WO2022120355A1 - Tead degraders and uses thereof - Google Patents

Tead degraders and uses thereof Download PDF

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Publication number
WO2022120355A1
WO2022120355A1 PCT/US2021/072685 US2021072685W WO2022120355A1 WO 2022120355 A1 WO2022120355 A1 WO 2022120355A1 US 2021072685 W US2021072685 W US 2021072685W WO 2022120355 A1 WO2022120355 A1 WO 2022120355A1
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ring
tbm
independently
formula
optionally substituted
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PCT/US2021/072685
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French (fr)
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Alfredo C. Castro
Michael Burke
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Ikena Oncology, Inc.
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Publication of WO2022120355A1 publication Critical patent/WO2022120355A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • TEAD DEGRADERS AND USES THEREOF SEQUENCE LISTING [0001] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 30, 2021, is named 187426_SL.txt and is 23,552 bytes in size. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for the modulation of Transcriptional Enhancer Associate Domain (TEAD) via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various diseases, disorders, and conditions as described herein.
  • TEAD Transcriptional Enhancer Associate Domain
  • Ubiquitin-Proteasome Pathway is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. [0004] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s.
  • UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
  • the pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting.
  • the UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation.
  • Bifunctional compounds composed of a target protein- binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression.
  • Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).
  • Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis.
  • the present application relates to novel bifunctional compounds, which function to recruit TEAD proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
  • the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of TEAD proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein.
  • monovalent compounds which find utility as inducers of targeted ubiquitination of TEAD proteins, which are then degraded and/or otherwise inhibited by the monovalent compounds as described herein.
  • An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of TEAD proteins.
  • the description provides methods of using an effective amount of the compounds as described herein for the treatment of various diseases, disorders, and conditions as described herein.
  • the present application further relates to targeted degradation of TEAD proteins through the use of bifunctional molecules, including bifunctional molecules that link a cereblon- binding moiety to a ligand that binds TEAD proteins.
  • the present invention provides a compound having the general formula I: or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined and described herein.
  • the present invention provides a compound having the general formula II: or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined and described herein.
  • Compounds of the present invention, and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating TEAD proteins. Such diseases, disorders, or conditions include those described herein.
  • FIG.1 depicts a schematic of Hippo pathway signaling.
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to LBM; and LBM is a ligase binding moiety.
  • TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to DIM; and DIM is a degradation inducing moiety.
  • Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bridged bicyclics include: [0021]
  • the term “lower alkyl” refers to a C 1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • alkylene refers to a bivalent alkyl group.
  • alkylene chain is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable monovalent substituents on R ° are independently halogen, is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1–4 aliphatic, – CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2– 3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, wherein each is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – or -NO 2 , wherein each is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the provided compounds are purified in salt form for convenience and/or ease of purification, e.g., using an acidic or basic mobile phase during chromatography.
  • Salts forms of the provided compounds formed during chromatographic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers.
  • the term “provided compound” refers to any genus, subgenus, and/or species set forth herein.
  • the terms “inhibitor” or “TEAD inhibitor” or “TEAD antagonist” are defined as a compound that binds to and/or inhibits TEAD with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • an inhibitor has an IC 50 and/or binding constant of less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • the term “degrader” is defined as a heterobifunctional compound that binds to and/or inhibits both a TEAD protein and an E3 ligase with measurable affinity resulting in the ubiquitination and subsequent degradation of the TEAD protein. In some embodiments, degradation in the presence of the degrader is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • the potency of a degrader is usually defined by its DC 50 value (the 50% degradation concentration).
  • a degrader has an DC 50 of less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • the term “monovalent” refers to a degrader compound without an appended E3 ligase binding moiety.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in TEAD activity between a sample comprising a compound of the present invention, or composition thereof, and TEAD, and an equivalent sample comprising TEAD, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to LBM; and LBM is a ligase binding moiety.
  • the present invention provides a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to DIM; and DIM is a degradation inducing moiety.
  • Ligase Binding Moiety LBM
  • LBM is an E3 ligase ligand.
  • E3 ligase ligands are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T.
  • the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-a-1, I-a-2, I-a-3, I-a-4, I-a-5, I-a-6, I-a-7, I-a-8, I-a-9, or I-a-10 respectively: I-a-9 I-a-10 or a compound of formula I-a ⁇ -1, I-a ⁇ -2, I-a ⁇ -3, I-a ⁇ -4, I-a ⁇ -5, I-a ⁇ -6, I-a ⁇ -7, I-a ⁇ -8, I-a ⁇ -9, or I-a ⁇ - 10 respectively: or a compound of formula I-a ⁇ -1, I-a ⁇ -2, I-a ⁇ -3, I-a ⁇ -4, I-a ⁇ -5, I-a ⁇ -6, I-a ⁇ -7, I-a ⁇ -8, I-a ⁇ -9, or I-a ⁇ -10 respectively:
  • each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables , X, X 1 , X 2 , Y, R 1 , R 3 , R 3 ’, R 4 , R 5 , t, m and n is independently as defined and described in WO 2017/007612 and US 2018/0134684, the content of each of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4, I-b-5, or I-b-6 respectively: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A, G, G’, Q 1 , Q 2 , Q 3 , Q 4 , R, R’, W, X, Y, Z, , and n is independently as defined and described in WO 2016/197114 and US 2018/0147202, the content of each of which is herein incorporated by reference in its entirety.
  • LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4, I-b-5,
  • LBM is or . In some embodiments, LBM is In some embodiments, LBM is . In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is [0056] In some embodiments, LBM is or In some embodiments, LBM is In some embodiments, LBM is . In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is [0057] In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is .
  • LBM is [0058]
  • the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-c-1, I-c-2, or I-c-3 respectively:
  • each of L and TBM is independently as defined above and described herein, and wherein each of the variables R 1 , R 2 , R 4 , R 5 , R 10 , R 11 , R 14 , R 17 , W 1 , W 2 , X, , and n is independently as defined in WO 2017/197051, the content of which is herein incorporated by reference in its entirety, and wherein 1 is attached to R , the ring formed by combining R 1 and R 2 , or R 17 at the site of attachment of R 12 as defined in WO 2017/197051 such that takes the place of the R 12 substituent.
  • the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-d-1, I-d-2, I-d-3, or I-d-4, respectively: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described herein, and wherein each of the variables R 1 , R 4 , R 10 , R 11 , R 14 , R 16 , W 1 , W 2 , X, , and n is independently as defined in WO 2018/237026, the content of which is herein incorporated by reference in its entirety, and wherein is attached to R 1 or R 16 at the site of attachment of R 12 as defined in WO 2018/237026, such that takes the place of the R 12 substituent.
  • LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-d-1, I-d-2,
  • the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-e-1 or I-e-3, respectively: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described herein, and wherein each of the variables R 1 , R 14 , and R 16 is independently as defined in WO 2018/237026, the content of which is herein incorporated by reference in its entirety, and wherein 1 16 is attached to R or R at the site of attachment of R 12 as defined in WO 2018/237026, such that takes the place of the R 12 substituent.
  • LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-e-1 or I-e-3, respectively: or a pharmaceutically acceptable salt thereof
  • each of L and TBM is independently as defined above and described herein
  • the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5, I-f-6, I-f-7, or I-f-8: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, L, x, y, and is independently as described and defined in WO 2017/161119, the content of which is herein incorporated by reference in its entirety.
  • LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f
  • the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-g: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A, B, C, W, X, Y, and Z is independently as described and defined in US 5,721,246, the content of which is herein incorporated by reference in its entirety.
  • LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-g: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A, B, C, W, X, Y, and Z is independently as described and defined in US 5,721,246, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-h: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 2 , and n is independently as described and defined in WO 2019/043214, the content of which is herein incorporated by reference in its entirety .
  • LBM is an IAP E3 Ubiquitin ligase binding moiety recited in Varfolomeev, E.
  • IAP Antagonists Induce Autoubiquitination of c-IAPs, NF- ⁇ B activation, and TNF ⁇ -Dependent Apoptosis, Cell, 2007, 131(4): 669-81, such as, for example:
  • the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-i-1, I-i-2, I-i-3, I-i-4, or I-i-5 respectively: I-i-5 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1’ , R 2’ , R 3’ , X, and X’ is as independently defined and described in WO 2013/106643 and US 2014/0356322, the content of each of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-j-1, I-j-2, I-j-3, I-j-4, I-j-5 or I-j-6 respectively:
  • each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1’ , R 2’ , R 3’ , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 14 , R 15 , R 16 , R 17 , R 23 , R 25 , E, G, M, X, X’, Y, Z 1 , Z 2 , Z 3 , Z 4 , and o is independently as defined and described in WO 2016/149668 and US 2016/0272639, the content of each of which is herein incorporated by reference in its entirety.
  • brackets around any LBM means that the moiety is covalently attached to said LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom.
  • available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structure are depicted below, wherein each wavy bond defines the point of attachment to said , .
  • the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-k-1, I-k-2, or I-k-3 respectively: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R p , R 9 , R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , W 3 , W 4 , W 5 , X 1 , X 2 , and o is independently as defined and described in WO 2016/118666 and US 2016/0214972, the content of each of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of Formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-l-1, I-l-2, I-l-3, I-l-4, I-l-5, I-l-6, or I-l-7 respectively:
  • each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A 1 , A 2 , A 3 , R 5 , G and Z is independently as defined and described in WO 2017/176958, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of Formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-l ⁇ -1, I-l ⁇ -1, I-l ⁇ -2, I-l ⁇ -2, I-l ⁇ -3, I-l ⁇ -3, I-l ⁇ -4, I-l ⁇ -4, I-l ⁇ -7 or I-l ⁇ -7 respectively: I-l ⁇ -7 I-l ⁇ -7 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A 1 , A 2 , A 3 , R 5 , G and Z is independently as defined and described in WO 2017/176958, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of Formula I, wherein LBM is a MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety thereby forming a compound of formula I-m-1, I-m-2, I-m-3, I-m-4, I-m-5, I-m-6, I-m-7, I-m-8, I-m-9, I-m-10, I-m-11, I-m-12, I-m-13, I-m-14, I-m-15, I-m-16, I-m-17, or I-m-18 respectively:
  • MDM2 i.e., human double minute 2 or HDM2
  • the present invention provides a compound of Formula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-n-1, I-n-2, I-n-3, or I-n-4 respectively: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , is independently as defined and described in WO 2017/011590 and US 2017/0037004, the content of each of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-o-1, I-o-2, or I-o-3:
  • each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables X, W 3 , W 5 , R 9 , R 10 , R 11 , R 14a , R 14b , R 15 , R 16 , and o is independently as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, the content of each of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is an IAP binding moiety thereby forming a compound of formula I-p: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables W, Y, Z, R 1 , R 2 , R 3 , R 4 , and R 5 is independently as described and defined in WO 2014/044622, US 2015/0225449, WO 2015/071393, and US 2016/0272596, the content of each of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a MDM2 binding moiety thereby forming a compound of formula I-q:
  • the present invention provides a compound of formula I, wherein LBM is a DCAF16 binding moiety thereby forming a compound of formula I-r: or a pharmaceutically acceptable salt thereof, as described and defined in Zhang, X. et al., bioRxiv (doi: https://doi.org/10.1101/443804), the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a RNF114 binding moiety thereby forming a compound of formula I-s: or a pharmaceutically acceptable salt thereof, as described and defined in Spradin, J.N. et al., bioRxiv (doi: https://doi.org/10.1101/436998), the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a RNF4 binding moiety thereby forming a compound of formula I-t: I-t or a pharmaceutically acceptable salt thereof, as described and defined in Ward, C.C., et al., bioRxiv (doi: https://doi.org/10.1101/439125), the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-u-1 or I-u-2: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 2 , R 3 , X, and Y is independently as defined and described in WO 2019/084026, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-v-1 or I-v-2: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 3 , and Y is independently as defined and described in WO 2019/084030, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-w-1, I-w-2, I-w-3, or I-w-4: I-w-1 I-w-2 I-w-3 I-w-4 or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and described herein, and wherein each of the variables R 4 , R 10 , R 11 , R 15 , R 16 , R 17 , W 1 , W 2 , and X is as defined in WO 2019/099868, the content of which is herein incorporated by reference in its entirety, and wherein is attached to R 17 or R 16 at the site of attachment of R 12 as defined in WO 2018/237026, such that takes the place of the R 12 substituent.
  • LBM is a E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-
  • the present invention provides a compound of formula I, wherein LBM is a RPN13 binding moiety thereby forming a compound of formula I-x: I-x or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and described in embodiments herein, and wherein each of the variables A, Y, and Z is as described and defined in WO 2019/165229, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a Ubr1 binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem.
  • the present invention provides a compound of formula I, wherein LBM is a CRBN binding moiety thereby forming a compound of formula I-z: I-z or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 2 , R 3 , R 4 , R 5 , Q, X, and n is independently as described and defined in US 2019/276474, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-aa-1, I-aa-2, I-aa-3 or I-aa-4: I-aa-1 I-aa-2 I-aa-3 I-aa-4 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Y, A 1 ,and A 3 is independently as described and defined in WO 2019/236483, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-bb-1, I-bb-2, I-bb-3, or I-bb-4: I-bb-4 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Ring A, Ring B, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , m, n, and p is independently as described and defined in WO 2019/060693, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-cc-1: I-cc-1 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, wherein each of the variables Ring A, Ring B, R 1 , R 2 , m, and n is independently as described and defined in WO 2019/140387, and wherein variable L’ corresponds to variable L in WO 2019/140387 and is selected from the embodiments for variable L as described and defined in WO 2019/140387.
  • the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-dd-1: I-dd-1 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, wherein each of the variables Ring A, R 1 , R 2 , X 1 , X 2 , X 3 , and m is independently as described and defined in WO 2020/010177, the content of which is herein incorporated by reference in its entirety.
  • LBM is selected from those depicted in Table 1, below.
  • DIM Degradation Inducing Moiety
  • the present invention provides a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as described above and herein, and DIM is a degradation inducing moiety selected from LBM, a lysine mimetic, or a hydrogen atom.
  • DIM is LBM as described above and herein.
  • DIM is a lysine mimetic.
  • the covalent attachment of ubiquitin to one or more members of the TEAD protein family is achieved through the action of a lysine mimetic.
  • TEAD1, TEAD2, TEAD3, or TEAD4 the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD1 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
  • UBP Ubiquitin-Proteasome Pathway
  • the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD2 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
  • the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD3 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
  • the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD4 for degradation via the Ubiquitin- Proteasome Pathway (UPP).
  • DIM is .
  • DIM is .
  • DIM is [0093]
  • the present invention provides the compound of formula II as a compound of formula II-a: II-a or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides the compound of formula II as a compound of formula II-b: II-b or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides the compound of formula II as a compound of formula II-c: II-c or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula II, wherein DIM is a lysine mimetic , , or ; thereby forming a compound of Formulae II-d-1, II-d-2, or II- d-3, respectively: or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R 1 , R 4 , R 5 , A, B, E, Y, Y ⁇ , Z, Z ⁇ , and k is independently as defined and described in U.S. Pat. No.7,622,496, the content of which is herein incorporated by reference in its entirety.
  • DIM is a hydrogen atom.
  • the covalent attachment of ubiquitin to one or more members of the TEAD protein family i.e., TEAD1, TEAD2, TEAD3, or TEAD4 is achieved through a provided compound wherein DIM is a hydrogen atom.
  • the moiety being hydrogen upon the binding of a compound of formula II to TEAD1, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD1 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
  • UBP Ubiquitin-Proteasome Pathway
  • the moiety being hydrogen upon the binding of a compound of formula II to TEAD2, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD2 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
  • the moiety being hydrogen upon the binding of a compound of formula II to TEAD3, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD3 for degradation via the Ubiquitin- Proteasome Pathway (UPP).
  • the moiety being hydrogen upon the binding of a compound of formula II to TEAD4 the moiety being hydrogen effectuates ubiquitination thereby marking TEAD4 for degradation via the Ubiquitin-Proteasome Pathway (UPP).
  • the present invention provides the compound of formula II wherein DIM is a hydrogen atom, thereby forming a compound of formula II-d-4: or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination.
  • DIM is selected from those depicted in Table 1, below.
  • TEAD Binding Moiety TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4.
  • TBM is a TEAD binding moiety capable of binding to TEAD1.
  • TBM is a TEAD binding moiety capable of binding to TEAD2. In some embodiments, TBM is a TEAD binding moiety capable of binding to TEAD3. In some embodiments, TBM is a TEAD binding moiety capable of binding to TEAD4. [00102] In some embodiments, TBM is a compound or a TEAD binding moiety as described in Pobbati et al., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy,” Structure 2015, 23, 2076–2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem.
  • TBM TEAD Binding Moiety
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula A: , thereby forming a compound of formula I-A or II-A: I-A II-A or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C, -N(R)C
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula A-1: thereby forming a compound of formula I-A-1 or II-A-1: I-A-1 II-A-1 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(N(R)-, -
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, - (R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)
  • L 1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, - SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(
  • L 1 is a covalent bond.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are optionally replaced with -CH(SR)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -S-, or -N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - CH(OR)-, -CH(SR)-, or –CH(N(R) 2 )-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO 2 -, -C(S)-, -C(S)O-, or -OC(S)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O- , -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-.
  • L 1 is -O-, -CH(OR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-.
  • L 1 is -CH(SR)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)- , -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O-, -S-, or -N(R)-. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -S-.
  • L 1 is -N(R)-. In some embodiments, L 1 is - NH-. [00120] In some embodiments, L 1 is -CH(OR)-, -CH(SR)-, or –CH(N(R) 2 )-. In some embodiments, L 1 is -CH(OR)-. In some embodiments, L 1 is -CH(SR)-. In some embodiments, L 1 is –CH(N(R) 2 )-.
  • L 1 is -C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO 2 -, -C(S)-, -C(S)O-, or -OC(S)-.
  • L 1 is -C(O)-.
  • L 1 is -C(O)O-.
  • L 1 is -OC(O)-.
  • L 1 is -SO-.
  • L 1 is -SO 2 - .
  • L 1 is -C(S)-.
  • L 1 is -C(S)O-.
  • L 1 is -OC(S)-.
  • L 1 is -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -C(O)N(R)-.
  • L 1 is -(R)NC(O)-.
  • L 1 is -OC(O)N(R)-. In some embodiments, L 1 is -(R)NC(O)O-. In some embodiments, L 1 is - N(R)C(O)N(R)-. In some embodiments, L 1 is -SO 2 N(R)-. In some embodiments, L 1 is -(R)NSO 2 - . In some embodiments, L 1 is -C(S)N(R)-. In some embodiments, L 1 is -(R)NC(S)-. or In some embodiments, L 1 is -(R)NC(S)N(R)-.
  • L 1 is –CH 2 -, -CH(CH 3 )-, -NH-CH 2 -, -NH-CH(CH 3 )-, -C(O)- NH-, or –N(CH 3 )-. [00124] In some embodiments, L 1 is [00125] In some embodiments, L 1 is selected from those depicted in Table A, below.
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, –NO 2 , or -C 1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO 2 .
  • Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is optionally substituted phenyl. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring.
  • Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00129] In some embodiments, Ring A is optionally substituted phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen. [00130] In some embodiments, Ring A is optionally substituted .
  • Ring A is optionally substituted 1-2 times by -halogen, -CN, – NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 0-6 times by -halogen, -CN, or –NO 2 .
  • Ring A is optionally substituted 1-2 times by halogen, -CN, –NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO 2 .
  • Ring A is optionally substituted 1-2 times by halogen, -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00133] In some embodiments, Ring A is a 8-10 membered bicyclic aromatic ring.
  • Ring A is a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is optionally substituted 1-2 times by halogen, -CN, – NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO 2 .
  • Ring A is optionally substituted 1-2 times by halogen, or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen.
  • Ring A is selected from and wherein each of R 1 and R 7 is independently as described herein.
  • Ring A is selected from , , or [00137]
  • R 1 is -H, -halogen, -CN, –NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 1 is unsubstituted –O-C 1-6 aliphatic.
  • R 1 is –OCH 3 .
  • R 1 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is –O-C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 1 is –OCF 3 . In some embodiments, R 1 is .
  • R 1 is -H, -halogen, -CN, –NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 1 is –H.
  • R 1 is –halogen.
  • R 1 is –F.
  • R 1 is –Cl.
  • R 1 is –Br.
  • R 1 is –CN.
  • R 1 is –NO 2 .
  • R 1 is unsubstituted -C 1-6 aliphatic.
  • R 1 is – CH 3 . In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 1 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 1 is –CF 3 . In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN.
  • R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO 2 .
  • R 7 is -H, -halogen, -CN, –NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 7 is unsubstituted –O-C 1-6 aliphatic.
  • R 7 is –OCH 3 .
  • R 7 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 7 is –O-C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 7 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 7 is –OCF 3 . In some embodiments, R 7 is .
  • R 7 is -H, -halogen, -CN, –NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 7 is –H.
  • R 7 is –halogen.
  • R 7 is –F.
  • R 7 is –Cl.
  • R 7 is –Br.
  • R 7 is –CN.
  • R 7 is –NO 2 .
  • R 7 is unsubstituted -C 1-6 aliphatic.
  • R 1 is – CH 3 .
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R 7 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R 7 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R 7 is –CF 3 .
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN.
  • R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO 2 .
  • Ring A is or [00142] In some embodiments, Ring A is [00143] In some embodiments, Ring A is selected from those depicted in Table A, below.
  • Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is optionally substituted phenyl. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic aromatic ring.
  • Ring B is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00146] In some embodiments, Ring B is optionally substituted phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen.
  • Ring B is optionally substituted [00148] In some embodiments, Ring B is optionally substituted 1-4 times by halogen, - S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , -C(O)OR, -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 0-6 times by halogen, - CN, or –NO 2 .
  • Ring B is optionally substituted 1-4 times by –F, -Cl, -Br-, - S(O) 2 NHCH 3 , -S(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 3 , -C(O)OH, -C(O)OCH 3 , -CH 3 , – OCH 3 , or -C(CH 3 ) 3 .
  • Ring B is [00151] In some embodiments, Ring B is selected from those depicted in Table A, below.
  • R 2 is -H, or an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is –H.
  • R 2 is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C 1-6 alkyl.
  • R 2 is , wherein R is as described herein. In some embodiments, R 2 is , wherein R is as described herein. [00156] In some embodiments, R 2 is 2 . In some embodiments, R is , or . [00157] In some embodiments, R 2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen. In some embodiments, R 2 is selected from and In 2 some embodiments, R is [00158] In some embodiments, R 2 is or . [00159] In some embodiments, R 2 is selected from those depicted in Table A, below. [00160] As defined generally above, in some embodiments, R 3 is –H.
  • R 3 is . In som 3 e embodiments, R is , , or [00162] In some embodiments, R 3 is selected from those depicted in Table A, below. [00163] As defined generally above, R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or - C(O)N(R) 2 . [00164] In some embodiments, R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , or - C(O)OR.
  • R 4 is –H. [00166] In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -Br. [00167] In some embodiments, R 4 is -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or -C(O)N(R) 2 . In some embodiments, R 4 is -S(O) 2 N(R) 2 . In some embodiments, R 4 is -S(O)N(R) 2 . In some embodiments, R 4 is -C(O)N(R) 2 .
  • R 4 is -S(O) 2 NHCH 3 .
  • R 4 is -S(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 3 , -C(O)OH, or -C(O)OCH 3 .
  • R 4 is 4 In some embodiments, R is or [00170] In some embodiments, R 4 is selected from those depicted in Table A, below. [00171] As defined generally above, R 6 is -H or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is –H, -halogen, -CN, –NO 2 , -C 1-6 aliphatic, -OC 1-6 aliphatic, or a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C 1-6 aliphatic or -OC 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -OC 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is –H.
  • R 6 is –F.
