-hydroxy-4-(phenylthio)pyrrolidine-1-carboxylate 5.0 g, 16.93 mmol, 1 eq
  • NaH 82.5 mg, 20.31 mmol, 60% purity, 1.2 eq
  • 1-(bromomethyl)-4- (trifluoromethyl)benzene 4.9 g, 20.31 mmol, 3.13 mL, 1.2 eq
  • Step 3 tert-butyl trans-3-(phenylsulfonyl)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate
  • tert-butyl trans-3-(phenylthio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 5.6 g, 12.35 mmol, 1 eq
  • m-CPBA 5.4 g, 24.70 mmol, 80% purity, 2 eq
  • Step 4 tert-butyl (3R,4R)-3-(phenylsulfonyl)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate and tert-butyl (3S,4S)-3-(phenylsulfonyl)- 4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (chiral configuration tentatively assigned) [0220] tert-Butyl trans-3-(phenylsulfonyl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1- carboxylate (950.0 mg, 1.96 mmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m; mobile phase: [Neu-MeOH]; B%: 25%-25%; 45min) to give (3S,4S) enantiomer (480.0
  • Step 5 (3R,4R)-3-(phenylsulfonyl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine [0221] To a solution of (3R,4R)-3-(phenylsulfonyl)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (120.0 mg, 247.16 ⁇ mol, 1 eq) in DCM (2.0 mL) was added HCl/dioxane (4 M, 24.00 mL, 388.41 eq), and the mixture was stirred at 25 °C for 1 hour.
  • Step 6 ((3R,4R)-3-(phenylsulfonyl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-1- yl)prop-2-en-1-one [0222] To a solution of (3R,4R)-3-(phenylsulfonyl)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine (90.0 mg, 233.52 ⁇ mol, 1 eq) and TEA (70.9 mg, 700.57 ⁇ mol, 97.51 uL, 3 eq) in DCM (4.0 mL) was added acryloyl chloride (63.5 mg, 700.57 ⁇ mol, 57.13 uL, 3 eq) at 0 °C.
  • Example 16 1-((3S,4S)-3-(pyrimidin-2-yloxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)prop-2-en-1-one S (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)prop-2-en-1-one.
  • Compounds show relative stereochemistry.
  • Step 1 tert-butyl trans-3-hydroxy-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate 8.0 g, 43.19 mmol, 1 eq
  • DMF 20.0 mL
  • NaH 2.1 g, 51.83 mmol, 60% purity, 1.2 eq
  • Step 2 tert-butyl trans-3-(pyrimidin-2-yloxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate
  • tert-butyl trans-3-hydroxy-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 4.8 g, 13.28 mmol, 1 eq
  • NaH 797.0 mg, 19.92 mmol, 60% purity, 1.5 eq
  • the mixture was stirred for 10 min.2-Chloropyrimidine (2.3 g, 19.92 mmol, 1.65 mL, 1.5 eq) was then added, and the mixture was stirred for 1 hour at 25 °C.
  • Step 3 tert-butyl (3S,4S)-3-(pyrimidin-2-yloxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate and tert-butyl (3R,4R)-3-(pyrimidin-2- yloxy)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (chiral configuration was tentatively assigned) [0225] tert-Butyl trans-3-(pyrimidin-2-yloxy)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine- 1-carboxylate was separated by SFC (column: DAICEL CHIRALPAK AD 250mm*30mm, 10 ⁇ m; mobile phase: [Neu-MeOH]; B%: 20%-20%; 65min) to give (3S, 4S) enantiomer (700.0 mg, 1.59 mmol, 41.2% yield) as a
  • Step 4 2-(((3S,4S)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)oxy)pyrimidine [0226] To a solution of tert-butyl (3S,4S)-3-(pyrimidin-2-yloxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (130.0 mg, 295.84 ⁇ mol, 1 eq) in DCM (4.0 mL) was added HCl/dioxane (4 M, 73.96 ⁇ L, 1 eq), and the mixture was stirred at 25 °C for 1 hour.