  • R 6 is –Cl. In some embodiments, R 6 is –Br. In some embodiments, R 6 is –CN. In some embodiments, R 6 is –NO 2 . [00174] In some embodiments, R 6 is -C 1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by - halogen, -CN, or –NO 2 . In some embodiments, R 6 is unsubstituted -C 1-6 aliphatic. In some embodiments, R 6 is –CH 3 . In some embodiments, R 6 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R 6 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 6 is –CF 3 . [00175] In some embodiments, R 6 is -OC 1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R 6 is unsubstituted -OC 1-6 aliphatic. In some embodiments, R 6 is –OCH 3 .
  • R 6 is -OC 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R 6 is -OC 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R 6 is -OC 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 6 is –OCF 3 .
  • R 6 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C 1-6 aliphatic or -OC 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -OC 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is a 5-membered ring having 1, 2, 3, or 4 nitrogen optionally substituted 1-3 times by -C 1-6 aliphatic.
  • R 6 is [00177] In some embodiments, R 6 is selected from those depicted in Table A, below. [00178] As defined generally above, R w is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00179] In some embodiments, R w is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R w is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C 1-6 alkyl.
  • R w is , wherein R is as described herein. In some embodiments, R w is , wherein R is as described herein. [00181] In some embodiments, R w is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C 1-6 alkyl. In some embodiments, R w is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen.
  • R w is [00182] In some embodiments, R w is [00183] In some embodiments, R w is , or [00184] In some embodiments, R w is selected from those depicted in Table A, below. [00185] As defined generally above, R is independently -H or optionally substituted -C 1-6 aliphatic. [00186] In some embodiments, R is –H. [00187] In some embodiments, R is optionally substituted -C 1-6 aliphatic. In some embodiments, R is unsubstituted -C 1-6 aliphatic. In some embodiments, R is –CH 3 .
  • R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CF 3 . [00188] In some embodiments, R is selected from those depicted in Table A, below.
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula A-2: , thereby forming a compound of formula I-A-2 or II-A-2: or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, DIM, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and L 1 is independently as defined and described in embodiments in Section of TBM of Formulas A, and A-1 to A-50.
  • the present invention provides a compound of formula I-A-2 or II-A-2, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein: (a): L 1 is -O- or -S-; R 1 is -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen; R 2 is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen; R 3 is -H; R 4 is -S(O) 2 N(R) 2 ; -S(O)N(R) 2 , or -C(O)N(R) 2 , each R independently is selected -H and optionally substituted -C 1-6 aliphatic; R 6 is -H or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen; and R 7 is -H; or (b): L 1 is -O- or -
  • the present invention provides a compound of Formula I-A or II-A, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen; Ring B is phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen; and each of R w and L 1 is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: i. Formula (A-19) or (A-20): A-19 A-20 wherein L 1 is a C 2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R 2 , R 4 , R 6 , and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; ii.
  • L 1 is a C 2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F, and R 2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; v.
  • TBM is a moiety set forth in Table A, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table A.
  • Table A Exemplified TEAD Binding Moiety (TBM) 2. TEAD Binding Moiety (TBM) of Formulas B, and B-1 to B-34
  • TBM TEAD Binding Moiety of Formulas B, and B-1 to B-34
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety as described in PCT/US2020/35111, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula B: thereby forming a compound of formula I-B or II-B: or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)-, -N(R
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of formula B-1 thereby forming a compound of formula I-B-1 or II-B-1: or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)N(R)-,
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, - (R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)
  • L 1 is a covalent bond, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, - SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(
  • L 1 is a covalent bond.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are optionally replaced with -CH(SR)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -S-, or -N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - CH(OR)-, -CH(SR)-, or –CH(N(R) 2 )-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO 2 -, -C(S)-, -C(S)O-, or -OC(S)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O-, -CH(OR)-, -CH(SR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O- , -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-.
  • L 1 is -O-, -CH(OR)-, –CH(N(R) 2 )-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-.
  • L 1 is -CH(SR)-, -S-, -SO-, -SO 2 -, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)- , -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-.
  • L 1 is -O-, -S-, or -N(R)-. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -S-.
  • L 1 is -N(R)-. In some embodiments, L 1 is - NH-. [00213] In some embodiments, L 1 is -CH(OR)-, -CH(SR)-, or –CH(N(R) 2 )-. In some embodiments, L 1 is -CH(OR)-. In some embodiments, L 1 is -CH(SR)-. In some embodiments, L 1 is –CH(N(R) 2 )-.
  • L 1 is -C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO 2 -, -C(S)-, -C(S)O-, or -OC(S)-.
  • L 1 is -C(O)-.
  • L 1 is -C(O)O-.
  • L 1 is -OC(O)-.
  • L 1 is -SO-.
  • L 1 is -SO 2 - .
  • L 1 is -C(S)-.
  • L 1 is -C(S)O-.
  • L 1 is -OC(S)-. [00215] In some embodiments, L 1 is -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -SO 2 N(R)-, -(R)NSO 2 -, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. In some embodiments, L 1 is -C(O)N(R)-. In some embodiments, L 1 is -(R)NC(O)-.
  • L 1 is -OC(O)N(R)-. In some embodiments, L 1 is -(R)NC(O)O-. In some embodiments, L 1 is - N(R)C(O)N(R)-. In some embodiments, L 1 is -SO 2 N(R)-. In some embodiments, L 1 is -(R)NSO 2 - . In some embodiments, L 1 is -C(S)N(R)-. In some embodiments, L 1 is -(R)NC(S)-. or In some embodiments, L 1 is -(R)NC(S)N(R)-.
  • L 1 is –CH 2 -, -CH(CH 3 )-, -NH-CH 2 -, -NH-CH(CH 3 )-, -C(O)- NH-, or –N(CH 3 )-. [00217] In some embodiments, L 1 is , [00218] In some embodiments, L 1 is selected from those depicted in Table B, below.
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, –NO 2 , or -C 1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO 2 .
  • Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is optionally substituted phenyl. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring.
  • Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00222] In some embodiments, Ring A is optionally substituted phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen.
  • Ring A is optionally substituted [00224] In some embodiments, Ring A is optionally substituted 1-2 times by -halogen, -CN, – NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 0-6 times by -halogen, -CN, or –NO 2 .
  • Ring A is optionally substituted 1-2 times by halogen, -CN, –NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO 2 .
  • Ring A is optionally substituted 1-2 times by halogen, -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00226] In some embodiments, Ring A is a 8-10 membered bicyclic aromatic ring.
  • Ring A is a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00227] In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -CN, – NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO 2 . In some embodiments, Ring A is optionally substituted 1-2 times by halogen, or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen. [00228] In some embodiments, Ring A is selected from , wherein each of R 1 and R 7 is independently as described herein.
  • Ring A is selected from , .
  • R 1 is -H, -halogen, -CN, –NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 1 is unsubstituted –O-C 1-6 aliphatic.
  • R 1 is –OCH 3 .
  • R 1 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is –O-C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. [00231] In some embodiments, R 1 is -H, -halogen, -CN, –NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R 1 is –H.
  • R 1 is –halogen. In some embodiments, R 1 is –F. In some embodiments, R 1 is –Cl. In some embodiments, R 1 is –Br. In some embodiments, R 1 is –CN. In some embodiments, R 1 is –NO 2 . In some embodiments, R 1 is unsubstituted -C 1-6 aliphatic. In some embodiments, R 1 is – CH 3 . In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 1 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 1 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 1 is –CF 3 . In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN. In some embodiments, R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO 2 . [00232] In some embodiments, R 1 is phenyl. In some embodiments, R 1 is –C(CH 3 ) 3 .
  • R 1 is –SCF 3 . In some embodiments, R 1 is –S(O) 2 CF 3 . In some embodiments, R 1 is –N(CH 3 ) 2 . In some embodiments, R 1 is -CHF 2 . In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is -CF 2 CF 3 . In some embodiments, R 1 is .
  • R 7 is -H, -halogen, -CN, –NO 2 , -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 7 is unsubstituted –O-C 1-6 aliphatic.
  • R 7 is –OCH 3 .
  • R 7 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R 7 is –O-C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 7 is –O-C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. [00234] In some embodiments, R 7 is -H, -halogen, -CN, –NO 2 , or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R 7 is –H. In some embodiments, R 7 is –halogen. In some embodiments, R 7 is –F. In some embodiments, R 7 is –Cl.
  • R 7 is –Br. In some embodiments, R 7 is –CN. In some embodiments, R 7 is –NO 2 . In some embodiments, R 7 is unsubstituted -C 1-6 aliphatic. In some embodiments, R 1 is – CH 3 . In some embodiments, R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 7 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R 7 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 7 is –CF 3 . In some embodiments, R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN. In some embodiments, R 7 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO 2 . [00235] In some embodiments, R 7 is phenyl. In some embodiments, R 7 is –C(CH 3 ) 3 . In some embodiments, R 7 is –SCF 3 . In some embodiments, R 7 is –S(O) 2 CF 3 .
  • R 7 is –N(CH 3 ) 2 . In some embodiments, R 7 is -CHF 2 . In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 is -CF 2 CF 3 . In some embodiments, R 7 is . [00236] In some embodiments, Ring A is [00237] In some embodiments, Ring A is [00238] In some embodiments, Ring A is selected from those depicted in Table B, below.
  • Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is optionally substituted phenyl. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic aromatic ring.
  • Ring B is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is an optionally substituted 6-, 7-, 8-, 9-, or 10- membered bicyclic carbocyclic ring.
  • Ring B is an optionally substituted 6- , 7-, 8-, 9-, or 10-membered bicyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is an optionally substituted 6-membered bicyclic heterocyclic ring having 1 nitrogen.
  • Ring B is optionally substituted phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen. [00243] In some embodiments, Ring B is optionally substituted [00244] In some embodiments, Ring B is optionally substituted 1-4 times by halogen, - S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , -C(O)OR, -C 1-6 aliphatic, or –O-C 1-6 aliphatic, wherein each of -C 1-6 aliphatic and –O-C 1-6 aliphatic is independently substituted 0-6 times by halogen, - CN, or –NO 2 .
  • Ring B is optionally substituted 1-4 times by –F, -Cl, -Br-, - S(O) 2 NHCH 3 , -S(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 3 , -C(O)OH, -C(O)OCH 3 , -CH 3 , – OCH 3 , or -C(CH 3 ) 3 .
  • Ring B is , , , [00247]
  • Ring B is [00248]
  • Ring B is selected from those depicted in Table B, below.
  • R 2 is -H, or a warhead group.
  • R 2 is –H.
  • R 2 is a warhead group.
  • R 2 is , , , , , In some emb 2 odiments, R is , , [00252] In some embodiments, R 2 is selected from those depicted in Table B, below.
  • R 3 is -H or a warhead group.
  • R 3 is –H.
  • R 3 is a warhead group.
  • R 3 is , , 3 , , In some embodiments, R is , [00256] In some embodiments, R 3 is selected from those depicted in Table B, below. [00257] As defined generally above, R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , or a warhead group.
  • R 4 is -H, halogen, -S(O) 2 N(R) 2 , -S(O)N(R) 2 , -C(O)N(R) 2 , - C(O)OR, or a warhead group. [00259] In some embodiments, R 4 is –H. [00260] In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -Br.
  • R 4 is -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or -C(O)N(R) 2 . In some embodiments, R 4 is -S(O) 2 N(R) 2 . In some embodiments, R 4 is -S(O)N(R) 2 . In some embodiments, R 4 is -C(O)N(R) 2 . In some embodiments, R 4 is -S(O) 2 NHCH 3 .
  • R 4 is -S(O)NHCH 3 , -C(O)N(CH 3 ) 2 , -C(O)NHCH 3 , -C(O)OH, or -C(O)OCH 3 .
  • R 4 is a warhead group.
  • R 4 is , , , In some embodimen 4 ts, R is [00264] In some embodiments, R 4 is selected from those depicted in Table B, below.
  • R 6 is -H or -C 1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is –H, -halogen, -CN, –NO 2 , -C 1-6 aliphatic, -OC 1-6 aliphatic, or a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C 1-6 aliphatic or -OC 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -OC 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is –H. In some embodiments, R 6 is –F. In some embodiments, R 6 is –Cl. In some embodiments, R 6 is –Br. In some embodiments, R 6 is –CN. In some embodiments, R 6 is –NO 2 . [00268] In some embodiments, R 6 is -C 1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by - halogen, -CN, or –NO 2 . In some embodiments, R 6 is unsubstituted -C 1-6 aliphatic. In some embodiments, R 6 is –CH 3 .
  • R 6 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R 6 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R 6 is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 6 is –CF 3 . [00269] In some embodiments, R 6 is -OC 1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is unsubstituted -OC 1-6 aliphatic. In some embodiments, R 6 is –OCH 3 . In some embodiments, R 6 is -OC 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R 6 is -OC 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R 6 is -OC 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R 6 is –OCF 3 .
  • R 6 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C 1-6 aliphatic or -OC 1-6 aliphatic, wherein each of -C 1-6 aliphatic and -OC 1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R 6 is a 5-membered ring having 1, 2, 3, or 4 nitrogen optionally substituted 1-3 times by -C 1-6 aliphatic.
  • R 6 is [00271] In some embodiments, R 6 is selected from those depicted in Table B, below. [00272] As defined generally above, R w is a warhead group; wherein when R w is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B. [00273] In some embodiments, R w is a warhead group. [00274] In some embodiments, R w is [00275] In some embodiments, wherein R w is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, R w forms a spiro bicyclic ring with Ring B.
  • R w is a saturated or partially unsaturated 4-, 5-, or 6- membered carbocyclic or heterocyclic ring
  • R w forms a spiro bicyclic ring with Ring B.
  • R w is optionally substituted , it forms a spiro bicyclic ring with Ring B.
  • R w is optionally substituted , it forms a spiro bicyclic ring with Ring B, for example, [00276]
  • R w is selected from those depicted in Table B, below. [00277] As defined generally above, R is independently -H or optionally substituted -C 1-6 aliphatic.
  • R is –H.
  • R is optionally substituted -C 1-6 aliphatic.
  • R is unsubstituted -C 1-6 aliphatic.
  • R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is –CF 3 .
  • R is –CH 3 , –C(CH 3 ) 3 , –CHF 2 , cyclopropyl, –CF 2 CF 3 , or .
  • R is selected from those depicted in Table B, below.
  • a “warhead group,” as used herein, is capable of covalently binding to an amino acid residue (such as cysteine, lysine, histidine, or other residues capable of being covalently modified) present in the binding pocket of a target protein, for example, TEAD, thereby irreversibly inhibiting the protein.
  • a warhead group is as defined and described in embodiments in PCT/US2020/35111, the content of which is herein incorporated by reference in its entirety.
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula B-2: , thereby forming a compound of formula I-B-2 or II-B-2: I-B-2 II-B-2 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, DIM, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and L 1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34.
  • the present invention provides a compound of formula I-B-2 or II-B-2, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein: (a): L 1 is -NH-; R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R 2 is a warhead group; R 3 is -H; R 4 is -H, -S(O) 2 N(R) 2 ; -S(O)N(R) 2 , or -C(O)N(R) 2 , each R independently is selected from -H and optionally substituted -C 1-6 aliphatic; R 6 is -H or -C 1-6 aliphatic; and R 7 is –H; or (b): L 1 is -NH-; R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula B-3: , thereby forming a compound of formula I-B-3 or II-B-3: I-B-3 II-B-3 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, DIM, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and L 1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34.
  • the present invention provides a compound of formula I-B-3 or II-B-3, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein: L 1 is -NH-; R 1 is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R 2 is a warhead group; R 3 is –H; R 4 is -S(O) 2 N(R) 2 , -S(O)N(R) 2 , or -C(O)N(R) 2 , each R independently is selected from -H and optionally substituted -C 1-6 aliphatic; R 6 is -H or -C 1-6 aliphatic; and R 7 is -H or halogen.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: i.
  • TBM is a moiety selected from B-4 to B-18, wherein L 1 is – CH 2 -, -O-, -CH(CH 3 )-, -NH-, -C(O)-, or -NH-CH 2 -; R 1 is –H or -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R w is a warhead group; and R 7 is –H or -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • the present invention provides a compound of Formula I-B or II-B, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen; Ring B is phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen; and each of R w and L 1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: i. Formula (B-19): B-19 wherein each of Ring A, R w , and L 1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ii.
  • Formula (B-31) B-31 wherein each of Ring B and L 1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; optionally, L 1 is –CH 2 –; xi.
  • TBM is a moiety set forth in Table B, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table B.
  • Table B Exemplified TEAD Binding Moiety (TBM) 3.
  • TBM TEAD Binding Moiety
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula C: thereby forming a compound of formula I-C or II-C: I-C II-C or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from each of which is optionally substituted; Ring B is selected from each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, ; each Y is independently N or CR 5 ;
  • L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-.
  • L 1 is a covalent bond.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- .
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-.
  • L 1 is -NH-.
  • L 1 is -NH-CH 2 -.
  • L 1 is -NH-CH 2 -CH 2 -.
  • L 1 is –CH 2 -.
  • L 1 is .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is selected from wherein each R 1 is independently R, halogen, -CN, -C(O)R, -C(O)NR 2 , -OR, -SR, -S(O) 2 NR 2 , or -S(O) 2 R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 1 is R.
  • R 1 is halogen.
  • R 1 is -CN.
  • R 1 is -C(O)R.
  • R 1 is - C(O)NR 2 .
  • R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(O) 2 NR 2 . In some embodiments, R 1 is -S(O) 2 R. [00316] In some embodiments, each R 1 is independently H, halogen, -C 1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen.
  • each R 1 is independently H, -CF 3 , -C(O)NH 2 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , -Cl, -S(O) 2 -NH 2 , -OCH 2 CH 3 , -F, -C(O)NHCH 3 , -CN, - S(O) 2 -CH 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 OH, , , [00318] In some embodiments, each R 1 is independently selected from those depicted in Table C, below.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [00320] In some embodiments, Ring A is selected from , , and , wherein each of R 1 is as defined above and described in embodiments herein, both singly and in combination. [00321] In some embodiments, Ring A is selected from , , and , wherein each R 1 is as defined above and as described in embodiments herein, both singly and in combination. [00322] In some embodiments, Ring A is , , , , [00323] In some embodiments, Ring A is selected from those depicted in Table C, below.
  • Ring B is selected from , wherein each of R 2 , R 3 , and R 4 is as defined herein and as described in embodiments herein, both singly and in combination. [00325] In some embodiments, Ring B is where 2 4 in each of R and R is as defined above and as described in embodiments herein, both singly and in combination. [00326] In some embodiments, Ring B is , wherein each of R 3 and R 4 is as defined above and as described in embodiments herein, both singly and in combination. [00327] In some embodiments, Ring B is 4 , wherein R is as defined above and as described in embodiments herein.
  • Ring B is , wherein each of R 2 and R 4 is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is 5 , wherein each of R, Y, m, and R is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of Y, R, and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each 5 of R and R is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of m, R, and R 5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is 5 , wherein each of R and R is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of R and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , where 5 in each of m, R, and R is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each R is independently as defined above and described in embodiments herein.
  • Ring B is , wherein R is as defined above and as described in embodiments herein.
  • Ring B is , wherein each of m, R, and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of R and R 5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined above and as described in embodiments herein, both singly and in combination. [00333] In some embodiments, Ring B is selected from those depicted in Table C, below. [00334] As defined generally above, each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, wherein each 5 of Y, m, and R is as defined herein and as described in embodiments herein, both singly and in combination..
  • R 2 is -OR. In some embodiments, R 2 is -C(O)NR 2 . In some embodiments, R 2 is optionally substituted -C 1-6 aliphatic. In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is In some em 2 bodiments, R is . In some embodiments, R 2 is 2 . In some embodiments, R is [00336] In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is 2 . In some embodiments, R 2 is 2 . In some embodiments, R 2 is 2 .
  • R is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is .
  • R 2 is selected from:
  • each Y is independently N or CR 5 .
  • Y is N.
  • Y is CR 5 .
  • Y is CH.
  • both Y are N.
  • both Y are CR 5 .
  • one Y is N, and the other Y is CR 5 .
  • both Y are CH.
  • one Y is N, and the other Y is CH.
  • Y is selected from those depicted in Table C, below.
  • R 3 is -H, -C(O)R, or optionally substituted -C 1-6 aliphatic, wherein R is as defined herein and described in embodiments herein.
  • R 3 is –H.
  • R 3 is -C(O)R.
  • R 3 is optionally substituted -C 1-6 aliphatic.
  • R 3 is selected from H, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , and . [00349] In some embodiments, R 3 is selected from those depicted in Table C, below. [00350] As defined generally above, each R 4 is independently -S(O) 2 NR 2 , -S(O) 2 R, -C(O)NR 2 , -C(O)R, or optionally substituted -C 1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein. [00351] In some embodiments, R 4 is -S(O) 2 NR 2 .
  • R 4 is -S(O) 2 R. [00353] In some embodiments, R 4 is -C(O)NR 2 . [00354] In some embodiments, R 4 is -C(O)R. [00355] In some embodiments, R 4 is -optionally substituted -C 1-6 aliphatic. [00356] In some embodiments, R 4 is selected from , , , , [00357] In some embodiments, R 4 is selected from: , , and . [00358] In some embodiments, R 4 is selected from those depicted in Table C, below.
  • each R 5 is independently R, -CN, -C(O)R, -C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 5 is R.
  • R 5 is -CN.
  • R 5 is -C(O)R.
  • R 5 is -C(O)NR 2 .
  • R 5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R 5 is independently selected from: H, -CH 3 , -CD 3 , -CH 2 CH 3 , -C(O)CH 3 , -CH 2 C(O)NHCH 3 , [00366]
  • each R 5 is independently selected from: -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CF 3 , -CH 2 CH 2 Cl, [00367]
  • R 5 is selected from those depicted in Table C, below.
  • each m is independently 0, 1, or 2. [00369] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00370] In some embodiments, m is selected from those depicted in Table C, below. [00371] As defined generally above, each R is independently H, optionally substituted -C 1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00372] In some embodiments, R is H.
  • R is optionally substituted -C 1-6 aliphatic. In some embodiments, R is unsubstituted -C 1-6 aliphatic. In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CH 3 . In some embodiments, R is –CH 2 CH 3 .
  • R is –CF 3 . In some embodiments, R is –CHF 2 . [00374] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is selected from -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 C(O)NHCH 3 , [00377] In some embodiments, R is selected from those depicted in Table C, below. [00378] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
  • TBM is a moiety set forth in Table C, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table C. Table C. Exemplified TEAD Binding Moiety (TBM)
  • TBM TEAD Binding Moiety
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula D: , thereby forming a compound of formula I-D or II-D: or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from , , , , , , each of which is optionally substituted;; Ring B is each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, ; each Y is
  • L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-.
  • L 1 is a covalent bond.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- .
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-.
  • L 1 is -NH-.
  • L 1 is -NH-CH 2 -.
  • L 1 is -NH-CH 2 -CH 2 -.
  • L 1 is –CH 2 -.
  • L 1 is 1 1 .
  • Ring A is optionally substituted . [00397] In some embodiments, Ring A is optionally substituted . [00398] In some embodiments, Ring A is optionally substituted . [00399] In some embodiments, Ring A is optionally substituted . [00400] In some embodiments, Ring A is optionally substituted . [00401] In some embodiments, Ring A is optionally substituted . [00402] In some embodiments, Ring A is optionally substituted . [00403] In some embodiments, Ring A is optionally substituted . [00404] In some embodiments, Ring A is optionally substituted .
  • Ring A is selected from , wherein each R 1 is independently R, halogen, -CN, -C(O)R, -C(O)NR 2 , -OR, -SR, -S(O) 2 NR 2 , or -S(O) 2 R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 1 is R. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is - C(O)NR 2 .
  • R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(O) 2 NR 2 . In some embodiments, R 1 is -S(O) 2 R. [00407] In some embodiments, each R 1 is independently H, halogen, -C 1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen.
  • each R 1 is independently H, -CF 3 , -C(O)NH 2 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , -Cl, -S(O) 2 -NH 2 , -OCH 2 CH 3 , -F, -C(O)NHCH 3 , -CN, - S(O) 2 -CH 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 OH, [00409] In some embodiments, each R 1 is independently selected from those depicted in Table D, below.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [00411] In some embodiments, Ring A is selected from and , wh 1 erein each of R is as defined herein and described in embodiments herein, both singly and in combination. [00412] In some embodiments, Ring A is selected from and wherein each R 1 is as defined herein and described in embodiments herein, both singly and in combination. [00413] In some embodiments, Ring A is
  • Ring A is selected from those depicted in Table D, below.
  • Ring B is , wherein each of R 2 and R 4 is as defined herein and as described in embodiments herein, both singly and in combination.
  • Ring B is 2 4 , wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is , whe 2 4 rein each of R and R is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is 5 , wherein each of R, Y, m, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein 5 each of Y, R, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination. [00419] In some embodiments, Ring B is 5 , wherein each of m, R, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B
  • Ring B is , wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is 5 , wherein each of m, R, and R is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each R is independently as defined herein and described in embodiments herein.
  • Ring B is , wherein R is as defined above and described in embodiments herein. [00421] In some embodiments, Ring B is , wherein each of m, R, and R 5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each of R and R 5 is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of R, Y, m, and R 5 is as defined herein and described in embodiments herein, both singly and in combination. [00423] In some embodiments, Ring B is selected from those depicted in Table D, below. [00424] As defined generally above, each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, , and , wherein 5 each of Y, m, and R is as defined herein and described in embodiments herein, both singly and in combination. [00425] In some embodiments, R 2 is -OR.
  • R 2 is -C(O)NR 2 . In some embodiments, R 2 is optionally substituted -C 1-6 aliphatic. In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is 2 . In some embodiments, R is [00426] In some embodiments, R 2 is . In some embodim 2 ents, R is In some embodiments, R 2 is . In some embo 2 2 diments, R is In some embodiments, R is . In some em 2 2 bodiments, R is .
  • R is In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 2 is 2 In some embodiments, R is
  • R 2 is selected from:
  • R 2 is selected from , and -OCH 3 .
  • R 2 is selected from those depicted in Table D, below.
  • each Y is independently N or CR 5 , wherein R 5 is as defined herein and as described in embodiments herein.
  • Y is N.
  • Y is CR 5 .
  • Y is CH.
  • both Y are N.
  • both Y are CR 5 .
  • both Y are CH.
  • one Y is N, and the other Y is CR 5 .
  • each R 4 is independently -S(O) 2 NR 2 , -S(O) 2 R, -C(O)NR 2 , -C(O)R, or optionally substituted -C 1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 4 is -S(O) 2 NR 2 .
  • R 4 is -S(O) 2 R.
  • R 4 is -C(O)NR 2 . [00438] In some embodiments, R 4 is -C(O)R. [00439] In some embodiments, R 4 is -optionally substituted -C 1-6 aliphatic. [00440] In some embodiments, R 4 is selected from [00441] In some embodiments, R 4 is selected from: and [00442] In some embodiments, R 4 is selected from those depicted in Table D, below.
  • each R 5 is independently R, -CN, -C(O)R, -C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is as defined herein and as described in embodiments herein.
  • R 5 is R.
  • R 5 is -CN.
  • R 5 is -C(O)R.
  • R 5 is -C(O)NR 2 .
  • R 5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R 5 is independently selected from: H, -CH 3 , -CD 3 , , -CH 2 CH 3 , -C(O)CH 3 , -CH 2 C(O)NHCH 3 , [00450]
  • each R 5 is independently selected from: -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CF 3 , -CH 2 CH 2 Cl, [00451]
  • R 5 is selected from those depicted in Table D, below.
  • each m is independently 0, 1, or 2. [00453] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00454] In some embodiments, m is selected from those depicted in Table D, below. [00455] As defined generally above, each R is independently H, optionally substituted -C 1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00456] In some embodiments, R is H.
  • R is optionally substituted -C 1-6 aliphatic. In some embodiments, R is unsubstituted -C 1-6 aliphatic. In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CH 3 . In some embodiments, R is –CH 2 CH 3 .
  • R is –CF 3 . In some embodiments, R is –CHF 2 . [00458] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is selected from -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 C(O)NHCH 3 , , [00461] In some embodiments, R is selected from those depicted in Table D, below.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: , ,
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
  • TBM is a moiety set forth in Table D, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table D.
  • Table D Exemplified TEAD Binding Moiety (TBM)
  • TBM TEAD Binding Moiety
  • the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula E: thereby forming a compound of formula I-E or II-E: or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from , , , , , , each of which is optionally substituted; Ring B is selected from each R w is independently selected from ; each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 ali
  • L 1 is a covalent bound, or a C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-.
  • L 1 is a covalent bond.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-.
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- .
  • L 1 is C 1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-.
  • L 1 is -NH-.
  • L 1 is -NH-CH 2 -.
  • L 1 is -NH-CH 2 -CH 2 -.
  • L 1 is –CH 2 -.
  • L 1 is .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is selected from , wherein each R 1 is independently R, halogen, -CN, -C(O)R, -C(O)NR 2 , -OR, -SR, -S(O) 2 NR 2 , or -S(O) 2 R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 1 is R.
  • R 1 is halogen.
  • R 1 is -CN.
  • R 1 is -C(O)R.
  • R 1 is - C(O)NR 2 .
  • R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(O) 2 NR 2 . In some embodiments, R 1 is -S(O) 2 R. [00491] In some embodiments, each R 1 is independently H, halogen, -C 1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen.
  • each R 1 is independently H, -CF 3 , -C(O)NH 2 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -CHF 2 , -OCF 3 , -OCHF 2 , -SCF 3 , -Cl, -S(O) 2 -NH 2 , -OCH 2 CH 3 , -F, -C(O)NHCH 3 , -CN, - S(O) 2 -CH 3 , -OCH(CH 3 ) 2 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 OH, [00493] In some embodiments, each R 1 is independently selected from those depicted in Table E, below.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [00495] In some embodiments, Ring A is selected from , , and , wherein each of R 1 is as defined above and described in embodiments herein, both singly and in combination. [00496] In some embodiments, Ring A is selected from , , and , wherein each R 1 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring A is , , , [00498] In some embodiments, Ring A is selected from [00499] In some embodiments, Ring A is selected from those depicted in Table E, below. [00500] As defined generally above, Ring B is selected from wherein each of R 2 , R 3 , R w , p, and R 4 is as defined herein and described in embodiments herein, both singly and in combination. [00501] In some embodiments, Ring B is wherein each of R 2 and R w is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is 4 w wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00503] In some embodiments, Ring B is wherein each of R 2 and R w is as defined herein and described in embodiments herein, both singly and in combination. [00504] In some embodiments, Ring B is wherein e 2 w ach of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00505] In some embodiments, Ring B is 4 w wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is 2 w wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00507] In some embodiments, Ring B is 3 wherein each of R and p is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is o . [00508] In some embodiments, Ring B is w wherein R is as defined herein and described in embodiments herein. In some embodiments, Ring B is wherein R w is as defined herein and described in embodiments herein. [00509] In some embodiments, Ring B is selected from those depicted in Table E, below.
  • R w is selected from , , a d .
  • R w is In some embodiments, R w is . In some embodiments, R w is w In some embodiments, R is In some embodiments, R w is w In some embodiments, R is In some embodiments, R w is [00512] In some embodiments, R w is selected from those depicted in Table E, below.
  • each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, 5 wherein each of Y, m, and R is as defined herein and described in embodiments herein, both singly and in combination..
  • R 2 is -OR.
  • R 2 is -C(O)NR 2 .
  • R 2 is optionally substituted -C 1-6 aliphatic.
  • R 2 is .
  • R 2 is .
  • R 2 is In some embodiments, R 2 is In som 2 e embodiments, R is In some embodiments, R 2 is 2 In some embodiments, R is [00515] In some embodiments, R 2 is 2 In some embodiments, R is . In some embodiments, R 2 is . In some embodiments, R 2 is 2 In some embodiments, R is . In some embodiments, R 2 is In some embodiments, R 2 is .
  • R 2 is In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 2 is In some embodiments, R 2 is In s 2 ome embodiments, R is In some embodiments, R 2 is In some embodime 2 2 nts, R is In some embodiments, R is In 2 some embodiments, R is [00516] In some embodiments, R 2 is selected from:
  • R 2 is selected from and -OCH 3 .
  • R 2 is selected from those depicted in Table E, below.
  • each Y is independently N or CR 5 .
  • Y is N.
  • Y is CR 5 .
  • Y is CH.
  • both Y are N.
  • both Y are CR 5 .
  • one Y is N, and the other Y is CR 5 .
  • both Y are CH.
  • one Y is N, and the other Y is CH.
  • one Y is N, and the other Y is CH.
  • Y is selected from those depicted in Table E, below.
  • each R 3 is independently H, -C(O)R, or optionally substituted -C 1-6 aliphatic, wherein R is as defined herein and described in embodiments herein.
  • R 3 is H.
  • R 3 is -C(O)R.
  • R 3 is optionally substituted -C 1-6 aliphatic.
  • R 3 is selected from H, -CH 3 , -CH 2 CH 3 , -C(O)CH 3 , and .
  • R 3 is selected from those depicted in Table E, below.
  • each R 4 is independently -S(O) 2 NR 2 , -S(O) 2 R, -C(O)NR 2 , -C(O)R, or optionally substituted -C 1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 4 is -S(O) 2 NR 2 .
  • R 4 is -S(O) 2 R.
  • R 4 is -S(O) 2 R.
  • R 4 is -C(O)NR 2 .
  • R 4 is -C(O)R. [00534] In some embodiments, R 4 is -optionally substituted -C 1-6 aliphatic. [00535] In some embodiments, R 4 is selected from
  • R 4 is selected from: and [00537] In some embodiments, R 4 is selected from those depicted in Table E, below. [00538] As defined generally above, each R 5 is independently R, -CN, -C(O)R, -C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is independently as defined herein and as described in embodiments herein. [00539] In some embodiments, R 5 is R. [00540] In some embodiments, R 5 is -CN. [00541] In some embodiments, R 5 is -C(O)R.
  • R 5 is -C(O)NR 2 .
  • R 5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R 5 is independently selected from: H, -CH 3 , -CD 3 , , -CH 2 CH 3 , -C(O)CH 3 , -CH 2 C(O)NHCH 3 , [00545] In some embodiments, each R 5 is independently selected from: -CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CF 3 , -CH 2 CH 2 Cl, [00546] In some embodiments, R 5 is selected from those depicted in Table E, below. [00547] As defined generally above, each m is independently 0, 1, or 2. [00548] In some embodiments, m is 0. In some embodiments, m is 1.
  • m is 2. [00549] In some embodiments, m is selected from those depicted in Table E, below. [00550] As defined generally above, p is 0, 1, or 2. [00551] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [00552] In some embodiments, p is selected from those depicted in Table E, below.
  • each R is independently H, optionally substituted -C 1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is H.
  • R is optionally substituted -C 1-6 aliphatic.
  • R is unsubstituted -C 1-6 aliphatic.
  • R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 . In some embodiments, R is -C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is —CH 3 . In some embodiments, R is –CH 2 CH 3 . In some embodiments, R is –CF 3 . In some embodiments, R is –CHF 2 .
  • R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO 2 .
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is selected from -CH 3 , -CD 3 , -CH 2 CH 3 , -CH 2 C(O)NHCH 3 , , , [00559] In some embodiments, R is selected from those depicted in Table E, below.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , Y, m, n, and R 5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: , , , or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , Y, n, and R 5 is independently as defined above and as described in the section of TBM of Formulas E, and E-1 to E-204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , L 1 , R w , and n is independently as defined and as described in the section of TBM of Formulas E, and E-1 to E-204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
  • each of R, R 1 , L 1 , R w , and n is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , and n is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , Y, m, n, and R 5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , Y, n, and R 5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , and R 5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204.
  • TBM is a moiety set forth in Table E, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table E.
  • Table E Exemplified TEAD binding moiety (TBM)
  • L is a bivalent moiety that connects TBM to LBM or TBM to DIM.
  • L is attached to a modifiable carbon, oxygen, or nitrogen atom within DIM or LBM including substitution or replacement of a defined group in DIM or LBM.
  • L is also attached to a modifiable carbon, oxygen, or nitrogen atom within TBM including substitution or replacement of a defined group in TBM.
  • L is a bivalent moiety that connects TBM to LBM.
  • L is a bivalent moiety that connects TBM to DIM.
  • L is a bivalent moiety that connects TBM to a lysine mimetic.
  • L is a bivalent moiety as described in WO 2018/237026, WO 2019/099926, WO 2019/199816, WO 2019/160915, WO 2019/060693, WO 2019/140387, or WO 2020/010177, the content of each of which is herein incorporated by reference in its entirety.
  • L is a covalent bond, or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 1-6 methylene units of L are independently and optionally replaced by –Cy-, -O-, -N(R I )-, -S-, -C(O)-, -S(O)-, -S(O) 2 -, , wherein each –Cy— is independently an optionally substituted bivalent ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, and a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each R I is independently H or optionally substituted -C 1-6 aliphatic, and wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • each –Cy– is independently an optionally substituted 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, each –Cy— is independently an optionally substituted 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00578] In some embodiments, -Cy- is . In some embodiments, -Cy- is . In some embodiments, -Cy- is . In some embodiments, -Cy- is [00579] In some embodiments, R I is H.
  • R I is optionally substituted -C 1- 6 aliphatic. In some embodiments, R I is optionally substituted -C 1-6 alkyl. In some embodiments, R I is optionally substituted -C 1-6 alkenyl. In some embodiments, R I is unsubstituted -C 1-6 aliphatic. In some embodiments, R I is unsubstituted -C 1-6 alkyl. In some embodiments, R I is unsubstituted - C 1-6 alkenyl. In some embodiments, R I is -CH 3 . In some embodiments, R I is -CH2CH 3 . [00580] In some embodiments, r is 0. In some embodiments, r is 1.
  • r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10. [00581] In some embodiments, L is a covalent bond. [00582] In some embodiments, L is . In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is . In some embodiments, L is . In some embodiments, L is In some embodiments, L is .
  • L is In some embodiments, L is [00583] In some embodiments, L is selected from , , [00584] In some embodiments, L is selected from , . [00585] In some embodiments, L is selected from , [00586] In some embodiments, L is selected from those depicted in Table 1, below. [00587] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or and TBM is a moiety of Formulas A, or A-1 to A-50, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from the compounds set forth in Table A above, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , , and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is , L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , , and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a , , and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is , , , and L is as defined above and described in embodiments herein. [00595] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is ,
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or TBM is , L is as defined above and described in embodiments herein, and R I is H or optionally substituted -C 1-6 aliphatic, for example, selected from the embodiments of R I as defined and described in the section of Linker(L).
  • the present invention provides a compound of formula I, or a , , , and L is as defined above and described in embodiments herein, and R I is H or optionally substituted -C 1-6 aliphatic, for example, selected from the embodiments of R I as defined and described in the section of Linker(L).
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is , , , and L is as defined above and described in embodiments herein, and R I is H or optionally substituted -C 1-6 aliphatic, for example, selected from the embodiments of R I as defined and described in the section of Linker(L).
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or TBM is a moiety selected from Formulas B, or B-1 to B-34, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from the compounds set forth in Table B above, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from Formulas C, or C-1 to C-85, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from the compounds set forth in Table C above, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from Formulas D, or D-1 to D-85, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from the compounds set forth in Table D above, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from Formulas E, or E-1 to E-204, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is or , TBM is a moiety selected from the compounds set forth in Table E above, and L is as defined above and described in embodiments herein.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is , or , TBM is a moiety selected from the compounds set forth in Tables A-E above, for example, TBM is and L is as defined above and described in embodiments herein.
  • LBM is a moiety selected from the compounds set forth in Tables A-E above, for example, TBM is and L is as defined above and described in embodiments herein.
  • Exemplary compounds of the invention are set forth in Table 1 below. Table 1. Exemplary Compounds
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4.
  • General Methods of Providing the Present Compounds The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. [00611] In the Schemes below, where a particular protecting group, leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J.
  • oxygen protecting group includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
  • Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy- crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference.
  • Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • Scheme 1 Synthesis of Compounds of the Invention
  • amine 1-A is coupled to acid 1-B using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond.
  • the squiggly bond represents the portion of the linker between TBM and the terminal amino group of 1-A or the portion of the linker between DIM and the terminal carboxyl group of 1-B, respectively.
  • an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • Scheme 2 Synthesis of Compounds of the Invention
  • amine 1-A is coupled to acid 1-B using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond.
  • the squiggly bond represents the portion of the linker between TBM and the terminal amino group of 1-A or the portion of the linker between DIM and the terminal carboxyl group of 1-B, respectively.
  • an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • Scheme 3 Synthesis of Compounds of the Invention
  • acid 2-A is coupled to amine 2-B using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond.
  • the squiggly bond represents the portion of the linker between TBM and the terminal carboxyl group of 2-A or the portion of the linker between DIM and the terminal amino group of 2-B, respectively.
  • an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • Scheme 4 Synthesis of Compounds of the Invention
  • acid 2-A is coupled to amine 2-B using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond.
  • the squiggly bond represents the portion of the linker between TBM and the terminal carboxyl group of 2-A or the portion of the linker between DIM and the terminal amino group of 2-B, respectively.
  • an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.
  • Scheme 5 Synthesis of Compounds of the Invention
  • an S N Ar displacement of fluoride 3-B by amine 3-A is effected in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising a secondary amine.
  • the squiggly bond represents the portion of the linker between TBM and the terminal amino group of 3-A.
  • Scheme 6 Synthesis of Compounds of the Invention
  • an SNAr displacement of fluoride 4-A by amine 4-B is effected in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising a secondary amine.
  • the squiggly bond represents the portion of the linker between DIM and the terminal amino group of 4-B.
  • Scheme 7 Synthesis of Compounds of the Invention
  • reductive alkylation of aldehyde 5-A by amine 5-B is effected in the presence of a mild hydride source (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to form a provided compound with a linker comprising a secondary amine.
  • a mild hydride source e.g., sodium cyanoborohydride or sodium triacetoxyborohydride
  • the squiggly bond represents the portion of the linker between TBM and the terminal aldehyde group of 5-A or the portion of the linker between DIM and the terminal amino group of 5-B.
  • Scheme 8 Synthesis of Compounds of the Invention
  • reductive alkylation of aldehyde 6-B by amine 6-A is effected in the presence of a mild hydride source (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to form a provided compound with a linker comprising a secondary amine.
  • a mild hydride source e.g., sodium cyanoborohydride or sodium triacetoxyborohydride
  • the squiggly bond represents the portion of the linker between TBM and the terminal amino group of 6-A or the portion of the linker between DIM and the terminal aldehyde group of 6-B.
  • the present invention provides a compound of formulas 1-A, 1- B, 2-A, 2-B, 3-A, 3-B, 4-A, 4-B, 5-A, 5-B, 6-A, or 6-B, or a pharmaceutically acceptable salt thereof.
  • various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration.
  • the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [00634]
  • patient or “subject” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxyprop
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term "inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of TEAD, or a variant or mutant thereof.
  • Compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.
  • compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
  • a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and polyethylene glycols.
  • Pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • compositions of this invention can be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food.
  • compositions of this invention are administered with food.
  • the amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form varies depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition also depends upon the particular compound in the composition.
  • Uses of Compounds and Pharmaceutically Acceptable Compositions The Hippo Signaling Network [00650]
  • the Hippo signaling network also known as the Salvador/Warts/Hippo (SWH) pathway
  • SWH Salvador/Warts/Hippo
  • the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co- activator with PDZ-binding motif (TAZ; also known as WWTR1).
  • YAP transcriptional co-activators Yes-associated protein
  • TEZ transcriptional co- activator with PDZ-binding motif
  • the Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control.
  • YAP also known as YAP1 or YAP65
  • TAZ TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis.
  • unregulated upregulation of these genes involved in proliferation, migration, and anti- apoptosis leads to development of cancer.
  • overexpression of YAP/TAZ is associated with cancer.
  • Representative reference amino acid sequences of human TEAD1, human TEAD2, human TEAD3, and human TEAD4 include UniProt KB ID P28347-1 (SEQ ID NO: 1), UniProtKB ID Q15562 (SEQ ID NO: 2), UniProtKB ID Q99594 (SEQ ID NO: 3), and UniProtKB ID Q15561 (SEQ ID NO: 4), respectively.
  • Table 1 of “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072, the entire content of which is incorporated herein by reference.
  • Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Lats1/2 (homologues of Warts/Wts), and their adaptor proteins Sav1 (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively.
  • MST1/2 kinase complexes with the scaffold protein Sav1, which in turn phosphorylates and activates Lats1/2 kinase.
  • Lats1/2 is also activated by the scaffold protein Mob.
  • Lats1/2 phosphorylates YAP at the [HXRXXS] (SEQ ID NO: 9) consensus motifs.
  • YAP comprises five [HXRXXS] (SEQ ID NO: 9) consensus motifs, wherein X denotes any amino acid residue.
  • Lats1/2 phosphorylates YAP at one or more of the consensus motifs.
  • Lats1/2 phosphorylates YAP at all five of the consensus motifs.
  • Lats1/2 phosphorylate at the S127 amino acid position.
  • the phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
  • Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK1 ⁇ / ⁇ in the degradation motif, which then signals for interaction with the ⁇ -TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.
  • Lats1/2 phosphorylates TAZ at the [HXRXXS] (SEQ ID NO: 9) consensus motifs.
  • TAZ comprises four [HXRXXS] (SEQ ID NO: 9) consensus motifs, wherein X denotes any amino acid residues.
  • Lats1/2 phosphorylates TAZ at one or more of the consensus motifs.
  • Lats1/2 phosphorylates TAZ at all four of the consensus motifs.
  • Lats1/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ.
  • the Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skp1, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme.
  • the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, ⁇ TrCP1, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2).
  • the SCF complex e.g. SCF ⁇ TrCP1
  • E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate.
  • Exemplary E1 ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1.
  • Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1.
  • the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.
  • the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
  • YAP/TAZ Interaction with TEAD [00658] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus.
  • YAP/TAZ interacts with the TEAD family of transcription factors (e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4)) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1.
  • TEAD1 UniProt KB ID P28347-1 (SEQ ID NO: 1)
  • human TEAD2 UniProtKB ID Q15562 (SEQ ID NO: 2)
  • human TEAD3 UniProtKB ID Q99594 (SEQ ID NO: 3)
  • human TEAD4 UniProtKB ID Q15561 (SEQ ID NO: 4)
  • TEAD TEAD
  • C327S and C359S Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation.
  • C53S, C327S and C359S Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation.
  • C359S mutant showed the greatest loss of palmitoylation, and C327S and C53S also showed decreased palmitoylation.
  • the TBM of the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD. [00661] In some embodiments, the TBM of the compounds described herein reversibly inhibit a TEAD transcription factor. In some embodiments, the transcription factor is TEAD1. In some embodiments, the transcription factor is TEAD2. In some embodiments, the transcription factor is TEAD3. In some embodiments, the transcription factor is TEAD4.
  • the TBM of the compounds described herein reversibly inhibit the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • a TEAD transcription factor e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 a TEAD transcription factor
  • the TBM of the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD2 and disrupt or inhibit the interaction between YAP and TEAD2.
  • the TBM of the compounds disclosed herein bind to TEAD3 and disrupt or inhibit the interaction between YAP and TEAD3.
  • the TBM of the compounds disclosed herein bind to TEAD4 and disrupt or inhibit the interaction between YAP and TEAD4.
  • the TBM of the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C327, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 at C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C353, and C405.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, C53, and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, C53, and C405. [00665] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD, prevent TEAD palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. [00666] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 at C380, and disrupt or inhibit the interaction between YAP and TEAD2.
  • the TBM of the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380. [00668] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2, prevent TEAD2 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380, and disrupt or inhibit the interaction between YAP and TEAD2.
  • the TBM of the compounds disclosed herein bind to TEAD3 at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3. [00670] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation.