  • Step 1 2-(((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)oxy)pyrimidine [0228] To a solution of tert-butyl (3R,4R)-3-(pyrimidin-2-yloxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (130.0 mg, 295.84 ⁇ mol, 1 eq) in DCM (4.0 mL) was added HCl/dioxane (4 M, 73.96 ⁇ L, 1 eq), and the mixture was stirred at 25 °C for 1 hour.
  • Step 2 1-((3R,4R)-3-(pyrimidin-2-yloxy)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin- 1-yl)prop-2-en-1-one [0229] To a solution of 2-(((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine (95.0 mg, 279.98 ⁇ mol, 1 eq) and DIEA (181.0 mg, 1.40 mmol, 243.84 uL, 5 eq) in DCM (4.0 mL) was added acryloyl chloride (50.7 mg, 559.96 ⁇ mol, 45.66 ⁇ L, 2 eq) at 0 °C.
  • Step 1 tert-butyl trans-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate [0230] To a solution of tert-butyl trans-3-hydroxy-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (3.2 g, 8.86 mmol, 1 eq) in DMF (20.0 mL) was added NaH (531.3 mg, 13.28 mmol, 60% purity, 1.5 eq) at 0 °C, and the mixture was stirred for 10 min.
  • Step 2 tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate and tert-butyl (3S,4S)-3-((5- fluoropyrimidin-2-yl)oxy)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (chiral configuration was tentatively assigned) [0231] tert-Butyl trans-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (1.8 g, 3.94 mmol) was further purified by SFC (column: DAICEL CHIRALCEL OJ 250mm*30mm, 10 ⁇ m; mobile phase: [Neu- EtOH]; B%: 40%-40%; 50
  • the desired products were collected as a mixture (peak 1 and peak 2).
  • the mixture was then separated by SFC (column: DAICEL CHIRALPAK IC 250mm*30mm, 10 ⁇ m; mobile phase: [0.1% NH 3 ⁇ H 2 O IPA]; B%: 20%-20%; 180min) to give the (3R, 4R) enantiomer (700.0 mg, 1.53 mmol, 38.9% yield) as a colorless oil and the (3S, 4S) enantiomer (700.0 mg, 1.53 mmol, 38.9% yield) as a colorless oil.
  • Step 3 5-fluoro-2-(((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine
  • tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 8.0.0 mg, 174.89 ⁇ mol, 1 eq) in DCM (4.0 mL) was added HCl/dioxane (4 M, 4 mL, 91.48 eq).
  • Step 4 1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0233] To a solution of 5-fluoro-2-(((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine (61.0 mg, 170.72 ⁇ mol, 1 eq) and DIEA (110.3 mg, 853.62 ⁇ mol, 148.68 ⁇ L, 5 eq) in DCM (4.0 mL) was added acryloyl chloride (30.9 mg, 341.45 ⁇ mol, 27.84 uL, 2 eq) at 0 °C.
  • Step 1 5-fluoro-2-(((SR,4S)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine
  • tert-butyl (3S,4S)-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 8.0.0 mg, 174.89 ⁇ mol, 1 eq) in DCM (4.0 mL) was added HCl/dioxane (4 M, 4 mL, 91.48 eq).
  • Step 2 1-((3S,4S)-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0235] To a solution of 5-fluoro-2-(((3S,4S)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine (60.0 mg, 167.9 ⁇ mol, 1 eq) and DIEA (108 mg, 839.6 ⁇ mol, 146.2 ⁇ L, 5 eq) in DCM (4.0 mL) was added acryloyl chloride (30.4 mg, 335.8 ⁇ mol, 27.4 ⁇ L, 2 eq) at 0 °C.
  • Example 20 (E)-1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)oxy)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)but-2-en-1-one [0236] To a solution of 5-fluoro-2-(((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)oxy)pyrimidine (80.0 mg, 203.17 ⁇ mol, 1 eq, HCl salt) in DMF (3.0 mL) was added DIEA (78.8 mg, 609.50 ⁇ mol, 106.16 ⁇ L, 3 eq) and (E)-but-2-enoyl chloride (23.6 mg, 203.17 ⁇ mol, 21.65 uL, 90% purity, 1 eq) at 0 °C.