  • the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368 and C371. [00671] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3, prevent TEAD3 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD3.
  • the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3. [00672] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 at C367, and disrupt or inhibit the interaction between YAP and TEAD4.
  • the TBM of the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367. [00674] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4, prevent TEAD4 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD4. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367, and disrupt or inhibit the interaction between YAP and TEAD4.
  • the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins.
  • G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs.
  • monomeric small GTPases and heterotrimeric G protein complexes.
  • the latter class of complexes comprise of alpha (G ⁇ ), beta (G ⁇ ), and gamma (G ⁇ ) subunits.
  • G ⁇ subunits there are several classes of G ⁇ subunits: G q/11 ⁇ , G 12/13 ⁇ , G i/o ⁇ (G inhibitory, G other), and G s ⁇ (G stimulatory).
  • Gi ⁇ G inhibitory
  • G o ⁇ G other
  • G q/ 11 ⁇ G12/13 ⁇ coupled GPCRs activate YAP/TAZ and promote nuclear translocation.
  • G s ⁇ G stimulatory coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
  • G i ⁇ G inhibitory
  • G o ⁇ G other
  • G q/11 ⁇ G 12/13 ⁇ coupled GPCRs activate YAP/TAZ through repression of Lats1/2 activities.
  • G s ⁇ in some embodiments, induces Lats1/2 activity, thereby promoting YAP/TAZ degradation.
  • G q Family G q ⁇ (also known as G q/11 protein), participates in the inositol trisphosphate (IP 3 ) signal transduction pathway and calcium (Ca 2+ ) release from intracellular storage through the activation of phospholipase C (PLC).
  • IP 3 inositol trisphosphate
  • Ca 2+ calcium
  • the activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to diacyl glycerol (DAG) and IP 3 .
  • IP 3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca 2+ channel.
  • the binding triggers the opening of the Ca 2+ channel, and thereby increases the release of Ca 2+ into the cytoplasm.
  • the GPCRs that interact with G q ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT 2 and 5-HT 3 ; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptor; histamine H1 receptor; metabotropic glutamate receptor, group I; muscarinic receptors M 1 , M 3 , and M 5 ; and trace amine-associated receptor 1.
  • 5-HT receptor 5-hydroxytryptamine receptor
  • G q ⁇ there are several types of G q ⁇ : G q , G q/11 , G q/14 , and G q/15 .
  • the G q protein is encoded by GNAQ.
  • G q/11 is encoded by GNA11.
  • G q/14 is encoded by GNA14.
  • G q/15 is encoded by GNA15.
  • mutations or modifications of the G q ⁇ genes have been associated with cancer. Indeed, studies have shown that mutations in G q ⁇ promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
  • mutations or modifications of the G q ⁇ genes have been associated with congenital diseases.
  • G 12/13 Family modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways.
  • GTPases include the Ras-related GTPase superfamily (e.g., Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
  • the GPCRs that interact with G 12/13 ⁇ include, but are not limited to, purinergic receptors (e.g., P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 ); muscarinic acetylcholine receptors M1 and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1-phosphate (e.g., S1P 2 , S1P 3 , S1P 4 and S1P 5 ); lysophosphatidic acid (e.g., LPA 1 , LPA 2 , LPA 3 ); angioten
  • G 12/13 ⁇ is further subdivided into G 12 and G 13 types which are encoded by GNA12 and GNA13, respectively.
  • G i/o Family G inhibitory, G other) (also known as G i /G o or G i protein) suppresses the production of 3’, 5’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
  • G inhibitory, G other also known as G i /G o or G i protein
  • the GPCRs that interact with Gi ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT 1 and 5-HT 5 ; muscarinic acetylcholine receptors such as M 2 and M 4 ; adenosine receptors such as A 1 and A 3 ; adrenergic receptors such as ⁇ 2A , ⁇ 2B , and ⁇ 2c ; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D 2 , D 3 , and D 4 ; GABA B receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7),
  • 5-HT receptor 5-hydroxytry
  • G i ⁇ 1 is encoded by GNAI1.
  • G i ⁇ 2 is encoded by GNAI2.
  • G i ⁇ 3 is encoded by GNAI3.
  • G o ⁇ the ⁇ o subunit, is encoded by GNAO1.
  • G t is encoded by GNAT1 and GNAT2.
  • Ggust is encoded by GNAT3.
  • G z is encoded by GNAZ.
  • G s Family [00689] G s ⁇ (also known as G stimulatory, G s alpha subunit, or G s protein) activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’,5’-cyclic AMP (cAMP) and pyrophosphate.
  • G stimulatory, G s alpha subunit, or G s protein activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’,5’-cyclic AMP (cAMP) and pyrophosphate.
  • ATP adenosine triphosphate
  • cAMP cyclic AMP
  • the GPCRs that interact with G s ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT 4 , 5-HT 6 , and 5-HT 7 ; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A 2a and A 2b ; arginine vasopressin receptor 2 (AVPR2); ⁇ -adrenergic receptors ⁇ 1 , ⁇ 2 , and ⁇ 3 ; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor D1-like family receptors such as D1 and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H 2 receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptor
  • G s there are two types of G s ⁇ : G s and G olf .
  • G s is encoded by GNAS.
  • G olf is encoded by GNAL.
  • Additional Regulators of the Hippo signaling network is the Crumbs (Crb) complex.
  • the Crumbs complex is a key regulator of cell polarity and cell shape.
  • the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity.
  • CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components.
  • AMOT Angiomotin
  • the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1. [00693] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity.
  • E-cad E-Cadherin
  • E-cad-associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm.
  • Ajuba protein family members interact with Lats1/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
  • additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
  • the TBM of the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
  • the TBM of the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the TBM of the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
  • the TBM of the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein.
  • an inhibitor of the Hippo pathway is an inhibitor of the G q ⁇ family proteins such as G q , G q/11 , G q/14 , and G q/15 ; the G 12/13 ⁇ family of proteins such as G 12 and G 13 ; or the G i ⁇ family of proteins such as G i ⁇ 1, G i ⁇ 2, G i ⁇ 3, G i ⁇ 4, G o ⁇ , G t , G gust , and G z .
  • an inhibitor of the Hippo pathway is an inhibitor of G q .
  • an inhibitor of the Hippo pathway is an inhibitor of G q/11 .
  • an inhibitor of the Hippo pathway is an inhibitor of G q/14 . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G q/15 . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G 12 . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G 13 . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 4.
  • an inhibitor of the Hippo pathway is an inhibitor of G o ⁇ . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G t . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G gust . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G z . [00697] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Sav1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ.
  • an inhibitor of the Hippo pathway is an inhibitor of TEAD.
  • an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g., 26S proteasome).
  • an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins.
  • an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins.
  • an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
  • Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein. [00701] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme.
  • GEFs guanine nucleotide exchange factors
  • an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease.
  • USP47 is a member of the ubiquitin-specific protease (USP/UBP) superfamily of cysteine proteases.
  • the TBM of the compounds disclosed herein are inhibitors of USP47.
  • the present invention provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
  • TBM of a compound utilized in this invention as an inhibitor of TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a variant or mutant thereof can be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof.
  • Alternate in vitro assays quantitate the ability of the inhibitor to bind to TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • the provided compounds are degraders and/or inhibitors of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) and are therefore useful for treating one or more disorders associated with activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • the present invention provides a method for treating a TEAD- mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • TEAD-mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, is known to play a role.
  • another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are known to play a role.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a therapeutically effective amount of refers to the amount of a TEAD degrader, and/or TEAD inhibitor or a pharmaceutically acceptable salt thereof, which is effective to reduce or attenuate the biological activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof, provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition in a biological sample or in a patient.
  • a therapeutically effective amount of refers to the amount of a TEAD degrader and/or a TEAD inhibitor or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, or any TEAD-mediated activity.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a therapeutically effective amount can encompass, in some embodiments, 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.
  • methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of the Hippo pathway is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a TEAD degrader compound and/or a TEAD inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • a cellular proliferative disorder is cancer.
  • the cancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms “increased expression” and/or “increased activity” of a substance, such as TEAD, in a sample or cancer or patient refers to an increase in the amount of the substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as TEAD, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g.
  • a subject can also be determined to have an “increased expression” or “increased activity” of TEAD if the expression and/or activity of TEAD is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of TEAD in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • 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 can 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.
  • Exemplary proliferative diseases include cancers (i.e.,“malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • Cancer i.e.,“malignant neoplasms”
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP).
  • a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • the cancer is characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
  • the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells.
  • the cancer is characterized or associated with a genetic alteration in one or more Hippo pathway genes.
  • the term “genetic alteration in one or more Hippo pathway genes” refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes.
  • a genetic alteration in a gene can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1-TFE3 fusion.
  • genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes,
  • genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes. In some embodiments, a Hippo pathway gene is NF2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is NF2 deficiency. In some embodiments, NF2 deficiency refers to NF2 loss of function mutations.
  • NF2 deficiency refers to NF2 copy losses or deletions. In some embodiments, NF2 deficiency refers to absent or very low NF2 mRNA expression.
  • a Hippo pathway gene is YAP1. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion. In some embodiments, a Hippo pathway gene is TAZ. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is TAZ amplification.
  • the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion.
  • a Hippo pathway gene is LATS 1/2.
  • the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion.
  • a Hippo pathway gene is MST1/2.
  • a Hippo pathway gene is BAP1.
  • a cancer is characterized by a mutant G ⁇ -protein.
  • a mutant G ⁇ -protein is selected from G12, G13, G q , G11, Gi, Go, and Gs.
  • a mutant G ⁇ -protein is G12.
  • a mutant G ⁇ -protein is G13. In some embodiments, a mutant G ⁇ -protein is G q . In some embodiments, a mutant G ⁇ -protein is G11. In some embodiments, a mutant G ⁇ -protein is Gi. In some embodiments, a mutant G ⁇ -protein is Go. In some embodiments, a mutant G ⁇ -protein is Gs. [00717] In some embodiments of the methods and uses described herein, a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor.
  • a cancer is treated by inhibiting or reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • size e.g., volume or mass
  • a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of the cancers or tumors prior to treatment.
  • a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • ORR objective response rate
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma.
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, mesothelioma, sarcoma, or epithelioid hemangioendothelioma (EHE).
  • the cancer is mesothelioma, such as malignant mesothelioma.
  • the cancer is EHE.
  • cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosar
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma
  • the cancer is acoustic neuroma, astrocytoma (e.g., Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g., Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia,
  • the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MP
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomy
  • the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma
  • HCC hepatocellular
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ova
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments,
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST.
  • MPNST peripheral nerve sheath tumors
  • a cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papilloma virus
  • a cancer is melanoma cancer.
  • a cancer is breast cancer.
  • a cancer is lung cancer.
  • a cancer is small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the compounds and compositions, according to the method of the present invention can be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer.
  • the exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient or “subject,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, 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, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Co-Administration with One or More Other Therapeutic Agent(s) [00744] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • a compound of the current invention can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current invention can besides, or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these.
  • One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of a compound of the invention and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration.
  • a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.
  • the one or more other therapeutic agent(s) and a compound of the invention can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent.
  • a dosage of between 0.01 – 1,000 ⁇ g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent(s) present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • the compounds of this invention, or pharmaceutical compositions thereof can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • one or more other therapeutic agent is a MEK inhibitor.
  • a MEK inhibitor refers to any inhibitor or blocker or antagonist that binds to and/or inhibits mitogen-activated protein kinase enzymes MEK1 and/or MEK2.
  • an MEK inhibitor is selected from those as described in Cheng et al., “Current Development Status of MEK Inhibitors,” Molecules 2017, 22, 1551, the contents of which are incorporated herein by reference in its entirety.
  • the MEK inhibitor is selected from binimetinib (MEK162, ARRY-438162, ARRAY BIOPHARMA INC.), cobimetinib(COTELLIC®, Exelexis/Genentech/Roche), refametinib (BAY 86–9766, RDEA119; Bayer AG), selumetinib (AZD6244, ARRY-142886; ASTRAZENECA), trametinib(MEKINIST®, Novartis), mirdametinib(PD-0325901, Spring Works Therapeutics), pimasertib (AS703026, MSC1936369B, Merck KGaA)or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • binimetinib MEK162, ARRY-438162, ARRAY BIOPHARMA INC.
  • cobimetinib(COTELLIC® Exelexis/Genentech/Roche
  • the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, mirdametinib, pimasertib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • MEK inhibitors for use as an other therapeutic agent in the methods and uses described herein include, but are not limited to, E6201 (Eisai Co Ltd./Strategia Theraputics), GDC-0623 (RG 7421, Genentech, Inc.), CH5126766 (RO5126766, Chugai Pharmaceutical Co., Roche), HL-085 (Shanghai Kechow Pharma, Inc.), SHR7390 (HENGRUI MEDICINE), TQ-B3234 (CHIATAI TIANQING), CS-3006 (CSTONE Pharmaceuticals), FCN- 159 (FosunPharmaceuticals), VS-6766 (Verastem Oncology), and IMM-1-104 (Immuneering Corp.).
  • MEK inhibitors for use as second anti-cancer agents in the methods and uses described herein include, but are not limited to, those described in WO2005/121142, WO2014/169843, WO2016/035008, WO2016/168704, WO2020/125747, WO2021/142144, WO2021/142345, WO2021/149776, the contents of each of which are herein incorporated by reference in their entireties.
  • one or more other therapeutic agent is an EGFR inhibitor.
  • an "EGFR inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits epidermal growth factor receptor (EGFR).
  • an EGFR inhibitor is selected from those as described in Ayati et al., "A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy," Bioorganic Chemistry 2020, 99: 103811, the contents of which are incorporated herein by reference in its entirety.
  • an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.
  • an EGFR inhibitor is cetuximab.
  • an EGFR inhibitor is necitumumab.
  • an EGFR inhibitor is panitumumab. In some embodiments, an EGFR inhibitor is zalutumumab. In some embodiments, an EGFR inhibitor is nimotuzumab. In some embodiments, an EGFR inhibitor is matuzumab. [00756] In some embodiments, an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, an EGFR inhibitor is osimertinib.
  • an EGFR inhibitor is gefitinib. In some embodiments, an EGFR inhibitor is erlotinib. In some embodiments, an EGFR inhibitor is lapatinib. In some embodiments, an EGFR inhibitor is neratinib. In some embodiments, an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib.
  • an EGFR inhibitor is a "1st generation EGFR tyrosine kinase inhibitor" (1st generation TKI).
  • a 1st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a "2nd generation EGFR tyrosine kinase inhibitor" (2nd generation TKI).
  • a 2nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a "3rd generation EGFR tyrosine kinase inhibitor" (3rd generation TKI).
  • a 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR.
  • one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor.
  • PARP Poly ADP ribose polymerase
  • a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).
  • one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).
  • one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor.
  • a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
  • one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins.
  • a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).
  • one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating
  • one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist.
  • Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi).
  • VEGFR inhibitors such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (
  • kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S.
  • one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake.
  • an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).
  • one or more other therapeutic agent is a proteasome inhibitor.
  • Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).
  • one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).
  • Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly).
  • Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).
  • one or more other therapeutic agent is an aromatase inhibitor.
  • an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).
  • one or more other therapeutic agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.
  • one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).
  • one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).
  • one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • one or more other therapeutic agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).
  • one or more other therapeutic agent is a glutaminase inhibitor.
  • Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).
  • one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (RITUXAN®, Genentech/BiogenIdec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline); obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab e
  • one or more other therapeutic agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline).
  • Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).
  • one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • one or more other therapeutic agent is an androgen receptor inhibitor.
  • Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).
  • one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • SERMs useful in the present invention include raloxifene (EVISTA®, Eli Lilly).
  • one or more other therapeutic agent is an inhibitor of bone resorption.
  • An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases.
  • Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).
  • one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53.
  • ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).
  • one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFß).
  • Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • TGF-beta trap such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • M7824 Merck KgaA - formerly MSB0011459X
  • NCT02699515 a bispecific, anti-PD- L1/TGFß trap compound
  • NCT02517398 NCT02517398
  • M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF ⁇ “trap.”
  • one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE.
  • gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
  • one or more other therapeutic agents is an antiproliferative compound.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AROMASINTM.
  • Formestane is marketed under the trade name LENTARONTM. Fadrozole is marketed under the trade name AFEMATM. Anastrozole is marketed under the trade name ARIMIDEXTM. Letrozole is marketed under the trade names FEMARATM or FEMArTM. Aminoglutethimide is marketed under the trade name ORIMETENTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • the term "antiestrogen” as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • Tamoxifen is marketed under the trade name NOLVADEXTM.
  • Raloxifene hydrochloride is marketed under the trade name EVISTATM.
  • Fulvestrant can be administered under the trade name FASLODEXTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEXTM).
  • CASODEXTM bicalutamide
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEXTM.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSARTM.
  • Topotecan is marketed under the trade name HYCAMPTINTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYXTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name ETOPOPHOSTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name ACRIBLASTINTM or ADRIAMYCINTM.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TAXOLTM. Docetaxel is marketed under the trade name TAXOTERETM. Vinblastine sulfate is marketed under the trade name VINBLASTIN R.PTM. Vincristine sulfate is marketed under the trade name FARMISTINTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTINTM. Ifosfamide is marketed under the trade name HOLOXANTM.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • Gemcitabine is marketed under the trade name GEMZARTM.
  • the term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLATTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATINTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K- C2 ⁇ , Vps34, p110- ⁇ , p110- ⁇ , p110- ⁇ , p110- ⁇ , p85- ⁇ , p85- ⁇ , p55- ⁇ , p150, p101, and p87.
  • PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
  • SYK spleen tyrosine kinase
  • Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition e.g., thalidomide (THALOMIDTM) and TNP-470.
  • TAALOMIDTM thalidomide
  • proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • the term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREXTM), rofecoxib (VIOXXTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DIDRONELTM.
  • Clodronic acid is marketed under the trade name BONEFOSTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name AREDIATM.
  • Alendronic acid is marketed under the trade name FOSAMAXTM.
  • Ibandronic acid is marketed under the trade name BONDRANATTM.
  • Risedronic acid is marketed under the trade name ACTONELTM.
  • Zoledronic acid is marketed under the trade name ZOMETATM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICANTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADETM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1- ⁇ -D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HERCEPTINTM), Trastuzumab-DM1, erbitux, bevacizumab (AVASTINTM), rituximab (RITUXAN ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl) ⁇ 2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art.
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1 ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATINTM; ENDOSTATINTM; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTINTM).
  • VEGF aptamer such as Macugon
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNETM and porfimer sodium.
  • Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications).
  • one or more other therapeutic agent is an immuno-oncology agent.
  • an immuno-oncology agent refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject.
  • the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer.
  • An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.
  • an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses.
  • Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • B7 family includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6 includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT ⁇ R, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin ⁇ /TNF ⁇ , TNFR2, TNF ⁇ , LT ⁇ R, Lymphotoxin ⁇ 1 ⁇ 2, FA
  • an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • a combination of a compound of the invention and an immuno- oncology agent can stimulate T cell responses.
  • an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM- 4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • T cell activation e.g., immune checkpoint inhibitors
  • an antagonist of a protein that inhibits T cell activation e.g.,
  • an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells.
  • an immuno-oncology agent is an antagonist of KIR, such as lirilumab.
  • an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • block inhibitory receptor engagement e.g., PD-L1/PD-1 interactions
  • Tregs e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex
  • an immuno-oncology agent is a CTLA-4 antagonist.
  • a CTLA-4 antagonist is an antagonistic CTLA-4 antibody.
  • an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
  • an immuno-oncology agent is a PD-1 antagonist.
  • a PD-1 antagonist is administered by infusion.
  • an immuno- oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity.
  • a PD-1 antagonist is an antagonistic PD-1 antibody.
  • an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493).
  • an immuno-oncology agent may be pidilizumab (CT- 011).
  • an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224.
  • an immuno-oncology agent is a PD-L1 antagonist.
  • a PD-L1 antagonist is an antagonistic PD-L1 antibody.
  • a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS- 936559 (WO2007/005874), and MSB0010718C (WO2013/79174).
  • an immuno-oncology agent is a LAG-3 antagonist.
  • a LAG-3 antagonist is an antagonistic LAG-3 antibody.
  • a LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).
  • an immuno-oncology agent is a CD137 (4-1BB) agonist.
  • a CD137 (4-1BB) agonist is an agonistic CD137 antibody.
  • a CD137 antibody is urelumab or PF-05082566 (WO12/32433).
  • an immuno-oncology agent is a GITR agonist.
  • a GITR agonist is an agonistic GITR antibody.
  • a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116), or MK- 4166 (WO11/028683).
  • an immuno-oncology agent is an indoleamine (2,3)- dioxygenase (IDO) antagonist.
  • an IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).
  • an immuno-oncology agent is an OX40 agonist.
  • an OX40 agonist is an agonistic OX40 antibody.
  • an OX40 antibody is MEDI-6383 or MEDI-6469.
  • an immuno-oncology agent is an OX40L antagonist.
  • an OX40L antagonist is an antagonistic OX40 antibody.
  • an OX40L antagonist is RG-7888 (WO06/029879).
  • an immuno-oncology agent is a CD40 agonist.
  • a CD40 agonist is an agonistic CD40 antibody.
  • an immuno- oncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab. [00852] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab. [00853] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).
  • an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab
  • an immuno-oncology agent is an immunostimulatory agent.
  • antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor- reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol.14, 1212–1218; Zou et al. (2016) Sci. Transl. Med.8.
  • the anti-PD-1 antibody nivolumab (OPDIVO ® , Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy.
  • the immunomodulatory therapeutic specifically induces apoptosis of tumor cells.
  • Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).
  • an immuno-oncology agent is a cancer vaccine.
  • the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma.
  • sipuleucel-T PROVENGE®, Dendreon/Valeant Pharmaceuticals
  • IMLYGIC® BioVex/Amgen, previously known as T-VEC
  • an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non- small cell lung cancer (NSCLC) (
  • an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5- fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNF ⁇ -IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can
  • an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR.
  • the T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.
  • CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes.
  • binding domains which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs
  • the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al.; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta).
  • an antigen binding domain such as a domain that binds to CD19
  • CD3 zeta intracellular signaling domain of the T cell antigen receptor complex
  • an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor ⁇ (ROR ⁇ t).
  • ROR ⁇ t is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells.
  • an activator of ROR ⁇ t is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).
  • an immunostimulatory agent is an agonist or activator of a toll- like receptor (TLR).
  • TLR toll- like receptor
  • Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax).
  • SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772).
  • Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).
  • immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol- Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.
  • urelumab BMS-663513, Bristol-
  • an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of ROR ⁇ t.
  • an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453).
  • an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12).
  • an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268).
  • a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.
  • an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol.14, pages 603-622, the content of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol.28, pages 319-329, the content of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.
  • an immuno-oncology agent is selected from those described in Sandra L.
  • an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis.
  • the bystander cells are in solid tumors.
  • the bystander cells being lysed are in proximity to the BITE®-activated T cells.
  • the bystander cells comprises tumor-associated antigen (TAA) negative cancer cells.
  • the bystander cells comprise EGFR-negative cancer cells.
  • an immuno- oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4.
  • an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell.
  • an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).
  • CARs chimeric antigen receptors
  • TAAs tumor-associated surface antigens
  • Exemplary Immune Checkpoint Inhibitors [00870]
  • an immuno-oncology agent is an immune checkpoint inhibitor as described herein. [00871]
  • the term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient.
  • T-cell exhaustion results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors.
  • inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
  • PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators.
  • an immune checkpoint inhibitor is an antibody to PD-1.
  • PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti-tumor immune response.
  • the checkpoint inhibitor is a biologic therapeutic or a small molecule.
  • the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof.
  • the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof.
  • the interleukin is IL-7 or IL-15.
  • the interleukin is glycosylated IL-7.
  • the vaccine is a dendritic cell (DC) vaccine.
  • DC dendritic cell
  • Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands.
  • Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, ⁇ , and memory CD8 + ( ⁇ ) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands.
  • CTLA-4 CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, ⁇ , and memory CD8 + ( ⁇ ) T cells
  • CD160 also referred to as BY55
  • B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- H4, B7-H5, B7-H6 and B7-H7.
  • Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049.
  • Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS- 936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor).
  • CTLA-4 blocking antibody PD-L1 monoclonal Antibody
  • Anti-B7-Hl MEDI4736
  • MK-3475 PD-1 blocker
  • Nivolumab anti-PD1 antibody
  • CT-011 anti-PD1 antibody
  • BY55 monoclonal antibody AMP
  • Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®).
  • the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech).
  • nivolumab anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb
  • pembrolizumab anti-PD-1 antibody, KEYTRUDA®, Merck
  • ipilimumab anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb
  • durvalumab anti-PD-L1 antibody, IMFINZI®,
  • the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.
  • MK-3475 lambrolizumab
  • BMS-936558 nivolumab
  • CT-011 pidilizumab
  • AMP-224 pidilizumab
  • MDX-1105 MEDI4736
  • MPDL3280A MPDL3280A
  • BMS-936559 ipilimumab
  • lirlumab IPH2101, pembrolizumab (KEYTRUDA®)
  • tremelimumab tremelimum
  • an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR
  • Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma.
  • AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).
  • a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3).
  • TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG453.
  • TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633).
  • LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109).
  • a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells.
  • TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).
  • a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3).
  • LAG-3 inhibitors that may be used in the present invention include BMS- 986016 and REGN3767 and IMP321.
  • BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981).
  • REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782).
  • IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).
  • Checkpoint inhibitors that can be used in the present invention include OX40 agonists.
  • OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol- My
  • Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB) agonists.
  • CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).
  • Checkpoint inhibitors that can be used in the present invention include CD27 agonists.
  • CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).
  • Checkpoint inhibitors that can be used in the present invention include glucocorticoid- induced tumor necrosis factor receptor (GITR) agonists.
  • GITR glucocorticoid- induced tumor necrosis factor receptor
  • GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).
  • TRX518 Leap Therapeutics
  • Checkpoint inhibitors that can be used in the present invention include inducible T-cell co-stimulator (ICOS, also known as CD278) agonists.
  • ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).
  • Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors.
  • KIR killer IgG-like receptor
  • KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).
  • Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa).
  • CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgG1, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC- 90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu
  • Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors.
  • CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti- CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).
  • Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173).
  • STING stimulator of interferon genes protein
  • Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).
  • Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors.
  • CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4- [2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumor
  • Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors.
  • NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • LBM Ligase Binding Moiety
  • DIM Degradation Inducing Moiety
  • TBM TEAD Binding Moiety
  • degraders can be prepared as described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T.
  • Example 1A Synthesis of Exemplary Compounds [00896] Certain exemplary compounds are prepared as described below.
  • I-1 Step 1 N-[2-[2-[(3S)-2,6-Dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyethoxy]ethyl]-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
  • reaction mixture was stirred under N 2 atmosphere at 25 °C for 1 h.
  • the reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5 ⁇ m; mobile phase: [water(0.05%NH 3 H 2 O+10mM NH 4 HCO 3 )-ACN]; B%: 50%-80%, 10 min) to yield N-[6-[2-[(3S)- 2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyhexyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (8.94 mg, 12.03 ⁇ mol, 21.6% yield, 96.4% purity) as a white solid.
  • Step 1 (S)-3-(1-Oxo-5-(4-(piperidin-4-yl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [00899] To a solution of tert-butyl 4-[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5- yl]piperazin-1-yl]piperidine-1-carboxylate (45.00 mg, 87.96 ⁇ mol, 1 eq) in DCM (1 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 30.71 eq) at 20 °C.
  • Step 2 (S)-3-(5-(4-(1-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
  • Step 1 (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1- yl)isoindoline-1,3-dione [00901]
  • tert-butyl 4-[2-[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (20 mg, 36.12 ⁇ mol, 1 eq) in DCM (1 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 74.78 eq).
  • Step 2 (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-(1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3- dione
  • Step 1 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3- dione [00906]
  • Step 2 (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(4-((1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline- 1,3-dione
  • Step 1 3-Bromo-4-fluoro-benzenesulfonamide
  • 3-bromo-4-fluoro-benzenesulfonyl chloride 5 g, 18.28 mmol, 1 eq
  • THF 100 mL
  • NH 3 ⁇ H 2 O 6.87 g, 54.84 mmol, 7.54 mL, 28.0%, 3 eq
  • the mixture was stirred at 0 °C for 1 h.
  • Step 2 tert-Butyl N-(3-bromo-4-fluoro-phenyl)sulfonylcarbamate
  • DCM DCM
  • DMAP 2.21 g, 18.10 mmol, 1 eq
  • Boc Boc
  • DIEA 7.02 g, 54.31 mmol, 9.46 mL, 3 eq
  • Step 3 tert-Butyl N-[3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]sulfonylcarbamate [00912] To a solution of 5-(trifluoromethyl)pyridin-2-amine (1.24 g, 7.62 mmol, 1 eq) in DMF (20 mL) was added NaH (914.76 mg, 22.87 mmol, 60.0%, 3 eq) at 0 °C.
  • Step 4 3-Bromo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide [00913] To a solution of tert-butyl N-[3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]sulfonylcarbamate (200 mg, 322.39 ⁇ mol, 80.0%, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was quenched with sat. aq.
  • Step 5 3-(1-Methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
  • 3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide 1.3 g, 2.79 mmol, 85.0%, 1 eq
  • tributyl-(1- methylimidazol-4-yl)stannane (1.73 g, 4.18 mmol, 90.0%, 1.5 eq) in DMF (10 mL) was added Pd(dppf)Cl 2 (204.08 mg, 278.91 ⁇ mol, 0.1 eq).
  • Step 6 3-(1-Methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonyl chloride [00915] A mixture of 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (1 g, 2.26 mmol, 90.0%, 1 eq) in HSO 3 Cl (12 mL) was stirred at 80 °C for 2 h.
  • Step 7 N-[2-[(2S)-2-(2,6-Dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxyethoxy]ethyl]-3-(1- methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide [00916] To a stirred solution of 3-[(2S)-5-[2-(2-aminoethoxy)ethoxy]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (20.00 mg, 57.58 ⁇ mol, N/A purity, 1 eq) and 3-(1-methylimidazol-4-yl)- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonyl chloride (24.00 mg, 57.58 ⁇ mol,
  • Step 2 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione
  • 3-aminopiperidine-2,6-dione 1.5 g, 9.11 mmol, 1 eq, HCl
  • 5- fluoroisobenzofuran-1,3-dione (1.48 g, 8.90 mmol, 9.77e-1 eq)
  • NaOAc (1.09 g, 13.29 mmol, 1.46 eq) was added AcOH (10 mL).
  • the mixture was stirred under N 2 atmosphere at 110 °C for 12 h.
  • Step 3 5-Fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (2.30 g, 7.99 mmol, 96%, 1 eq) in DMF (15 mL) was added NaH (383.66 mg, 9.59 mmol, 60.0%, 1.2 eq) at 0 °C under N 2 atmosphere.
  • Step 4 tert-Butyl 4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazine-1-carboxylate
  • 5-fluoro-2-(1-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione 1.4 g, 4.44 mmol, 92.0%, 1 eq
  • DIEA (1.15 g, 8.88 mmol, 1.55 mL, 2 eq
  • tert-butyl piperazine-1-carboxylate 909.16 mg, 4.88 mmol, 1.1 eq).
  • Step 5 2-(1-Methyl-2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione [00921]
  • tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin- 5-yl]piperazine-1-carboxylate (1.8 g, 3.75 mmol, 95.0%, 1 eq) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3.00 mL, 10.82 eq).
  • Step 6 tert-Butyl 4-(2-(4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate [00922] To a soluiton of 2-(1-methyl-2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3- dione (820 mg, 2.30 mmol, 100.0%, 1 eq) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (523.00 mg, 2.30 mmol, 1 eq) in MeOH (10 mL) was added 2 drops of AcOH at 25 °C under N 2 atmosphere.
  • Step 7 2-(1-Methyl-2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1- yl)isoindoline-1,3-dione [00923]
  • tert-butyl 4-[2-[4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate 50 mg, 87.20 ⁇ mol, 99.0%, 1 eq
  • TFA 385.00 mg, 3.38 mmol, 250.00 ⁇ L, 38.72 eq).
  • Step 8 5-(4-(2-(1-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(1-methyl- 2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [00924] To a solution of 3-(4-methylimidazol-1-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (38.91 mg, 101.59 ⁇ mol, 98.0%, 1 eq) in DCM (3 mL) and DIEA (367.14 mg, 2.84 mmol, 494.79 ⁇ L, 27.96 eq) was added HATU (77.26 mg, 203.18 ⁇ mol, 2 eq) at 25
  • Step 4 3-[6-[tert-Butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-1-methyl-piperidine-2,6- dione [00928]
  • 3-amino-1-methyl-piperidine-2,6-dione (1.22 g, 4.76 mmol, N/A purity, 1 eq, TFA) and DIEA (3.08 g, 23.79 mmol, 4.14 mL, 5 eq) in MeCN (40 mL) was stirred at 80 °C for 12 h.
  • Step 5 3-(6-Hydroxy-1-oxo-isoindolin-2-yl)-1-methyl-piperidine-2,6-dione [00929] To a solution of 3-[6-[tert-butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-1-methyl- piperidine-2,6-dione (600 mg, 1.49 mmol, 96.3% purity, 1 eq) in MeCN (20 mL) was added HCl/H 2 O (2 M, 10 mL, 13.45 eq). The mixture was stirred at 20 °C for 2 h.
  • Step 6 tert-Butyl N-[2-[2-[2-(1-methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5- yl]oxyethoxy]ethyl]carbamate [00930] A mixture of 3-(6-hydroxy-1-oxo-isoindolin-2-yl)-1-methyl-piperidine-2,6-dione (80 mg, 291.68 ⁇ mol, 100% purity, 1 eq), tert-butyl N-[2-(2-bromoethoxy)ethyl]carbamate (100.00 mg, 372.93 ⁇ mol, 1.28 eq) and Na 2 CO 3 (150.00 mg, 1.42 mmol, 4.85 eq) in DMF (4 mL) was stirred at 80 °C for 36 h.
  • Step 7 3-[6-[2-(2-Aminoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-1-methyl-piperidine-2,6- dione [00931]
  • Step 8 N-[2-[2-[2-(1-Methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]oxyethoxy]ethyl]- 3-(1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide [00932] A mixture of 3-[6-[2-(2-aminoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-1-methyl- piperidine-2,6-dione (40 mg, 91.69 ⁇ mol, 91.2% purity, 1 eq, HCl), 3-(1-methylimidazol-4-yl)-4- [[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (40 mg, 104.44 ⁇ mol, 98% purity, 1.14 eq), HATU (50.90 mg,
  • reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (0.05%HCl)-ACN]; B%: 30%-45%, 10 min) and lyophilized.
  • Step 9 tert-Butyl N-(1-methyl-2,6-dioxo-3-piperidyl)carbamate [00933] To a solution of tert-butyl N-(2,6-dioxo-3-piperidyl)carbamate (3 g, 13.14 mmol, 1 eq) in DMF (50 mL) was added NaH (630.84 mg, 15.77 mmol, 1.2 eq) at 0 °C under N 2 atmosphere. After being stirred for 30 min, CH 3 I (2.05 g, 14.46 mmol, 900.07 uL, 1.1 eq) was added at 0 °C.
  • Step 2 3-(1-Methyl-1H-imidazol-4-yl)-N-(2-(2-oxoethoxy)ethyl)-4-((5- (trifluoromethyl)pyridin-2-yl)amino)benzamide [00936] To a stirred mixture of N-[2-(2,2-dimethoxyethoxy)ethyl]-3-(1-methylimidazol-4-yl)- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzamide (100.00 mg, 101.32 ⁇ mol, 50% purity, 1 eq) in THF (4 mL), H 2 O (1 mL) was added TsOH (8.72 mg, 50.66 ⁇ mol, 0.5 eq).
  • Step 3 (2S,4R)-1-((S)-3,3-Dimethyl-2-((2-(2-(3-(1-methyl-1H-imidazol-4-yl)-4-((5- (trifluoromethyl)pyridin-2-yl)amino)benzamido)ethoxy)ethyl)amino)butanoyl)-4-hydroxy- N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 2-Bromo-4-isopropenyl-pyridine
  • Step 1 2-Bromo-5-isopropenyl-pyridine
  • Step 2 tert-Butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate [00946] To a solution of tert-butyl N-[2-bromo-4-[(4-methoxyphenyl)methyl-methyl- sulfamoyl]phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (2.1 g, 3.19 mmol, 95.9%, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.06 g, 15.97 mmol, 5
  • the mixture was degassed and purged with N 2 for three times and stirred under N 2 atmosphere at 90 °C for 12 h.
  • the reaction mixture was diluted with EtOAc (50 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue.
  • the residue was added to water (50 mL) and extracted with EtOAc (50 mL x 4).
  • Step 3 3-(5-Cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide [00947]
  • tert-butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2- pyridyl]carbamate 150 mg, 206.34 ⁇ mol, 93.2%, 1 eq
  • 6-bromopyridine-3-carbonitrile 43.72 mg, 226.97 ⁇ mol, 95%, 1.1 eq) in 1,4-dioxane (6 mL) and water (2 mL) was added
  • Step 4 3-(5-Cyano-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
  • reaction mixture was stirred at 20 °C for 12 h.
  • the reaction mixture was added to saturated NaHCO 3 solution (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and the filtrate was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5 ⁇ m; mobile phase: [water (0.05% NH 3 H 2 O+10mM NH 4 HCO 3 )-ACN]; B%: 50%-80%, 10min).
  • Step 2 3-(4-Cyano-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
  • Step 3 N-Methyl-3-(1-methylimidazol-4-yl)-4-[[(1R)-5-(trifluoromethyl)indan-1- yl]amino]benzenesulfonamide
  • DMF 3 mL
  • DIEA 255.97 mg, 1.98 mmol, 344.98 ⁇ L, 3 eq
  • 1-bromo-5-(trifluoromethyl)indane 250.00 mg, 660.20 ⁇ mol, 70%, 1 eq).
  • Step 2 4-[(5-Isopropenyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide [00956] To a stirred solution of 4-[(5-bromo-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]- N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (100 mg, 178.82 ⁇ mol, 97.0% purity, 1 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.07 mg, 268.23 ⁇ mol, 1.5 eq) in 1,4-dioxane (6 mL) and H 2 O (2 mL) was added Cs 2 CO 3 (116.53 mg, 3
  • Step 3 4-[(5-Isopropyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide [00957] To a stirred solution of 4-[(5-isopropenyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (80 mg, 155.67 ⁇ mol, 98.0% purity, 1 eq) in EtOAc (10 mL) was added Pd/C (100 mg, 10%).
  • reaction mixture was stirred under H 2 atmosphere (15 Psi) at 25 °C for 1 h.
  • the reaction mixture was filtered and concentrated under reduced pressure to yield 4-[(5-isopropyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (63 mg, 124.60 ⁇ mol, 80.1% yield, 100.0% purity) as a yellow solid.
  • Step 4 4-[(5-Isopropyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide [00958] To a stirred solution of 4-[(5-isopropyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (63 mg, 124.60 ⁇ mol, 100.0% purity, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 216.80 eq).
  • reaction mixture was stirred at 25 °C for 1 h.
  • the reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 ⁇ m; mobile phase: [water(0.05%NH 3 H 2 O+10mM NH 4 HCO 3 )-ACN]; B%: 48%-78%, 10 min) to yield 4-[(5-isopropyl-2-pyridyl)amino]-N-methyl- 3-(1-methylimidazol-4-yl)benzenesulfonamide (21.17 mg, 54.92 ⁇ mol, 44.1% yield, 100.0% purity) as a white solid.
  • Step 2 3-[1-(2-Hydroxyethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide [00960] To a solution of 2-(4-bromoimidazol-1-yl)ethanol (250 mg, 785.24 ⁇ mol, 60% purity, 1 eq) in H 2 O (5 mL) and 1,4-dioxane (15 mL) were added tert-butyl N-[4-[(4- methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (729.80 mg, 785.24 ⁇
  • Step 3 3-[1-(2-Hydroxyethyl)imidazol-4-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide [00961] To a solution of 3-[1-(2-hydroxyethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]- N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (50 mg, 74.61 ⁇ mol, 83.8% purity, 1 eq) in DCM (4 mL) was added TFA (645.26 mg, 5.66 mmol, 419.00 ⁇ L, 75.85 eq).
  • Step 2 tert-Butyl N-[5-(1-hydroxycyclobutyl)-2-pyridyl]carbamate
  • i-PrMgCl 2 M, 366.13 ⁇ L, 1 eq
  • n-BuLi 2.5 M, 732.26 ⁇ L, 2.5 eq
  • Step 3 5-Cyclobutylpyridin-2-amine [00964] To a stirred solution of tert-butyl N-[5-(1-hydroxycyclobutyl)-2-pyridyl]carbamate (120 mg, 440.38 ⁇ mol, 97.0% purity, 1 eq) in triethylsilane (1.09 g, 9.39 mmol, 1.5 mL, 21.33 eq) was added TFA (2.31 g, 20.26 mmol, 1.5 mL, 46.00 eq). The reaction mixture was stirred under N 2 atmosphere at 70 °C for 1 h.
  • Step 4 3-Bromo-4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N- methyl-benzenesulfonamide
  • N-cyclobutylpyridin-2-amine 55 mg, 367.40 ⁇ mol, 99.0% purity, 1 eq
  • NaH 44.08 mg, 1.10 mmol, 60%, 3 eq
  • stirred 0.5 h.3- Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (150.15 mg, 367.40 ⁇ mol, 95.0% purity, 1 eq) was added.
  • Step 5 4-[(5-Cyclobutyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide [00966] To a stirred solution of 3-bromo-4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (100 mg, 189.76 ⁇ mol, 98.0% purity, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (284.56 mg, 759.03 ⁇ mol, 99.0% purity, 4 eq) in DMF (10 mL) was added Pd(dppf)Cl 2 (13.88 mg, 18.98 ⁇ mol, 0.1 eq).
  • reaction mixture was stirred under N 2 atmosphere at 130 °C for 12 h.
  • Step 6 4-[(5-Cyclobutyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide [00967] To a stirred solution of 4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (50 mg, 96.59 ⁇ mol, 100.0% purity, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 279.66 eq).
  • reaction mixture was stirred at 25 °C for 4 h.
  • the reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5 ⁇ m; mobile phase: [water (0.05%NH 3 H 2 O+10mM NH 4 HCO 3 )- ACN]; B%: 45%-75%, 10 min) to yield 4-[(5-cyclobutyl-2-pyridyl)amino]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide (34.31 mg, 86.32 ⁇ mol, 89.4% yield, 100.0% purity) as a white solid.
  • Step 1 N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[(5-vinyl-2- pyridyl)amino]benzenesulfonamide
  • 4-[(5-bromo-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]- N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide 150 mg, 251.64 ⁇ mol, 91%, 1 eq
  • 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 58.13 mg, 377.46 ⁇ mol, 64.02 ⁇ L, 1.5 eq
  • 1,4- dioxane (6 mL) and H 2 O (2 mL) was added Cs 2 CO 3 (163.98 mg, 503.27 ⁇ mol,
  • Step 2 4-[(5-Ethyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide [00969] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[(5-vinyl-2-pyridyl)amino]benzenesulfonamide (110 mg, 198.03 ⁇ mol, 88.1%, 1 eq) in EtOAc (15 mL) was added Pd/C (100 mg, 10%, 1.00 eq) under H 2 atmosphere.
  • Step 3 4-[(5-Ethyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide [00970] To a solution of 4-[(5-ethyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N- methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (80 mg, 151.26 ⁇ mol, 92.9%, 1 eq) in DCM (6 mL) was added TFA (2.86 g, 25.11 mmol, 1.86 mL, 165.99 eq).
  • Step 2 N-[(4-Methoxyphenyl)methyl]-N-methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
  • 4-bromo-1-(oxetan-3-yl)imidazole 200 mg, 871.77 ⁇ mol, 88.5% purity, 1 eq
  • Pd(dppf)Cl 2 6.38 mg, 8.72 ⁇ mol, 0.01 eq
  • Cs 2 CO 3 568.08 mg, 1.74 mmol, 2 eq
  • Step 3 N-Methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
  • reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C 18 150*25mm*5um; mobile phase: [water(0.05% NH 3 H 2 O+10 mM NH 4 HCO 3 )-ACN]; B%: 44%-59%,14min), followed by lyophilization to yield N-methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (19.77 mg, 43.60 ⁇ mol, 41.7% yield, 100.0% purity) as a yellow solid.
  • Step 2 3-Bromo-N,N-dimethyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • Step 3 N,N-Dimethyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • 3-bromo-N,N-dimethyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide 310 mg, 574.24 ⁇ mol, 81%, 1 eq
  • Pd(dppf)Cl 2 42.02 mg, 57.42 ⁇ mol, 0.1 eq
  • tributyl-(1- methylimidazol-4-yl)stannane 538.20 mg, 1.44 mmol, 99%, 2.5 eq).
  • Step 1 4,4,5,5-Tetramethyl-2-[(Z)-1-methylprop-1-enyl]-1,3,2-dioxaborolane [00978]
  • a stirred solution of (E)-2-bromobut-2-ene (0.4 g, 2.96 mmol, 1 eq) in THF (10 mL) was cooled to –78 °C and t-BuLi (1.3 M, 4.10 mL, 1.8 eq) was added dropwise.
  • Step 2 N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(E)-1- methylprop-1-enyl]-2-pyridyl]amino]benzenesulfonamide
  • Step 3 N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[(5-sec-butyl-2- pyridyl)amino]benzenesulfonamide [00980] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[[5-[(E)-1-methylprop-1-enyl]-2-pyridyl]amino]benzenesulfonamide (170 mg, 299.71 ⁇ mol, 91.2%, 1 eq) in EtOAc (10 mL) was added Pd/C (100 mg, 10%) under H 2 atmosphere.
  • Step 4 N-Methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(1R)-1-methylpropyl]-2- pyridyl]amino]benzenesulfonamide and N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(1S)-1- methylpropyl]-2-pyridyl]amino]benzenesulfonamide [00981] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[(5-sec-butyl-2-pyridyl)amino]benzenesulfonamide (140 mg, 242.47 ⁇ mol, 90%, 1 eq) in DCM (10 mL) was added TFA (2.77 g, 24.31 mmol, 1.80 mL, 100.26 eq).
  • Peak 2 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H 2 O (20 mL) and lyophilized to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(1S)-1- methylpropyl]-2-pyridyl]amino]benzenesulfonamide (15.26 mg, 38.20 ⁇ mol, 15.7% yield, 100.0% purity) as a white solid.
  • Step 2 N-Methyl-3-(1-methylimidazol-4-yl)-4-(2-phenylethylamino)benzenesulfonamide
  • tributyl-(1-methylimidazol-4- yl)stannane 397.97 mg, 1.06 mmol, 99%, 2 eq
  • Pd(dppf)Cl 2 38.84 mg, 53.08 ⁇ mol, 0.1 eq
  • Step 2 N-Methyl-3-(1-methylimidazol-4-yl)-4-[[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]methylamino]benzenesulfonamide [00985] To a solution of N-[2-(1-methylimidazol-4-yl)-4-(methylsulfamoyl)phenyl]-3- (trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide (130 mg, 300.40 ⁇ mol, 99% purity, 1 eq) in THF (5 mL) was added LiAlH 4 (34.20 mg, 901.20 ⁇ mol, 3 eq) at 25 °C and stirred for 16 h.