  • Example 21 (E)-4,4,4-trifluoro-1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)but-2-en-1-one [0237] To a solution of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine (35.24 mg, 251.61 ⁇ mol, 1.5 eq) in THF (1 mL) were added HATU (191.34 mg, 503.22 ⁇ mol, 3 eq) and TEA (151.75 mg, 1.50 mmol, 208.74 ⁇ L, 8.94 eq), followed by (E)-4,4,4-trifluorobut-2-enoic acid (80 mg, 167.74 ⁇ mol, 90% purity, 1
  • Step 2 tert-butyl trans-3-(pyrimidin-2-ylthio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate [0239] To a solution of tert-butyl trans-3-hydroxy-4-(pyrimidin-2-ylthio)pyrrolidine-1- carboxylate (160 mg, 484.24 ⁇ mol, 90% purity, 1 eq) in THF (5 mL) was added NaH (25.18 mg, 629.51 ⁇ mol, 60% purity, 1.3 eq) at 25 °C under N 2 . The mixture was stirred at 25 °C for 0.5 h under N 2 .
  • Step 3 trans-2-((4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)thio)pyrimidine
  • tert-butyl trans-3-(pyrimidin-2-ylthio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 120 mg, 237.11 ⁇ mol, 90% purity, 1 eq
  • HCl/dioxane 4 M, 1 mL, 16.87 eq
  • Step 4 1-(trans-3-(pyrimidin-2-ylthio)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-1- yl)prop-2-en-1-one [0241] To a solution of trans-2-((4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)thio)pyrimidine (90.00 mg, 206.72 ⁇ mol, 1 eq, HCl) and DIEA (122.21 mg, 945.60 ⁇ mol, 164.71 ⁇ L, 5 eq) in DCM (1 mL) was added acryloyl chloride (20.54 mg, 226.94 ⁇ mol, 18.50 ⁇ L, 1.2 eq).
  • Step 1 ethyl (E)-4-fluorobut-2-enoate [0242] To a solution of ethyl (E)-4-bromobut-2-enoate (400.0 mg, 2.07 mmol, 285.71 ⁇ L, 1 eq) in MeCN (10.0 mL) was added AgF (788.7 mg, 6.22 mmol, 134.81 ⁇ L, 3 eq), and the mixture was stirred at 25 °C for 24 h under N 2 in the dark. The mixture was concentrated under reduced pressure to give the title compound (225 mg, crude) as a yellow oil, which was used directly in next step.
  • Step 2 (E)-4-fluorobut-2-enoic acid [0243] To a solution of ethyl (E)-4-fluorobut-2-enoate (314.0 mg, 2.38 mmol, 1 eq) in THF (2.0 mL) and H 2 O (2.0 mL) was added LiOH . H 2 O (299.2 mg, 7.13 mmol, 3 eq), and the mixture was stirred for 2.5 h at 25 °C. The mixture was diluted with H 2 O (20 mL), pH adjusted to 4 with 2 N HCl, and then extracted with DCM (10 mL ⁇ 2).
  • Step 3 (E)-4-fluoro-1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)but-2-en-1-one [0244] To a solution of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine (70 mg, 196.45 ⁇ mol, 1 eq), (E)-4-fluorobut-2-enoic acid and N,N,N’,N’- tetramethylchloroformamidinium hexafluorophosphat (TCFH, 66.2 mg, 235.74 ⁇ mol, 1.2 eq) in MeCN (4.0 mL) was added N-methylimidazol (NMI, 56.5 mg, 687.59 ⁇ mol
  • Step 1 ethyl 4,4-difluoro-3-hydroxybutanoate [0245] To a solution of ethyl 4,4-difluoro-3-oxobutanoate (3.2 g, 19.26 mmol, 1 eq) in toluene (120 mL) was added NaBH4 (830.74 mg, 21.96 mmol, 1.14 eq) at 0 °C under N 2 atmosphere. The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched by the addition of saturated aqueous NH 4 Cl solution (100 mL) and extracted with EtOAc (100 mL ⁇ 3).