  • Step 2 3-Bromo-N-(2-hydroxyethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • 3-bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide 400 mg, 1.34 mmol, N/A purity, 1 eq
  • DMSO 3 mL
  • [4- (trifluoromethyl)phenyl]methanamine 470.00 mg, 2.68 mmol, 382.11 ⁇ L, 2 eq.
  • the mixture was stirred at 140 °C for 12 h.
  • Step 3 N-(2-Hydroxyethyl)-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide [00989] A mixture of 3-bromo-N-(2-hydroxyethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (580 mg, 959.69 ⁇ mol, 75% purity, 1 eq), tributyl-(1-methylimidazol-4-yl)stannane (890.46 mg, 2.40 mmol, 2.5 eq), Pd(dppf)Cl 2 (70.22 mg, 95.97 ⁇ mol, 0.1 eq), tributyl-(1-methylimidazol-4-yl)stannane (890.46 mg, 2.40 mmol, 2.5 eq) in DMF (6 mL) was de
  • Step 2 3-Bromo-N-ethyl-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • DMSO dimethyl sulfoxide
  • Step 3 N-Ethyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • Step 2 3-(1-Methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide [00994] To a solution of N-[(4-methoxyphenyl)methyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (695 mg, 1.31 mmol, 1 eq) in DCM (10 mL) was added TFA (15.40 g, 135.06 mmol, 10.00 mL, 103.10 eq). The mixture was stirred at 25 °C for 48 h.
  • Step 2 3-(1-Cyclopropylimidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide [00996] To a solution of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (150 mg, 287.04 ⁇ mol, 90%, 1 eq) and 1-cyclopropyl-4-iodo-imidazole (201.54 mg, 344.45 ⁇ mol, 40%, 1.2 eq) in 1,4-dioxane (5 mL) and H 2 O (1.5 mL) was added Cs 2 CO 3 (187.05 mg, 574.09 ⁇ mol, 2 eq) and Pd(dppf)Cl 2 (21.00 mg, 28.70
  • Step 1 3-Bromo-N-cyclopropyl-4-fluoro-benzenesulfonamide
  • Step 2 3-Bromo-N-cyclopropyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • DMSO dimethyl sulfoxide
  • Step 3 N-Cyclopropyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
  • 3-bromo-N-cyclopropyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide 150 mg, 307.15 ⁇ mol, 92.0% purity, 1 eq
  • tributyl-(1-methylimidazol-4-yl)stannane 230.30 mg, 614.31 ⁇ mol, 99.0% purity, 2 eq
  • DMF 4 mL

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Description

TEAD DEGRADERS AND USES THEREOF SEQUENCE LISTING [0001] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 30, 2021, is named 187426_SL.txt and is 23,552 bytes in size. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for the modulation of Transcriptional Enhancer Associate Domain (TEAD) via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various diseases, disorders, and conditions as described herein. BACKGROUND OF THE INVENTION [0003] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. [0004] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled “Roles of F-box proteins in cancer.” [0005] UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles. [0006] Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e., abnormal or accelerated degradation of the protein target. [0007] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein- binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46). [0008] Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers. SUMMARY OF THE INVENTION [0009] The present application relates to novel bifunctional compounds, which function to recruit TEAD proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of TEAD proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein. Also provided are monovalent compounds, which find utility as inducers of targeted ubiquitination of TEAD proteins, which are then degraded and/or otherwise inhibited by the monovalent compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of TEAD proteins. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment of various diseases, disorders, and conditions as described herein. [0010] The present application further relates to targeted degradation of TEAD proteins through the use of bifunctional molecules, including bifunctional molecules that link a cereblon- binding moiety to a ligand that binds TEAD proteins. [0011] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of TEAD proteins. In some embodiments, the present invention provides a compound having the general formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined and described herein. [0012] In some embodiments, the present invention provides a compound having the general formula II:
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined and described herein. [0013] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating TEAD proteins. Such diseases, disorders, or conditions include those described herein. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG.1 depicts a schematic of Hippo pathway signaling. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0015] Compounds of the present invention, and compositions thereof, are useful as degraders and/or inhibitors of one or more TEAD proteins. In some embodiments, a provided compound degrades and/or inhibits one or more of TEAD1, TEAD2, TEAD3, or TEAD4. [0016] In certain embodiments, the present invention provides a compound of formula I:
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to LBM; and LBM is a ligase binding moiety. [0017] In certain embodiments, the present invention provides a compound of formula II:
Figure imgf000005_0002
or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to DIM; and DIM is a degradation inducing moiety. 2. Compounds and Definitions: [0018] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0019] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0020] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
Figure imgf000007_0001
[0021] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0022] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0023] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0024] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation. [0025] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0026] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0027] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0028] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:
Figure imgf000008_0001
[0029] The term “halogen” means F, Cl, Br, or I. [0030] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [0031] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0032] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl). [0033] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0034] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0035] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0036] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R °; –(CH2)0–4OR °; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR °)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R °)2; –(CH2)0–4N(R °)C(O)R °; –N(R °)C(S)R °; –(CH2)0– 4N(R °)C(O)NR °2; -N(R °)C(S)NR °2; –(CH2)0–4N(R °)C(O)OR °; – N(R °)N(R °)C(O)R °; -N(R °)N(R °)C(O)NR °2; -N(R °)N(R °)C(O)OR °; –(CH2)0–4C(O)R °; – C(S)R °; –(CH2)0–4C(O)OR °; –(CH2)0–4C(O)SR °; -(CH2)0–4C(O)OSiR °3; –(CH2)0–4OC(O)R °; – OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R °; –(CH2)0–4C(O)NR °2; –C(S)NR °2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR °2; -C(O)N(OR °)R °; –C(O)C(O)R °; –C(O)CH2C(O)R °; – C(NOR °)R °; -(CH2)0–4SSR °; –(CH2)0–4S(O)2R °; –(CH2)0–4S(O)2OR °; –(CH2)0–4OS(O)2R °; – S(O)2NR °2; -(CH2)0–4S(O)R °; -N(R °)S(O)2NR °2; –N(R °)S(O)2R °; –N(OR °)R °; –C(NH)NR °2; – P(O)2R °; -P(O)R °2; -OP(O)R °2; –OP(O)(OR °)2; SiR °3; –(C1–4 straight or branched alkylene)O– N(R °)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R °)2, wherein each R ° may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0– 1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R °, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [0037] Suitable monovalent substituents on R ° (or the ring formed by taking two independent occurrences of R ° together with their intervening atoms), are independently halogen,
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0004
Figure imgf000011_0003
is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ° include =O and =S. [0038] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR* 2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or –S(C(R* 2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR* 2)2– 3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0039] Suitable substituents on the aliphatic group of R* include halogen,
Figure imgf000012_0003
Figure imgf000012_0004
wherein each is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0040] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR† 2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR† 2, –C(S)NR† 2, –C(NH)NR† 2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0041] Suitable substituents on the aliphatic group of R† are independently halogen, –
Figure imgf000012_0001
or -NO2, wherein each
Figure imgf000012_0002
is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0042] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0043] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. In some embodiments, the provided compounds are purified in salt form for convenience and/or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromatographic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art. [0044] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention [0045] As used herein, the term “provided compound” refers to any genus, subgenus, and/or species set forth herein. [0046] As used herein, the terms “inhibitor” or “TEAD inhibitor” or “TEAD antagonist” are defined as a compound that binds to and/or inhibits TEAD with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions. The potency of an inhibitor is usually defined by its IC50 value (half maximal inhibitory concentration or concentration required to inhibit 50% of the agonist response). The lower the IC50 value the greater the potency of the antagonist and the lower the concentration that is required to inhibit the maximum biological response. In certain embodiments, an inhibitor has an IC50 and/or binding constant of less than about 100 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0047] As used herein, the term “degrader” is defined as a heterobifunctional compound that binds to and/or inhibits both a TEAD protein and an E3 ligase with measurable affinity resulting in the ubiquitination and subsequent degradation of the TEAD protein. In some embodiments, degradation in the presence of the degrader is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions. The potency of a degrader is usually defined by its DC50 value (the 50% degradation concentration). The lower the DC50 value the greater the potency of the degrader and the lower the concentration that is required to degrade the protein. In certain embodiments, a degrader has an DC50 of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. As used herein, the term “monovalent” refers to a degrader compound without an appended E3 ligase binding moiety. [0048] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change or inhibition in TEAD activity between a sample comprising a compound of the present invention, or composition thereof, and TEAD, and an equivalent sample comprising TEAD, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments: [0049] As described above, in certain embodiments, the present invention provides a compound of formula I:
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to LBM; and LBM is a ligase binding moiety. [0050] As described above, in certain embodiments, the present invention provides a compound of formula II:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to DIM; and DIM is a degradation inducing moiety. Ligase Binding Moiety (LBM) [0051] In some embodiments, LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO 2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO 2012/003281, US 2013/0190340, US 2016/0022642, WO 2014/063061, US 2015/0274738, WO 2016/118666, US 2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US 2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US 2017/0008904, WO 2017/011590, US 2017/0037004, WO 2017/079267, US 2017/0121321, WO 2017/117473, WO 2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, WO 2017/197046, WO 2017/197051, WO 2017/197055, WO 2017/197056, WO 2019/060693, WO 2019/140387, and WO 2020/010177, the content of each of which is herein incorporated by reference in its entirety. [0052] As defined herein and described below, wherein a formula is depicted using square brackets, e.g., L is attached to a modifiable carbon,
Figure imgf000016_0002
oxygen, or nitrogen atom within DIM or LBM including substitution or replacement of a defined group in DIM or LBM. [0053] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-a-1, I-a-2, I-a-3, I-a-4, I-a-5, I-a-6, I-a-7, I-a-8, I-a-9, or I-a-10 respectively:
Figure imgf000017_0001
I-a-9 I-a-10 or a compound of formula I-aʹ-1, I-aʹ-2, I-aʹ-3, I-aʹ-4, I-aʹ-5, I-aʹ-6, I-aʹ-7, I-aʹ-8, I-aʹ-9, or I-aʹ- 10 respectively:
Figure imgf000018_0001
or a compound of formula I-aʹʹ-1, I-aʹʹ-2, I-aʹʹ-3, I-aʹʹ-4, I-aʹʹ-5, I-aʹʹ-6, I-aʹʹ-7, I-aʹʹ-8, I-aʹʹ-9, or I-aʹʹ-10 respectively:
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables
Figure imgf000019_0002
, X, X1, X2, Y, R1, R3, R3’, R4, R5, t, m and n is independently as defined and described in WO 2017/007612 and US 2018/0134684, the content of each of which is herein incorporated by reference in its entirety. [0054] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4, I-b-5, or I-b-6 respectively:
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A, G, G’, Q1, Q2, Q3, Q4, R, R’, W, X, Y, Z,
Figure imgf000020_0002
, and n is independently as defined and described in WO 2016/197114 and US 2018/0147202, the content of each of which is herein incorporated by reference in its entirety. [0055] In some embodiments, LBM is
Figure imgf000021_0001
or
Figure imgf000021_0002
. In some embodiments, LBM is
Figure imgf000021_0003
In some embodiments, LBM is
Figure imgf000021_0013
. In some embodiments, LBM is
Figure imgf000021_0004
In some embodiments, LBM is
Figure imgf000021_0012
In some embodiments, LBM is
Figure imgf000021_0014
In some embodiments, LBM is
Figure imgf000021_0005
[0056] In some embodiments, LBM is
Figure imgf000021_0011
or
Figure imgf000021_0006
In some embodiments, LBM is
Figure imgf000021_0010
In some embodiments, LBM is
Figure imgf000021_0009
. In some embodiments, LBM is
Figure imgf000021_0007
In some embodiments, LBM is
Figure imgf000021_0008
In some embodiments, LBM is
Figure imgf000022_0010
In some embodiments, LBM is
Figure imgf000022_0004
[0057] In some embodiments, LBM is
Figure imgf000022_0005
In some embodiments, LBM is
Figure imgf000022_0006
In some embodiments, LBM is
Figure imgf000022_0007
In some embodiments, LBM is
Figure imgf000022_0003
In some embodiments, LBM is
Figure imgf000022_0008
In some embodiments, LBM is
Figure imgf000022_0009
. In some embodiments, LBM is
Figure imgf000022_0002
[0058] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-c-1, I-c-2, or I-c-3 respectively:
Figure imgf000022_0001
Figure imgf000023_0004
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described herein, and wherein each of the variables R1, R2, R4, R5, R10, R11, R14, R17, W1, W2, X, , and n is independently as defined in WO 2017/197051, the content of which is herein incorporated by reference in its entirety, and wherein 1
Figure imgf000023_0002
is attached to R , the ring formed by combining R1 and R2, or R17 at the site of attachment of R12 as defined in WO 2017/197051 such that
Figure imgf000023_0001
takes the place of the R12 substituent. [0059] In some embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-d-1, I-d-2, I-d-3, or I-d-4, respectively:
Figure imgf000023_0003
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described herein, and wherein each of the variables R1, R4, R10, R11, R14, R16, W1, W2, X, , and n is independently as defined in WO 2018/237026, the content of which is herein incorporated by reference in its entirety, and wherein
Figure imgf000024_0002
is attached to R1 or R16 at the site of attachment of R12 as defined in WO 2018/237026, such that
Figure imgf000024_0003
takes the place of the R12 substituent. [0060] In some embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-e-1 or I-e-3, respectively:
Figure imgf000024_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described herein, and wherein each of the variables R1, R14, and R16 is independently as defined in WO 2018/237026, the content of which is herein incorporated by reference in its entirety, and wherein 1 16
Figure imgf000024_0004
is attached to R or R at the site of attachment of R12 as defined in WO 2018/237026, such that
Figure imgf000024_0005
takes the place of the R12 substituent. [0061] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5, I-f-6, I-f-7, or I-f-8:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Ar, R1, R2, R3, R4, R5, R6, R7, R8, A, L, x, y, and
Figure imgf000025_0002
is independently as described and defined in WO 2017/161119, the content of which is herein incorporated by reference in its entirety. [0062] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-g:
Figure imgf000026_0002
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A, B, C, W, X, Y, and Z is independently as described and defined in US 5,721,246, the content of which is herein incorporated by reference in its entirety. [0063] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-h:
Figure imgf000026_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R2, and n is independently as described and defined in WO 2019/043214, the content of which is herein incorporated by reference in its entirety . [0064] In some embodiments, LBM is an IAP E3 Ubiquitin ligase binding moiety recited in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4): 669-81, such as, for example:
and
Figure imgf000027_0002
Figure imgf000027_0004
wherein
Figure imgf000027_0003
is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom. [0065] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-i-1, I-i-2, I-i-3, I-i-4, or I-i-5 respectively:
Figure imgf000027_0001
I-i-5 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1’, R2’, R3’, X, and X’ is as independently defined and described in WO 2013/106643 and US 2014/0356322, the content of each of which is herein incorporated by reference in its entirety. [0066] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-j-1, I-j-2, I-j-3, I-j-4, I-j-5 or I-j-6 respectively:
Figure imgf000028_0001
Figure imgf000029_0004
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1’, R2’, R3’, R5, R6, R7, R9, R10, R11, R14, R15, R16, R17, R23, R25, E, G, M, X, X’, Y, Z1, Z2, Z3, Z4, and o is independently as defined and described in WO 2016/149668 and US 2016/0272639, the content of each of which is herein incorporated by reference in its entirety. [0067] As used herein, depiction of brackets around any LBM
Figure imgf000029_0003
means that the
Figure imgf000029_0001
moiety is covalently attached to said LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom. For purposes of clarity and by way of example, such available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structure are depicted below, wherein each wavy bond defines the point of attachment to said
Figure imgf000029_0002
,
Figure imgf000030_0001
. [0068] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-k-1, I-k-2, or I-k-3 respectively:
Figure imgf000030_0002
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Rp, R9, R10, R11, R14a, R14b, R15, R16, W3, W4, W5, X1, X2, and o is independently as defined and described in WO 2016/118666 and US 2016/0214972, the content of each of which is herein incorporated by reference in its entirety. [0069] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-l-1, I-l-2, I-l-3, I-l-4, I-l-5, I-l-6, or I-l-7 respectively:
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A1, A2, A3, R5, G and Z is independently as defined and described in WO 2017/176958, the content of which is herein incorporated by reference in its entirety. [0070] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-lʹ-1, I-lʹʹ-1, I-lʹ-2, I-lʹʹ-2, I-lʹ-3, I-lʹʹ-3, I-lʹ-4, I-lʹʹ-4, I-lʹ-7 or I-lʹʹ-7 respectively:
Figure imgf000032_0001
I-lʹ-7 I-lʹʹ-7 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables A1, A2, A3, R5, G and Z is independently as defined and described in WO 2017/176958, the content of which is herein incorporated by reference in its entirety. [0071] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety thereby forming a compound of formula I-m-1, I-m-2, I-m-3, I-m-4, I-m-5, I-m-6, I-m-7, I-m-8, I-m-9, I-m-10, I-m-11, I-m-12, I-m-13, I-m-14, I-m-15, I-m-16, I-m-17, or I-m-18 respectively:
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R1’, R2’, R3’, R4’, R5’, R6’, R7’, R8’, R9’, R10’, R11’, R12’, R1’’, A, A’, A’’, X, Y, and Z is independently as defined and described in WO 2017/011371 and US 2017/0008904, the content of each of which is herein incorporated by reference in its entirety . [0072] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-n-1, I-n-2, I-n-3, or I-n-4 respectively:
Figure imgf000036_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, R4, R5, R6, and R7, is independently as defined and described in WO 2017/011590 and US 2017/0037004, the content of each of which is herein incorporated by reference in its entirety. [0073] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-o-1, I-o-2, or I-o-3:
Figure imgf000036_0002
Figure imgf000037_0002
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables X, W3, W5, R9, R10, R11, R14a, R14b, R15, R16, and o is independently as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, the content of each of which is herein incorporated by reference in its entirety. [0074] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an IAP binding moiety thereby forming a compound of formula I-p:
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables W, Y, Z, R1, R2, R3, R4, and R5 is independently as described and defined in WO 2014/044622, US 2015/0225449, WO 2015/071393, and US 2016/0272596, the content of each of which is herein incorporated by reference in its entirety. [0075] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a MDM2 binding moiety thereby forming a compound of formula I-q:
Figure imgf000038_0003
or a pharmaceutically acceptable salt thereof, as described and defined in Hines, J. et al., Cancer Res. (DOI: 10.1158/0008-5472.CAN-18-2918), the content of which is herein incorporated by reference in its entirety. [0076] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a DCAF16 binding moiety thereby forming a compound of formula I-r:
Figure imgf000038_0002
or a pharmaceutically acceptable salt thereof, as described and defined in Zhang, X. et al., bioRxiv (doi: https://doi.org/10.1101/443804), the content of which is herein incorporated by reference in its entirety. [0077] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a RNF114 binding moiety thereby forming a compound of formula I-s:
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof, as described and defined in Spradin, J.N. et al., bioRxiv (doi: https://doi.org/10.1101/436998), the content of which is herein incorporated by reference in its entirety. [0078] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a RNF4 binding moiety thereby forming a compound of formula I-t:
Figure imgf000039_0001
I-t or a pharmaceutically acceptable salt thereof, as described and defined in Ward, C.C., et al., bioRxiv (doi: https://doi.org/10.1101/439125), the content of which is herein incorporated by reference in its entirety. [0079] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-u-1 or I-u-2:
Figure imgf000039_0002
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, X, and Y is independently as defined and described in WO 2019/084026, the content of which is herein incorporated by reference in its entirety. [0080] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety thereby forming a compound of formula I-v-1 or I-v-2:
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R3, and Y is independently as defined and described in WO 2019/084030, the content of which is herein incorporated by reference in its entirety. [0081] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-w-1, I-w-2, I-w-3, or I-w-4:
Figure imgf000040_0002
I-w-1 I-w-2
Figure imgf000041_0001
I-w-3 I-w-4 or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and described herein, and wherein each of the variables R4, R10, R11, R15, R16, R17, W1, W2, and X is as defined in WO 2019/099868, the content of which is herein incorporated by reference in its entirety, and wherein
Figure imgf000041_0002
is attached to R17 or R16 at the site of attachment of R12 as defined in WO 2018/237026, such that
Figure imgf000041_0003
takes the place of the R12 substituent. [0082] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a RPN13 binding moiety thereby forming a compound of formula I-x:
Figure imgf000041_0004
I-x or a pharmaceutically acceptable salt thereof, wherein L and TBM are as defined above and described in embodiments herein, and wherein each of the variables A, Y, and Z is as described and defined in WO 2019/165229, the content of which is herein incorporated by reference in its entirety. [0083] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a Ubr1 binding moiety as described in Shanmugasundaram, K. et al, J. Bio. Chem. 2019, doi: 10.1074/jbc.AC119.010790, the content of which is herein incorporated by reference in its entirety, thereby forming a compound of formula I-y-1 or I-y-2:
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein. [0084] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN binding moiety thereby forming a compound of formula I-z:
Figure imgf000042_0001
I-z or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, R4, R5, Q, X, and n is independently as described and defined in US 2019/276474, the content of which is herein incorporated by reference in its entirety. [0085] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-aa-1, I-aa-2, I-aa-3 or I-aa-4:
Figure imgf000042_0002
I-aa-1 I-aa-2
Figure imgf000043_0001
I-aa-3 I-aa-4 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Y, A1,and A3 is independently as described and defined in WO 2019/236483, the content of which is herein incorporated by reference in its entirety. [0086] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-bb-1, I-bb-2, I-bb-3, or I-bb-4:
Figure imgf000043_0002
I-bb-4 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables Ring A, Ring B, R1, R2, R3, X1, X2, X3, X4, m, n, and p is independently as described and defined in WO 2019/060693, the content of which is herein incorporated by reference in its entirety. [0087] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-cc-1:
Figure imgf000044_0001
I-cc-1 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, wherein each of the variables Ring A, Ring B, R1, R2, m, and n is independently as described and defined in WO 2019/140387, and wherein variable L’ corresponds to variable L in WO 2019/140387 and is selected from the embodiments for variable L as described and defined in WO 2019/140387. The content of WO 2019/140387 is herein incorporated by reference in its entirety. [0088] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety thereby forming a compound of formula I-dd-1:
Figure imgf000044_0002
I-dd-1 or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, wherein each of the variables Ring A, R1, R2, X1, X2, X3, and m is independently as described and defined in WO 2020/010177, the content of which is herein incorporated by reference in its entirety. [0089] In some embodiments, LBM is selected from those depicted in Table 1, below. Degradation Inducing Moiety (DIM) [0090] In certain embodiments, the present invention provides a compound of formula II:
Figure imgf000045_0001
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as described above and herein, and DIM is a degradation inducing moiety selected from LBM, a lysine mimetic, or a hydrogen atom. [0091] In some embodiments, DIM is LBM as described above and herein. In some embodiments, DIM is a lysine mimetic. In some embodiments, the covalent attachment of ubiquitin to one or more members of the TEAD protein family (i.e., TEAD1, TEAD2, TEAD3, or TEAD4) is achieved through the action of a lysine mimetic. In some embodiments, upon the binding of a compound of formula II to TEAD1, the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD1 for degradation via the Ubiquitin-Proteasome Pathway (UPP). In some embodiments, upon the binding of a compound of formula II to TEAD2, the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD2 for degradation via the Ubiquitin-Proteasome Pathway (UPP). In some embodiments, upon the binding of a compound of formula II to TEAD3, the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD3 for degradation via the Ubiquitin-Proteasome Pathway (UPP). In some embodiments, upon the binding of a compound of formula II to TEAD4, the moiety that mimics a lysine undergoes ubiquitination thereby marking TEAD4 for degradation via the Ubiquitin- Proteasome Pathway (UPP). [0092] In some embodiments, DIM is
Figure imgf000045_0003
. In some embodiments, DIM is
Figure imgf000045_0002
. In some embodiments, DIM is
Figure imgf000045_0004
[0093] In some embodiments, the present invention provides the compound of formula II as a compound of formula II-a:
Figure imgf000046_0001
II-a or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination. [0094] In some embodiments, the present invention provides the compound of formula II as a compound of formula II-b:
Figure imgf000046_0002
II-b or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination. [0095] In some embodiments, the present invention provides the compound of formula II as a compound of formula II-c:
Figure imgf000046_0003
II-c or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination. [0096] In certain embodiments, the present invention provides a compound of Formula II, wherein DIM is a lysine mimetic
Figure imgf000046_0004
, , or
Figure imgf000047_0001
; thereby forming a compound of Formulae II-d-1, II-d-2, or II- d-3, respectively:
Figure imgf000047_0002
or a pharmaceutically acceptable salt thereof, wherein each of L and TBM is independently as defined above and described in embodiments herein, and wherein each of the variables R1, R4, R5, A, B, E, Y, Yʹ, Z, Zʹ, and k is independently as defined and described in U.S. Pat. No.7,622,496, the content of which is herein incorporated by reference in its entirety. [0097] In some embodiments, DIM is a hydrogen atom. In some embodiments, the covalent attachment of ubiquitin to one or more members of the TEAD protein family (i.e., TEAD1, TEAD2, TEAD3, or TEAD4) is achieved through a provided compound wherein DIM is a hydrogen atom. In some embodiments, upon the binding of a compound of formula II to TEAD1, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD1 for degradation via the Ubiquitin-Proteasome Pathway (UPP). In some embodiments, upon the binding of a compound of formula II to TEAD2, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD2 for degradation via the Ubiquitin-Proteasome Pathway (UPP). In some embodiments, upon the binding of a compound of formula II to TEAD3, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD3 for degradation via the Ubiquitin- Proteasome Pathway (UPP). In some embodiments, upon the binding of a compound of formula II to TEAD4, the moiety being hydrogen effectuates ubiquitination thereby marking TEAD4 for degradation via the Ubiquitin-Proteasome Pathway (UPP). [0098] In some embodiments, the present invention provides the compound of formula II wherein DIM is a hydrogen atom, thereby forming a compound of formula II-d-4:
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein each of TBM and L is as defined above and described in embodiments herein, both singly and in combination. [0099] In some embodiments, DIM is selected from those depicted in Table 1, below. TEAD Binding Moiety (TBM) [00100] As defined above and described herein, TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4. [00101] In some embodiments, TBM is a TEAD binding moiety capable of binding to TEAD1. In some embodiments, TBM is a TEAD binding moiety capable of binding to TEAD2. In some embodiments, TBM is a TEAD binding moiety capable of binding to TEAD3. In some embodiments, TBM is a TEAD binding moiety capable of binding to TEAD4. [00102] In some embodiments, TBM is a compound or a TEAD binding moiety as described in Pobbati et al., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy,” Structure 2015, 23, 2076–2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072; Bum-Erdene et al., “Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD•Yap Protein-Protein Interaction,” Cell Chemical Biology 2019, 26, 1–12; Holden et. al., “Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant- Negative Inhibition of HippoPathway Signaling,” Cell Reports 2020, 31, 107809; WO 2017/053706, WO 2017/111076, WO 2018/204532, WO 2018/235926, US 20190010136, WO 2019/040380, WO 2019/113236, WO 2019/222431, WO 2019/232216, WO 2020/051099, WO 2020/081572, WO 2020/097389, WO 2020/190774, or WO 2020/214734, the content of each of which is herein incorporated by reference in its entirety. [00103] As defined herein and described below, wherein a formula is depicted using square brackets, e.g.,
Figure imgf000049_0001
, L is attached to a modifiable carbon, oxygen, or nitrogen atom within TBM including substitution or replacement of a defined group in TBM. 1. TEAD Binding Moiety (TBM) of Formulas A, and A-1 to A-50 [00104] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety as described in PCT/US2020/35098, the content of which is herein incorporated by reference in its entirety. [00105] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula A:
Figure imgf000049_0002
, thereby forming a compound of formula I-A or II-A:
Figure imgf000049_0003
I-A II-A or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Rw is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R is independently -H or optionally substituted -C1-6 aliphatic. [00106] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula A-1:
Figure imgf000050_0002
thereby forming a compound of formula I-A-1 or II-A-1:
Figure imgf000050_0001
I-A-1 II-A-1 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by -halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0-6 times by -halogen, -CN, or –NO2; R2 is -H, or an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is -H; R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, or -C(O)N(R)2; R6 is -H or -C1-6 aliphatic substituted 0-6 times by -halogen, -CN, or –NO2; and each R is independently -H or optionally substituted -C1-6 aliphatic. [00107] As defined generally above, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, - (R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00108] In some embodiments, L1 is a covalent bond, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00109] In some embodiments, L1 is a covalent bond. [00110] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-. [00111] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are optionally replaced with -CH(SR)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-. [00112] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -S-, or -N(R)-. [00113] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - CH(OR)-, -CH(SR)-, or –CH(N(R)2)-. [00114] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO2-, -C(S)-, -C(S)O-, or -OC(S)-. [00115] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -SO2N(R)-, -(R)NSO2-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00116] In some embodiments, L1 is -O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O- , -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-. [00117] In some embodiments, L1 is -O-, -CH(OR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-. [00118] In some embodiments, L1 is -CH(SR)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)- , -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00119] In some embodiments, L1 is -O-, -S-, or -N(R)-. In some embodiments, L1 is -O-. In some embodiments, L1 is -S-. In some embodiments, L1 is -N(R)-. In some embodiments, L1 is - NH-. [00120] In some embodiments, L1 is -CH(OR)-, -CH(SR)-, or –CH(N(R)2)-. In some embodiments, L1 is -CH(OR)-. In some embodiments, L1 is -CH(SR)-. In some embodiments, L1 is –CH(N(R)2)-. [00121] In some embodiments, L1 is -C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO2-, -C(S)-, -C(S)O-, or -OC(S)-. In some embodiments, L1 is -C(O)-. In some embodiments, L1 is -C(O)O-. In some embodiments, L1 is -OC(O)-. In some embodiments, L1 is -SO-. In some embodiments, L1 is -SO2- . In some embodiments, L1 is -C(S)-. In some embodiments, L1 is -C(S)O-. In some embodiments, L1 is -OC(S)-. [00122] In some embodiments, L1 is -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -SO2N(R)-, -(R)NSO2-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. In some embodiments, L1 is -C(O)N(R)-. In some embodiments, L1 is -(R)NC(O)-. In some embodiments, L1 is -OC(O)N(R)-. In some embodiments, L1 is -(R)NC(O)O-. In some embodiments, L1 is - N(R)C(O)N(R)-. In some embodiments, L1 is -SO2N(R)-. In some embodiments, L1 is -(R)NSO2- . In some embodiments, L1 is -C(S)N(R)-. In some embodiments, L1 is -(R)NC(S)-. or In some embodiments, L1 is -(R)NC(S)N(R)-. [00123] In some embodiments, L1 is –CH2-, -CH(CH3)-, -NH-CH2-, -NH-CH(CH3)-, -C(O)- NH-, or –N(CH3)-. [00124] In some embodiments, L1 is
Figure imgf000053_0001
[00125] In some embodiments, L1 is selected from those depicted in Table A, below. [00126] As defined generally above, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO2. [00127] In some embodiments, Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00128] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00129] In some embodiments, Ring A is optionally substituted phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen. [00130] In some embodiments, Ring A is optionally substituted
Figure imgf000054_0002
Figure imgf000054_0001
. [00131] In some embodiments, Ring A is optionally substituted 1-2 times by -halogen, -CN, – NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 0-6 times by -halogen, -CN, or –NO2. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -CN, –NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO2. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 1, 2, 3, 4, 5, or 6 times by halogen. [00132] In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00133] In some embodiments, Ring A is a 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00134] In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -CN, – NO2, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO2. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen. [00135] In some embodiments, Ring A is selected from
Figure imgf000055_0002
and
Figure imgf000055_0003
wherein each of R1 and R7 is independently as described herein. [00136] In some embodiments, Ring A is selected from
Figure imgf000055_0004
Figure imgf000055_0005
, , or
Figure imgf000055_0006
[00137] In some embodiments, R1 is -H, -halogen, -CN, –NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R1 is unsubstituted –O-C1-6 aliphatic. In some embodiments, R1 is –OCH3. In some embodiments, R1 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is –O-C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R1 is –OCF3. In some embodiments, R1 is
Figure imgf000055_0001
. [00138] In some embodiments, R1 is -H, -halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R1 is –H. In some embodiments, R1 is –halogen. In some embodiments, R1 is –F. In some embodiments, R1 is –Cl. In some embodiments, R1 is –Br. In some embodiments, R1 is –CN. In some embodiments, R1 is –NO2. In some embodiments, R1 is unsubstituted -C1-6 aliphatic. In some embodiments, R1 is – CH3. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R1 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R1 is –CF3. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO2. [00139] In some embodiments, R7 is -H, -halogen, -CN, –NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R7 is unsubstituted –O-C1-6 aliphatic. In some embodiments, R7 is –OCH3. In some embodiments, R7 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is –O-C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R7 is –OCF3. In some embodiments, R7 is
Figure imgf000056_0001
. [00140] In some embodiments, R7 is -H, -halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R7 is –H. In some embodiments, R7 is –halogen. In some embodiments, R7 is –F. In some embodiments, R7 is –Cl. In some embodiments, R7 is –Br. In some embodiments, R7 is –CN. In some embodiments, R7 is –NO2. In some embodiments, R7 is unsubstituted -C1-6 aliphatic. In some embodiments, R1 is – CH3. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R7 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R7 is –CF3. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO2. [00141] In some embodiments, Ring A is
Figure imgf000057_0001
Figure imgf000057_0002
or
Figure imgf000057_0003
[00142] In some embodiments, Ring A is
Figure imgf000057_0004
Figure imgf000057_0005
[00143] In some embodiments, Ring A is selected from those depicted in Table A, below. [00144] As defined generally above, Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00145] In some embodiments, Ring B is optionally substituted phenyl. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00146] In some embodiments, Ring B is optionally substituted phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen. [00147] In some embodiments, Ring B is optionally substituted
Figure imgf000058_0001
Figure imgf000058_0002
[00148] In some embodiments, Ring B is optionally substituted 1-4 times by halogen, - S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, -C(O)OR, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 0-6 times by halogen, - CN, or –NO2. [00149] In some embodiments, Ring B is optionally substituted 1-4 times by –F, -Cl, -Br-, - S(O)2NHCH3, -S(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH3, -C(O)OH, -C(O)OCH3, -CH3, – OCH3, or -C(CH3)3. [00150] In some embodiments, Ring B is
Figure imgf000059_0001
Figure imgf000059_0002
[00151] In some embodiments, Ring B is selected from those depicted in Table A, below. [00152] As defined generally above, R2 is -H, or an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00153] In some embodiments, R2 is –H. [00154] In some embodiments, R2 is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C1-6 alkyl. [00155] In some embodiments, R2 is
Figure imgf000060_0001
, wherein R is as described herein. In some embodiments, R2 is
Figure imgf000060_0002
, wherein R is as described herein. [00156] In some embodiments, R2 is 2
Figure imgf000060_0014
. In some embodiments, R is
Figure imgf000060_0003
Figure imgf000060_0004
, or
Figure imgf000060_0005
. [00157] In some embodiments, R2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen. In some embodiments, R2 is selected from
Figure imgf000060_0006
and In 2
Figure imgf000060_0007
some embodiments, R is
Figure imgf000060_0015
[00158] In some embodiments, R2 is
Figure imgf000060_0013
Figure imgf000060_0008
or
Figure imgf000060_0009
. [00159] In some embodiments, R2 is selected from those depicted in Table A, below. [00160] As defined generally above, in some embodiments, R3 is –H. [00161] In some embodiments, R3 is . In som 3
Figure imgf000060_0010
e embodiments, R is
Figure imgf000060_0011
, , or
Figure imgf000060_0012
[00162] In some embodiments, R3 is selected from those depicted in Table A, below. [00163] As defined generally above, R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, or - C(O)N(R)2. [00164] In some embodiments, R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, or - C(O)OR. [00165] In some embodiments, R4 is –H. [00166] In some embodiments, R4 is halogen. In some embodiments, R4 is -F. In some embodiments, R4 is -Cl. In some embodiments, R4 is -Br. [00167] In some embodiments, R4 is -S(O)2N(R)2, -S(O)N(R)2, or -C(O)N(R)2. In some embodiments, R4 is -S(O)2N(R)2. In some embodiments, R4 is -S(O)N(R)2. In some embodiments, R4 is -C(O)N(R)2. In some embodiments, R4 is -S(O)2NHCH3. [00168] In some embodiments, R4 is -S(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH3, -C(O)OH, or -C(O)OCH3. [00169] In some embodiments, R4 is 4
Figure imgf000061_0002
In some embodiments, R is
Figure imgf000061_0003
or
Figure imgf000061_0001
[00170] In some embodiments, R4 is selected from those depicted in Table A, below. [00171] As defined generally above, R6 is -H or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. [00172] In some embodiments, R6 is –H, -halogen, -CN, –NO2, -C1-6 aliphatic, -OC1-6 aliphatic, or a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C1-6 aliphatic or -OC1-6 aliphatic, wherein each of -C1-6 aliphatic and -OC1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. [00173] In some embodiments, R6 is –H. In some embodiments, R6 is –F. In some embodiments, R6 is –Cl. In some embodiments, R6 is –Br. In some embodiments, R6 is –CN. In some embodiments, R6 is –NO2. [00174] In some embodiments, R6 is -C1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by - halogen, -CN, or –NO2. In some embodiments, R6 is unsubstituted -C1-6 aliphatic. In some embodiments, R6 is –CH3. In some embodiments, R6 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R6 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R6 is –CF3. [00175] In some embodiments, R6 is -OC1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is unsubstituted -OC1-6 aliphatic. In some embodiments, R6 is –OCH3. In some embodiments, R6 is -OC1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is -OC1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R6 is -OC1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R6 is –OCF3. [00176] In some embodiments, R6 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C1-6 aliphatic or -OC1-6 aliphatic, wherein each of -C1-6 aliphatic and -OC1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is a 5-membered ring having 1, 2, 3, or 4 nitrogen optionally substituted 1-3 times by -C1-6 aliphatic. In some embodiments, R6 is
Figure imgf000062_0003
[00177] In some embodiments, R6 is selected from those depicted in Table A, below. [00178] As defined generally above, Rw is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00179] In some embodiments, Rw is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rw is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C1-6 alkyl. [00180] In some embodiments, Rw is
Figure imgf000062_0001
, wherein R is as described herein. In some embodiments, Rw is
Figure imgf000062_0002
, wherein R is as described herein. [00181] In some embodiments, Rw is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-3 times by -C1-6 alkyl. In some embodiments, Rw is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen. In some embodiments, Rw is
Figure imgf000063_0007
Figure imgf000063_0001
[00182] In some embodiments, Rw is
Figure imgf000063_0002
[00183] In some embodiments, Rw is
Figure imgf000063_0003
Figure imgf000063_0004
, or
Figure imgf000063_0005
[00184] In some embodiments, Rw is selected from those depicted in Table A, below. [00185] As defined generally above, R is independently -H or optionally substituted -C1-6 aliphatic. [00186] In some embodiments, R is –H. [00187] In some embodiments, R is optionally substituted -C1-6 aliphatic. In some embodiments, R is unsubstituted -C1-6 aliphatic. In some embodiments, R is –CH3. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CF3. [00188] In some embodiments, R is selected from those depicted in Table A, below. [00189] In some embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula A-2:
Figure imgf000063_0006
, thereby forming a compound of formula I-A-2 or II-A-2:
Figure imgf000064_0001
or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, DIM, R1, R2, R3, R4, R6, R7, and L1 is independently as defined and described in embodiments in Section of TBM of Formulas A, and A-1 to A-50. [00190] In some embodiments, the present invention provides a compound of formula I-A-2 or II-A-2, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein: (a): L1 is -O- or -S-; R1 is -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen; R2 is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen; R3 is -H; R4 is -S(O)2N(R)2; -S(O)N(R)2, or -C(O)N(R)2, each R independently is selected -H and optionally substituted -C1-6 aliphatic; R6 is -H or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen; and R7 is -H; or (b): L1 is -NH-; R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen; R3 is -H; R4 is -S(O)2N(R)2, -S(O)N(R)2, or -C(O)N(R)2, each R independently is selected from -H and optionally substituted -C1-6 aliphatic; R6 is -C1-6 aliphatic; and R7 is -H. [00191] In some embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula:
Figure imgf000065_0001
A-18 , thereby forming a compound of formula I-A-3, II-A-3, I-A-4, II-A-4, I-A-5, II-A-5, I-A-6, II- A-6, I-A-7, II-A-7, I-A-8, II-A-8, I-A-9, II-A-9, I-A-10, II-A-10, I-A-11, II-A-11, I-A-12, II-A- 12, I-A-13, II-A-13, I-A-14, II-A-14, I-A-15, II-A-15, I-A-16, II-A-16, I-A-17, II-A-17, I-A-18, or II-A-18:
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
I-A-18 II-A-18 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein each of X is independently C or N, and each of Ring A, Rw, R1, R2, R3, R4, R6, R7, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50. [00192] In some embodiments, the present invention provides a compound of Formula I-A or II-A, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen; Ring B is phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen; and each of Rw and L1 is as defined above and described in embodiments herein, both singly and in combination. [00193] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: i. Formula (A-19) or (A-20):
Figure imgf000068_0002
A-19 A-20 wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R4, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; ii. Formula (A-21) or (A-22):
Figure imgf000069_0003
wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; iii. Formula (A-23) or (A-24):
Figure imgf000069_0002
wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, each of R2 and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; iv. Formula (A-25) or (A-26):
Figure imgf000069_0001
wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; v. Formula (A-27) or (A-28):
Figure imgf000070_0001
wherein L1 is a C2-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is optionally substituted -C1-6 aliphatic, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; vi. Formula (A-29) or (A-30):
Figure imgf000070_0004
wherein L1 is a C2-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; vii. Formula (A-31) or (A-32):
Figure imgf000070_0002
wherein R2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen; viii. Formula (A-33) or (A-34):
Figure imgf000070_0003
(A-33) (A-34) wherein R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; ix. Formula (A-35) or (A-36):
Figure imgf000071_0001
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R4, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; x. Formula (A-37) or (A-38):
Figure imgf000071_0002
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xi. Formula (A-39) or (A-40):
Figure imgf000071_0003
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, each of R2 and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xii. Formula (A-41) or (A-42):
Figure imgf000072_0004
A-41 A-42 wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xiii. Formula (A-43) or (A-44):
Figure imgf000072_0003
A-43 A-44 wherein L1 is a C1-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is optionally substituted -C1-6 aliphatic, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xiv. Formula (A-45) or (A-46):
Figure imgf000072_0002
A-45 A-46 wherein L1 is a C1-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xv. Formula (A-47) or (A-48):
Figure imgf000072_0001
A-47 A-48 wherein R2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen; or xvi. Formula (A-49) or (A-50):
Figure imgf000073_0001
A-49 A-50 wherein R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50. [00194] In some embodiments, TBM is a moiety set forth in Table A, or a pharmaceutically acceptable salt thereof. [00195] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table A. [00196] Table A. Exemplified TEAD Binding Moiety (TBM)
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
2. TEAD Binding Moiety (TBM) of Formulas B, and B-1 to B-34 [00197] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety as described in PCT/US2020/35111, the content of which is herein incorporated by reference in its entirety. [00198] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula B:
Figure imgf000080_0001
thereby forming a compound of formula I-B or II-B:
Figure imgf000080_0002
or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is a covalent bond, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Rw is a warhead group; wherein when Rw is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B; and each R is independently -H or optionally substituted -C1-6 aliphatic. [00199] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of formula B-1
Figure imgf000081_0001
thereby forming a compound of formula I-B-1 or II-B-1:
Figure imgf000081_0002
or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO2; R2 is -H, or a warhead group; R3 is -H or a warhead group; R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, or a warhead group; R6 is -H or -C1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO2; and each R is independently -H or optionally substituted -C1-6 aliphatic. [00200] As defined generally above, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, - (R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, - (R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00201] In some embodiments, L1 is a covalent bond, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, - SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00202] In some embodiments, L1 is a covalent bond. [00203] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -CH(OR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-. [00204] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are optionally replaced with -CH(SR)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-. [00205] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -S-, or -N(R)-. [00206] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - CH(OR)-, -CH(SR)-, or –CH(N(R)2)-. [00207] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO2-, -C(S)-, -C(S)O-, or -OC(S)-. [00208] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -SO2N(R)-, -(R)NSO2-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00209] In some embodiments, L1 is -O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O- , -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-. [00210] In some embodiments, L1 is -O-, -CH(OR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, or -N(R)C(O)N(R)-. [00211] In some embodiments, L1 is -CH(SR)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)- , -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. [00212] In some embodiments, L1 is -O-, -S-, or -N(R)-. In some embodiments, L1 is -O-. In some embodiments, L1 is -S-. In some embodiments, L1 is -N(R)-. In some embodiments, L1 is - NH-. [00213] In some embodiments, L1 is -CH(OR)-, -CH(SR)-, or –CH(N(R)2)-. In some embodiments, L1 is -CH(OR)-. In some embodiments, L1 is -CH(SR)-. In some embodiments, L1 is –CH(N(R)2)-. [00214] In some embodiments, L1 is -C(O)-, -C(O)O-, -OC(O)-, -SO-, -SO2-, -C(S)-, -C(S)O-, or -OC(S)-. In some embodiments, L1 is -C(O)-. In some embodiments, L1 is -C(O)O-. In some embodiments, L1 is -OC(O)-. In some embodiments, L1 is -SO-. In some embodiments, L1 is -SO2- . In some embodiments, L1 is -C(S)-. In some embodiments, L1 is -C(S)O-. In some embodiments, L1 is -OC(S)-. [00215] In some embodiments, L1 is -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -SO2N(R)-, -(R)NSO2-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. In some embodiments, L1 is -C(O)N(R)-. In some embodiments, L1 is -(R)NC(O)-. In some embodiments, L1 is -OC(O)N(R)-. In some embodiments, L1 is -(R)NC(O)O-. In some embodiments, L1 is - N(R)C(O)N(R)-. In some embodiments, L1 is -SO2N(R)-. In some embodiments, L1 is -(R)NSO2- . In some embodiments, L1 is -C(S)N(R)-. In some embodiments, L1 is -(R)NC(S)-. or In some embodiments, L1 is -(R)NC(S)N(R)-. [00216] In some embodiments, L1 is –CH2-, -CH(CH3)-, -NH-CH2-, -NH-CH(CH3)-, -C(O)- NH-, or –N(CH3)-. [00217] In some embodiments, L1 is
Figure imgf000084_0001
Figure imgf000084_0002