  • Step 2 ethyl (E)-4,4-difluorobut-2-enoate
  • a mixture of ethyl 4,4-difluoro-3-hydroxybutanoate (2.91 g, 15.58 mmol, 1 eq) and P 2 O 5 (1.11 g, 7.79 mmol, 480.65 ⁇ L, 0.5 eq) was stirred at 60 °C for 1 h under a N 2 atmosphere. The mixture was distilled at 120 °C under 0.05 mm-Hg pressure to afford the title compound (1.7 g, 10.19 mmol, 65.4% yield, 90% purity) as a colorless liquid.
  • Step 4 (E)-4,4-difluoro-1-((3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)but-2-en-1-one [0248] To a solution of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)pyrimidin-2-amine (120 mg, 251.61 ⁇ mol, 1 eq, 2HCl) in THF (1 mL) were added HATU (287.01 mg, 754.82 ⁇ mol, 3 eq) and TEA (178.22 mg, 1.76 mmol, 245.14 ⁇ L, 7 eq), followed by (E)-4,4-difluorobut-2-enoic acid (34.13 mg, 251.61 ⁇ mol, 1
  • Step 2 tert-butyl trans-3-(benzoylthio)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine- 1-carboxylate
  • tert-butyl trans-3-(benzoylthio)-4-hydroxypyrrolidine-1- carboxylate (1.22 g, 3.58 mmol, 95% purity, 1 eq) in DMF (20 mL) was added K 2 CO 3 (990.58 mg, 7.17 mmol, 2 eq) under N 2 .
  • Step 3 tert-butyl trans-3-mercapto-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl trans-3-(benzoylthio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 970 mg, 1.61 mmol, 1 eq
  • EtOH 10 mL
  • H 2 O 2 mL
  • LiOH ⁇ H 2 O 338.13 mg, 8.06 mmol, 5 eq
  • Step 4 tert-butyl trans-3-((5-fluoropyrimidin-2-yl)thio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate [0252] At 0 °C, to a mixture of tert-butyl trans-3-mercapto-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (200.00 mg, 450.43 ⁇ mol, 1 eq) in THF (10 mL) was added NaH (27.03 mg, 675.64 ⁇ mol, 60% purity, 1.5 eq) in portions (0.5 h) under N 2 .2-Chloro-5-fluoropyrimidine (89.54 mg, 675.64 ⁇ mol, 83.68 ⁇ L, 1.5 eq) was added, and the mixture was stirred at 25 °C for 2 h before being quenched with a saturated aqueous NH 4 Cl solution (5
  • Step 5 5-fluoro-2-((trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)thio)pyrimidine
  • trans-tert-butyl 3-((5-fluoropyrimidin-2-yl)thio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate 100.00 mg, 211.20 ⁇ mol, 1 eq
  • DCM 5 mL
  • HCl/dioxane 4 M, 2.50 mL, 47.35 eq
  • Step 6 1-(trans-3-((5-fluoropyrimidin-2-yl)thio)-4-((4- (trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)prop-2-en-1-one [0254] To a solution of 5-fluoro-2-((trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3- yl)thio)pyrimidine (80.00 mg, 195.20 ⁇ mol, 1 eq, HCl) in DCM (2 mL) were added DIEA (75.68 mg, 585.61 ⁇ mol, 102.00 ⁇ L, 3 eq) and acryloyl chloride (19.43 mg, 214.72 ⁇ mol, 17.51 ⁇ L, 1.1 eq) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 30 min before being quenched with water (10 mL).
  • the mixture was extracted with DCM (3 ⁇ 20 mL), and the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.
  • the residue was purified by prep- HPLC (column: Phenomenex C1875mm*30mm, 3 ⁇ m; mobile phase: [water (NH3 ⁇ H 2 O+NH 4 HCO 3 )-ACN]; B%: 40%-70%, 8min) to give the title compound (46.52 mg, 108.69 ⁇ mol, 55.7% yield, 99.9% purity) as a colorless gum.
  • Scheme 18 Synthetic route for the formation of 1-(trans-3-((5-fluoropyrimidin-2-yl)oxy)-4-(4- (trifluoromethyl)phenethyl)pyrrolidin-1-yl)prop-2-en-1-one. Compounds show relative stereochemistry.
  • Step 1 trans-tert-butyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate
  • tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate 5 g, 26.99 mmol, 1 eq
  • CuI 1.03 g, 5.40 mmol, 0.2 eq
  • THF 65 mL
  • bromo(vinyl)magnesium 1 M, 53.98 mL, 2 eq
  • reaction mixture was quenched with a saturated NH 4 Cl solution (80 mL) and filtered.
  • the filtrate was separated, and the aqueous layer was extracted with ethyl acetate (80 mL ⁇ 3).
  • the combined organics were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2 tert-butyl trans-3-formyl-4-hydroxypyrrolidine-1-carboxylate
  • tert-butyl trans-3-hydroxy-4-vinylpyrrolidine-1-carboxylate 200 mg, 937.77 ⁇ mol, 1 eq
  • NaIO 4 601.74 mg, 2.81 mmol, 3 eq
  • K2OsO4 ⁇ 2H 2 O 17.28 mg, 46.89 ⁇ mol, 0.05 eq
  • the reaction mixture was diluted with water (15 mL), and extracted with ethyl acetate (15 mL ⁇ 3). The combined organic layers were washed with saturated Na2SO3 solution (20 mL ⁇ 3) and brine (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (90 mg, 376.31 ⁇ mol, 40.1% yield, 90% purity) as a colorless gum, which was used directly in next step without further purification.
  • Step 3 triphenyl(4-(trifluoromethyl)benzyl)phosphonium bromide
  • a solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (911.35 mg, 3.81 mmol, 587.96 ⁇ L, 1 eq) and PPh3 (1 g, 3.81 mmol, 1 eq) in xylene (30 mL) was heated at 145 °C for 6 h. A white solid precipitated out after 0.5 h. The reaction mixture was cooled to room temperature and filtered.
  • Step 4 tert-butyl trans-3-hydroxy-4-(4-(trifluoromethyl)styryl)pyrrolidine-1- carboxylate
  • triphenyl(4-(trifluoromethyl)benzyl)phosphonium bromide 169.55 mg, 338.22 ⁇ mol, 1.3 eq
  • n-BuLi 2.5 M, 124.88 uL, 1.2 eq
  • reaction mixture was stirred at -78 °C for 30 mins, then a solution of tert-butyl trans-3-formyl-4-hydroxypyrrolidine-1-carboxylate (70 mg, 260.17 ⁇ mol, 1 eq) in THF (0.5 mL) was added.
  • the reaction mixture was warmed to 25 °C slowly and stirred at 25 °C for 3 h under N 2 .
  • the reaction mixture was quenched with a saturated NH 4 Cl solution (20 mL), and extracted with ethyl acetate (20 mL ⁇ 3). The combined organics were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered.
  • Step 5 tert-butyl trans-3-hydroxy-4-(4-(trifluoromethyl)phenethyl)pyrrolidine-1- carboxylate
  • E and Z mixture of tert-butyl trans-3-hydroxy-4-(4- (trifluoromethyl)styryl)pyrrolidine-1-carboxylate (45.00 mg, 113.33 ⁇ mol, 90% purity, 1 eq) in MeOH (10 mL) was added Pd/C (30 mg, 50.37 ⁇ mol, 10% purity, 1 eq).
  • Pd/C 30 mg, 50.37 ⁇ mol, 10% purity, 1 eq
  • Step 6 tert-butyl trans-3-((5-fluoropyrimidin-2-yl)oxy)-4-(4- (trifluoromethyl)phenethyl) pyrrolidine-1-carboxylate [0260] To a solution of tert-butyl trans-3-hydroxy-4-(4- (trifluoromethyl)phenethyl)pyrrolidine-1-carboxylate (38 mg, 95.16 ⁇ mol, 1 eq) in THF (1 mL) was added NaH (7.61 mg, 190.33 ⁇ mol, 60% purity, 2 eq) at 0 °C.
  • reaction mixture was stirred at 0 °C for 30 mins, then a solution of 2-chloro-5-fluoropyrimidine (16.39 mg, 123.71 ⁇ mol, 15.28 ⁇ L, 1.3 eq) in THF (0.1 mL) was added. The reaction mixture was stirred at 25 °C for 15 h. The reaction mixture was poured into stirring ice-water (10 mL) carefully, and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered.
  • Step 7 5-fluoro-2-((trans-4-(4-(trifluoromethyl)phenethyl)pyrrolidin-3- yl)oxy)pyrimidine
  • tert-butyl trans-3-((5-fluoropyrimidin-2-yl)oxy)-4-(4- (trifluoromethyl)phenethyl)pyrrolidine-1-carboxylate (30 mg, 59.28 ⁇ mol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 0.5 mL, 33.74 eq). The reaction mixture was stirred at 25 °C for 4.5 h.
  • Step 8 1-(trans-3-((5-fluoropyrimidin-2-yl)oxy)-4-(4- (trifluoromethyl)phenethyl)pyrrolidin-1-yl)prop-2-en-1-one [0262] To a solution of 5-fluoro-2-((trans-4-(4-(trifluoromethyl)phenethyl)pyrrolidin-3- yl)oxy)pyrimidine (23 mg, 52.83 ⁇ mol, 1 eq, HCl) and TEA (42.77 mg, 422.68 ⁇ mol, 58.83 ⁇ L, 8 eq) in DCM (2 mL) was added acryloyl chloride (19.13 mg, 211.34 ⁇ mol, 17.17 ⁇ L, 4 eq) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 2 h, before being quenched with water (0.1 mL).
  • the mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Welch Xtimate C18150mm*30mm, 5 ⁇ m; mobile phase: [water (NH 3 ⁇ H 2 O+NH 4 HCO 3 )-ACN]; B%: 56%-86%, 7min) to give the title compound (16.8 mg, 41.04 ⁇ mol, 77.7% yield, 100% purity) as a brown gum.
  • Example 27 Biological Assay 1, Assessment of TEAD cellular activity using MCF7 luciferase reporter assay [0263]
  • the MCF7 TEAD reporter cell line was purchased commercially.
  • the cell line contains the firefly luciferase gene under the control of TEAD responsive elements stably integrated into the human breast cancer cell line MCF7.
  • basal unphosphorylated YAP/TAZ remains in the nucleus and induces the constitutive expression of luciferase reporter. It is used to assess the in vitro cellular activity of TEAD inhibitors. Briefly, 10,000 cells/well were seeded in 384-well plates at 37 ⁇ C overnight. Compounds were added and then incubated at 37 ⁇ C for another 22-24 hours.
  • the compounds of the present invention were surprisingly found to possess upto a ten-fold greater plasma stability than prior art known compounds. Increased stability in human plasma is beneficial for potential therapeutic compounds.
  • compounds may be subject to enzymatic degradation in plasma, particularly hydrolases and esterases (Di et al., Int. J. Pharm.297(1– 2):110–119 (2005)).
  • the stability of drug candidates in plasma is essential for maintaining acceptable drug concentrations and half-life in order to achieve desirable pharmacological effects.
  • compounds with poor plasma stability tend to exhibit rapid clearance, short half-lives and consequently poor in vivo activity.

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Abstract

La présente invention concerne des composés représentés par la formule (I), dans laquelle R1, R2, X, Y, z1 et z2 sont tels que définis dans la description, et des sels pharmaceutiquement acceptables de ceux-ci. La présente invention concerne également des compositions pharmaceutiques comprenant un composé de formule (I), et des sels pharmaceutiquement acceptables de celui-ci, ainsi que des méthodes d'utilisation des composés et des compositions pour inhiber certaines interactions protéine-protéine et pour traiter le cancer.
PCT/US2023/035818 2022-10-25 2023-10-24 Inhibiteurs de tead heterocycliques WO2024091511A1 (fr)

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