, [00218] In some embodiments, L1 is selected from those depicted in Table B, below. [00219] As defined generally above, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO2. [00220] In some embodiments, Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00221] In some embodiments, Ring A is optionally substituted phenyl. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00222] In some embodiments, Ring A is optionally substituted phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen. [00223] In some embodiments, Ring A is optionally substituted
Figure imgf000085_0001
Figure imgf000085_0002
[00224] In some embodiments, Ring A is optionally substituted 1-2 times by -halogen, -CN, – NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 0-6 times by -halogen, -CN, or –NO2. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -CN, –NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO2. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 1, 2, 3, 4, 5, or 6 times by halogen. [00225] In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00226] In some embodiments, Ring A is a 8-10 membered bicyclic aromatic ring. In some embodiments, Ring A is a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00227] In some embodiments, Ring A is optionally substituted 1-2 times by halogen, -CN, – NO2, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen, -CN, or –NO2. In some embodiments, Ring A is optionally substituted 1-2 times by halogen, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by halogen. [00228] In some embodiments, Ring A is selected from
Figure imgf000086_0001
, wherein each of R1 and R7 is independently as described herein. [00229] In some embodiments, Ring A is selected from
Figure imgf000086_0002
,
Figure imgf000086_0003
. [00230] In some embodiments, R1 is -H, -halogen, -CN, –NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R1 is unsubstituted –O-C1-6 aliphatic. In some embodiments, R1 is –OCH3. In some embodiments, R1 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is –O-C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. [00231] In some embodiments, R1 is -H, -halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R1 is –H. In some embodiments, R1 is –halogen. In some embodiments, R1 is –F. In some embodiments, R1 is –Cl. In some embodiments, R1 is –Br. In some embodiments, R1 is –CN. In some embodiments, R1 is –NO2. In some embodiments, R1 is unsubstituted -C1-6 aliphatic. In some embodiments, R1 is – CH3. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R1 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R1 is –CF3. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN. In some embodiments, R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO2. [00232] In some embodiments, R1 is phenyl. In some embodiments, R1 is –C(CH3)3. In some embodiments, R1 is –SCF3. In some embodiments, R1 is –S(O)2CF3. In some embodiments, R1 is –N(CH3)2. In some embodiments, R1 is -CHF2. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is -CF2CF3. In some embodiments, R1 is
Figure imgf000087_0001
. [00233] In some embodiments, R7 is -H, -halogen, -CN, –NO2, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R7 is unsubstituted –O-C1-6 aliphatic. In some embodiments, R7 is –OCH3. In some embodiments, R7 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is –O-C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is –O-C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. [00234] In some embodiments, R7 is -H, -halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R7 is –H. In some embodiments, R7 is –halogen. In some embodiments, R7 is –F. In some embodiments, R7 is –Cl. In some embodiments, R7 is –Br. In some embodiments, R7 is –CN. In some embodiments, R7 is –NO2. In some embodiments, R7 is unsubstituted -C1-6 aliphatic. In some embodiments, R1 is – CH3. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R7 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R7 is –CF3. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –CN. In some embodiments, R7 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –NO2. [00235] In some embodiments, R7 is phenyl. In some embodiments, R7 is –C(CH3)3. In some embodiments, R7 is –SCF3. In some embodiments, R7 is –S(O)2CF3. In some embodiments, R7 is –N(CH3)2. In some embodiments, R7 is -CHF2. In some embodiments, R7 is cyclopropyl. In some embodiments, R7 is -CF2CF3. In some embodiments, R7 is
Figure imgf000087_0002
. [00236] In some embodiments, Ring A is
Figure imgf000088_0001
Figure imgf000088_0002
[00237] In some embodiments, Ring A is
Figure imgf000088_0003
Figure imgf000088_0004
[00238] In some embodiments, Ring A is selected from those depicted in Table B, below. [00239] As defined generally above, Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00240] In some embodiments, Ring B is optionally substituted phenyl. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring B is optionally substituted 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic aromatic ring. In some embodiments, Ring B is optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00241] In some embodiments, Ring B is an optionally substituted 6-, 7-, 8-, 9-, or 10- membered bicyclic carbocyclic ring. In some embodiments, Ring B is an optionally substituted 6- , 7-, 8-, 9-, or 10-membered bicyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is an optionally substituted 6-membered bicyclic heterocyclic ring having 1 nitrogen. [00242] In some embodiments, Ring B is optionally substituted phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen. [00243] In some embodiments, Ring B is optionally substituted
Figure imgf000089_0001
Figure imgf000089_0002
[00244] In some embodiments, Ring B is optionally substituted 1-4 times by halogen, - S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, -C(O)OR, -C1-6 aliphatic, or –O-C1-6 aliphatic, wherein each of -C1-6 aliphatic and –O-C1-6 aliphatic is independently substituted 0-6 times by halogen, - CN, or –NO2. [00245] In some embodiments, Ring B is optionally substituted 1-4 times by –F, -Cl, -Br-, - S(O)2NHCH3, -S(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH3, -C(O)OH, -C(O)OCH3, -CH3, – OCH3, or -C(CH3)3. [00246] In some embodiments, Ring B is
Figure imgf000090_0002
, , ,
Figure imgf000090_0003
[00247] In some embodiments, Ring B is
Figure imgf000090_0001
[00248] In some embodiments, Ring B is selected from those depicted in Table B, below. [00249] As defined generally above, R2 is -H, or a warhead group. [00250] In some embodiments, R2 is –H. [00251] In some embodiments, R2 is a warhead group. In some embodiments, R2 is
Figure imgf000091_0006
, , , , In some emb 2
Figure imgf000091_0008
odiments, R is
Figure imgf000091_0007
, ,
Figure imgf000091_0001
[00252] In some embodiments, R2 is selected from those depicted in Table B, below. [00253] As defined generally above, R3 is -H or a warhead group. [00254] In some embodiments, R3 is –H. [00255] In some embodiments, R3 is a warhead group. In some embodiments, R3 is
Figure imgf000091_0002
, , 3
Figure imgf000091_0003
, , In some embodiments, R is
Figure imgf000091_0004
,
Figure imgf000091_0005
[00256] In some embodiments, R3 is selected from those depicted in Table B, below. [00257] As defined generally above, R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, or a warhead group. [00258] In some embodiments, R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, - C(O)OR, or a warhead group. [00259] In some embodiments, R4 is –H. [00260] In some embodiments, R4 is halogen. In some embodiments, R4 is -F. In some embodiments, R4 is -Cl. In some embodiments, R4 is -Br. [00261] In some embodiments, R4 is -S(O)2N(R)2, -S(O)N(R)2, or -C(O)N(R)2. In some embodiments, R4 is -S(O)2N(R)2. In some embodiments, R4 is -S(O)N(R)2. In some embodiments, R4 is -C(O)N(R)2. In some embodiments, R4 is -S(O)2NHCH3. [00262] In some embodiments, R4 is -S(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH3, -C(O)OH, or -C(O)OCH3. [00263] In some embodiments, R4 is a warhead group. In some embodiments, R4 is
Figure imgf000092_0001
, , , In some embodimen 4
Figure imgf000092_0002
ts, R is
Figure imgf000092_0003
Figure imgf000092_0004
[00264] In some embodiments, R4 is selected from those depicted in Table B, below. [00265] As defined generally above, R6 is -H or -C1-6 aliphatic substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. [00266] In some embodiments, R6 is –H, -halogen, -CN, –NO2, -C1-6 aliphatic, -OC1-6 aliphatic, or a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C1-6 aliphatic or -OC1-6 aliphatic, wherein each of -C1-6 aliphatic and -OC1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. [00267] In some embodiments, R6 is –H. In some embodiments, R6 is –F. In some embodiments, R6 is –Cl. In some embodiments, R6 is –Br. In some embodiments, R6 is –CN. In some embodiments, R6 is –NO2. [00268] In some embodiments, R6 is -C1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by - halogen, -CN, or –NO2. In some embodiments, R6 is unsubstituted -C1-6 aliphatic. In some embodiments, R6 is –CH3. In some embodiments, R6 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R6 is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R6 is –CF3. [00269] In some embodiments, R6 is -OC1-6 aliphatic, substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is unsubstituted -OC1-6 aliphatic. In some embodiments, R6 is –OCH3. In some embodiments, R6 is -OC1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is -OC1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -F. In some embodiments, R6 is -OC1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R6 is –OCF3. [00270] In some embodiments, R6 is a 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted 1-3 times by -C1-6 aliphatic or -OC1-6 aliphatic, wherein each of -C1-6 aliphatic and -OC1-6 aliphatic is independently substituted 0, 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R6 is a 5-membered ring having 1, 2, 3, or 4 nitrogen optionally substituted 1-3 times by -C1-6 aliphatic. In some embodiments, R6 is
Figure imgf000093_0001
[00271] In some embodiments, R6 is selected from those depicted in Table B, below. [00272] As defined generally above, Rw is a warhead group; wherein when Rw is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B. [00273] In some embodiments, Rw is a warhead group. [00274] In some embodiments, Rw is
Figure imgf000094_0002
Figure imgf000094_0003
[00275] In some embodiments, wherein Rw is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, Rw forms a spiro bicyclic ring with Ring B. In some embodiments, wherein Rw is a saturated or partially unsaturated 4-, 5-, or 6- membered carbocyclic or heterocyclic ring, Rw forms a spiro bicyclic ring with Ring B. In some embodiments, wherein Rw is optionally substituted
Figure imgf000094_0001
, it forms a spiro bicyclic ring with Ring B. In some embodiments, wherein Rw is optionally substituted
Figure imgf000094_0004
, it forms a spiro bicyclic ring with Ring B, for example,
Figure imgf000094_0005
[00276] In some embodiments, Rw is selected from those depicted in Table B, below. [00277] As defined generally above, R is independently -H or optionally substituted -C1-6 aliphatic. [00278] In some embodiments, R is –H. [00279] In some embodiments, R is optionally substituted -C1-6 aliphatic. In some embodiments, R is unsubstituted -C1-6 aliphatic. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CF3. [00280] In some embodiments, R is –CH3, –C(CH3)3, –CHF2, cyclopropyl, –CF2CF3, or
Figure imgf000095_0003
. [00281] In some embodiments, R is selected from those depicted in Table B, below. [00282] A “warhead group,” as used herein, is capable of covalently binding to an amino acid residue (such as cysteine, lysine, histidine, or other residues capable of being covalently modified) present in the binding pocket of a target protein, for example, TEAD, thereby irreversibly inhibiting the protein. In some embodiments, a warhead group is as defined and described in embodiments in PCT/US2020/35111, the content of which is herein incorporated by reference in its entirety. [00283] In some embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula B-2:
Figure imgf000095_0002
, thereby forming a compound of formula I-B-2 or II-B-2:
Figure imgf000095_0001
I-B-2 II-B-2 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, DIM, R1, R2, R3, R4, R6, R7, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34. [00284] In some embodiments, the present invention provides a compound of formula I-B-2 or II-B-2, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein: (a): L1 is -NH-; R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is a warhead group; R3 is -H; R4 is -H, -S(O)2N(R)2; -S(O)N(R)2, or -C(O)N(R)2, each R independently is selected from -H and optionally substituted -C1-6 aliphatic; R6 is -H or -C1-6 aliphatic; and R7 is –H; or (b): L1 is -NH-; R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is an optionally substituted 5-membered aromatic ring having 1, 2, 3, or 4 nitrogen; R3 is -H; R4 is a warhead group; R6 is -H or -C1-6 aliphatic; and R7 is -H; or (c): L1 is -O-; R1 is -H, or -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is –H; R3 is a warhead group; R4 is –H; R6 is -H or -C1-6 aliphatic; R7 is -H; or (d): L1 is -O-; R1 is -H, or -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is –H; R3 is a warhead group; R4 is –H; R6 is –H; R7 is -H or halogen; or (e): L1 is -O-; R1 is -H, or -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is –H; R3 is a warhead group; R4 is –H; R6 is -H or -C1-6 aliphatic; and R7 is -H or halogen; or (f): L1 is -NH-; R1 is -H, or -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is –H; R3 is a warhead group; R4 is –H; R6 is -H or -C1-6 aliphatic; R7 is -H or halogen; or (g): L1 is -NH-; R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; each of R2 and R4 independently is a warhead group; R3 is –H; R6 is -H or -C1-6 aliphatic; and R7 is -H or halogen. [00285] In some embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula B-3:
Figure imgf000097_0001
, thereby forming a compound of formula I-B-3 or II-B-3:
Figure imgf000098_0001
I-B-3 II-B-3 or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, DIM, R1, R2, R3, R4, R6, R7, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34. [00286] In some embodiments, the present invention provides a compound of formula I-B-3 or II-B-3, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein: L1 is -NH-; R1 is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; R2 is a warhead group; R3 is –H; R4 is -S(O)2N(R)2, -S(O)N(R)2, or -C(O)N(R)2, each R independently is selected from -H and optionally substituted -C1-6 aliphatic; R6 is -H or -C1-6 aliphatic; and R7 is -H or halogen. [00287] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: i. Formula (B-4):
Figure imgf000098_0002
B-4 wherein each of X is independently C or N; and each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ii. Formula (B-5) or (B-6):
Figure imgf000099_0001
B-5 B-6 wherein each of R1, R7, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; iii. Formula (B-7):
Figure imgf000099_0002
B-7 wherein each of X is independently C or N; and each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; iv. Formula (B-8) or (B-9):
Figure imgf000099_0003
B-8 B-9 wherein each of R1, R7, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; v. Formula (B-10):
Figure imgf000099_0004
B-10 wherein each of X is independently C or N; and each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; vi. Formula (B-11) or (B-12):
Figure imgf000099_0005
, B-11 B-12 wherein each of R1, R7, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; vii. Formula (B-13):
Figure imgf000100_0001
B-13 wherein each of X is independently C or N; and each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; viii. Formula (B-14) or (B-15):
Figure imgf000100_0002
B-14 B-15 wherein each of R1, R7, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ix. Formula (B-16):
Figure imgf000100_0003
B-16 wherein each of X is independently C or N; and each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; or x. Formula (B-17) or (B-18):
Figure imgf000100_0004
B-17 B-18 wherein each of R1, R7, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34. [00288] In some embodiments, TBM is a moiety selected from B-4 to B-18, wherein L1 is – CH2-, -O-, -CH(CH3)-, -NH-, -C(O)-, or -NH-CH2-; R1 is –H or -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen; Rw is a warhead group; and R7 is –H or -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen. [00289] In some embodiments, the present invention provides a compound of Formula I-B or II-B, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen, or a 10-membered bicyclic heteroaromatic ring having 1-2 nitrogen; Ring B is phenyl or a 6-membered monocyclic heteroaromatic ring having 1 or 2 nitrogen; and each of Rw and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34. [00290] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: i. Formula (B-19):
Figure imgf000101_0001
B-19 wherein each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ii. Formula (B-20) or (B-21):
Figure imgf000101_0002
B-20 B-21 wherein each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; iii. Formula (B-22):
Figure imgf000101_0003
B-22 wherein each of Ring B, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; optionally, L1 is not –NH-C(O)- or -O-CH2-; iv. Formula (B-23):
Figure imgf000102_0001
wherein each of Ring B and Rw is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; v. Formula (B-24):
Figure imgf000102_0002
wherein each of Ring A, Ring B, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34, with the proviso that Ring B is not
Figure imgf000102_0003
optionally, Ring B is an optionally substituted 6-, 7-, 8-, 9-, or 10-membered bicyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; further optionally, Ring B is an optionally substituted 6-membered bicyclic heterocyclic ring having 1 nitrogen; vi. Formula (B-25):
Figure imgf000102_0004
wherein each of Rw and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; vii. Formula (B-26) or (B-27):
Figure imgf000102_0005
wherein each of Rw and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; viii. Formula (B-28):
Figure imgf000103_0001
B-28 wherein each of Ring A and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ix. Formula (B-29) or (B-30):
Figure imgf000103_0002
B-29 B-30 wherein each of Ring A and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; x. Formula (B-31):
Figure imgf000103_0003
B-31 wherein each of Ring B and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; optionally, L1 is –CH2–; xi. Formula (B-32):
Figure imgf000103_0004
B-32 wherein L1 is as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; or xii. Formula (B-33) or (B-34):
Figure imgf000103_0005
B-33 B-34 wherein L1 is as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34. [00291] In some embodiments, TBM is a moiety set forth in Table B, or a pharmaceutically acceptable salt thereof. [00292] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table B. Table B. Exemplified TEAD Binding Moiety (TBM)
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0006
3. TEAD Binding Moiety (TBM) of Formulas C, and C-1 to C-85 [00293] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula C:
Figure imgf000129_0001
thereby forming a compound of formula I-C or II-C:
Figure imgf000129_0002
I-C II-C or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from
Figure imgf000129_0003
Figure imgf000129_0004
each of which is optionally substituted; Ring B is selected from
Figure imgf000129_0005
each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000130_0001
; each Y is independently N or CR5; R3 is H, -C(O)R, or optionally substituted -C1-6 aliphatic; each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00294] As defined generally above, L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-. [00295] In some embodiments, L1 is a covalent bond. [00296] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-. [00297] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- . [00298] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-. [00299] In some embodiments, L1 is -NH-. In some embodiments, L1 is -NH-CH2-. In some embodiments, L1 is -NH-CH2-CH2-. In some embodiments, L1 is –CH2-. In some embodiments, L1 is
Figure imgf000131_0003
. In some embodiments, L1 is
Figure imgf000131_0002
. In some embodiments, L1 is
Figure imgf000131_0001
. In some embodiments, L1 is
Figure imgf000131_0004
. In some embodiments, L1 is -CH=CH-. In some embodiments, L1 is
Figure imgf000131_0005
. In some embodiments, L1 is
Figure imgf000131_0006
. In some embodiments, L1 is -NH-C(O)-. [00300] In some embodiments, L1 is selected from those depicted in Table C, below. [00301] As defined generally above, Ring A is selected from
Figure imgf000131_0015
Figure imgf000131_0016
Figure imgf000131_0007
, each of which is optionally substituted. [00302] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0008
. [00303] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0009
. [00304] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0010
. [00305] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0011
. [00306] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0012
. [00307] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0013
. [00308] In some embodiments, Ring A is optionally substituted
Figure imgf000131_0014
. [00309] In some embodiments, Ring A is optionally substituted
Figure imgf000132_0001
. [00310] In some embodiments, Ring A is optionally substituted
Figure imgf000132_0002
. [00311] In some embodiments, Ring A is optionally substituted
Figure imgf000132_0003
.
Figure imgf000132_0004
[00312] In some embodiments, Ring A is optionally substituted . [00313] In some embodiments, Ring A is optionally substituted
Figure imgf000132_0005
. [00314] In some embodiments, Ring A is selected from
Figure imgf000132_0006
Figure imgf000132_0007
Figure imgf000132_0008
wherein each R1 is independently R, halogen, -CN, -C(O)R, -C(O)NR2, -OR, -SR, -S(O)2NR2, or -S(O)2R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein. [00315] In some embodiments, R1 is R. In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments, R1 is -C(O)R. In some embodiments, R1 is - C(O)NR2. In some embodiments, R1 is -OR. In some embodiments, R1 is -SR. In some embodiments, R1 is -S(O)2NR2. In some embodiments, R1 is -S(O)2R. [00316] In some embodiments, each R1 is independently H, halogen, -C1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen. [00317] In some embodiments, each R1 is independently H, -CF3, -C(O)NH2, -CH3, -CH2CH3, -OCH3, -CHF2, -OCF3, -OCHF2, -SCF3, -Cl, -S(O)2-NH2, -OCH2CH3, -F, -C(O)NHCH3, -CN, - S(O)2-CH3, -OCH(CH3)2, -CH(CH3)2, -C(CH3)3, -CH2OH,
Figure imgf000133_0005
, , [00318] In some embodiments, each R1 is independently selected from those depicted in Table C, below. [00319] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [00320] In some embodiments, Ring A is selected from
Figure imgf000133_0001
, , and
Figure imgf000133_0002
, wherein each of R1 is as defined above and described in embodiments herein, both singly and in combination. [00321] In some embodiments, Ring A is selected from
Figure imgf000133_0003
, , and
Figure imgf000133_0004
, wherein each R1 is as defined above and as described in embodiments herein, both singly and in combination. [00322] In some embodiments, Ring A is
Figure imgf000134_0001
Figure imgf000134_0002
, , , ,
Figure imgf000135_0001
[00323] In some embodiments, Ring A is selected from those depicted in Table C, below. [00324] As defined generally above, Ring B is selected from
Figure imgf000135_0004
Figure imgf000135_0002
, wherein each of R2, R3, and R4 is as defined herein and as described in embodiments herein, both singly and in combination. [00325] In some embodiments, Ring B is where 2 4
Figure imgf000135_0003
in each of R and R is as defined above and as described in embodiments herein, both singly and in combination. [00326] In some embodiments, Ring B is
Figure imgf000136_0001
, wherein each of R3 and R4 is as defined above and as described in embodiments herein, both singly and in combination. [00327] In some embodiments, Ring B is 4
Figure imgf000136_0002
, wherein R is as defined above and as described in embodiments herein. [00328] In some embodiments, Ring B is
Figure imgf000136_0003
, wherein each of R2 and R4 is as defined above and as described in embodiments herein, both singly and in combination. [00329] In some embodiments, Ring B is 5
Figure imgf000136_0004
, wherein each of R, Y, m, and R is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000136_0005
, wherein each of Y, R, and R5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein each 5
Figure imgf000137_0004
of R and R is as defined above and as described in embodiments herein, both singly and in combination. [00330] In some embodiments, Ring B is
Figure imgf000137_0003
, wherein each of m, R, and R5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is 5
Figure imgf000137_0002
, wherein each of R and R is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000137_0001
, wherein each of R and R5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000138_0001
, wherein each of R and R5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000138_0002
, wherein each of R and R5 is as defined above and as described in embodiments herein, both singly and in combination. [00331] In some embodiments, Ring B is , where 5
Figure imgf000138_0003
in each of m, R, and R is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000138_0004
, wherein each R is independently as defined above and described in embodiments herein. In some embodiments, Ring B is
Figure imgf000139_0004
, wherein R is as defined above and as described in embodiments herein. [00332] In some embodiments, Ring B is
Figure imgf000139_0003
, wherein each of m, R, and R5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000139_0002
, wherein each of R and R5 is as defined above and as described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000139_0001
, wherein each of R and R5 is as defined above and as described in embodiments herein, both singly and in combination. [00333] In some embodiments, Ring B is selected from those depicted in Table C, below. [00334] As defined generally above, each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000140_0001
wherein each 5
Figure imgf000140_0002
of Y, m, and R is as defined herein and as described in embodiments herein, both singly and in combination.. [00335] In some embodiments, R2 is -OR. In some embodiments, R2 is -C(O)NR2. In some embodiments, R2 is optionally substituted -C1-6 aliphatic. In some embodiments, R2 is
Figure imgf000140_0003
. In some embodiments, R2 is
Figure imgf000140_0004
. In some embodiments, R2 is
Figure imgf000140_0006
. In some embodiments, R2 is In some em 2
Figure imgf000140_0005
bodiments, R is
Figure imgf000140_0007
. In some embodiments, R2 is 2
Figure imgf000140_0009
. In some embodiments, R is
Figure imgf000140_0008
[00336] In some embodiments, R2 is
Figure imgf000141_0003
. In some embodiments, R2 is
Figure imgf000141_0004
. In some embodiments, R2 is
Figure imgf000141_0014
. In some embodiments, R2 is
Figure imgf000141_0005
. In some embodiments, R2 is
Figure imgf000141_0015
. In some embodiments, R2 is 2
Figure imgf000141_0013
. In some embodiments, R is
Figure imgf000141_0006
. In some embodiments, R2 is
Figure imgf000141_0012
. In some embodiments, R2 is
Figure imgf000141_0007
. In some embodiments, R2 is
Figure imgf000141_0011
. In some embodiments, R2 is
Figure imgf000141_0008
In some embodiments, R2 is
Figure imgf000141_0010
. In some embodiments, R2 is . In some embodiments, R2
Figure imgf000141_0009
is
Figure imgf000141_0001
. In some embodiments, R2 is
Figure imgf000141_0002
[00337] In some embodiments, R2 is selected from:
Figure imgf000142_0001
Figure imgf000142_0002
Figure imgf000143_0003
, , , , , [00338] In some embodiments, R2 is selected from
Figure imgf000143_0002
Figure imgf000143_0001
, and -OCH3. [00339] In some embodiments, R2 is selected from those depicted in Table C, below. [00340] As defined generally above, each Y is independently N or CR5. [00341] In some embodiments, Y is N. In some embodiments, Y is CR5. In some embodiments, Y is CH. [00342] In some embodiments, both Y are N. In some embodiments, both Y are CR5. In some embodiments, one Y is N, and the other Y is CR5. In some embodiments, both Y are CH. In some embodiments, one Y is N, and the other Y is CH. [00343] In some embodiments, Y is selected from those depicted in Table C, below. [00344] As defined generally above, R3 is -H, -C(O)R, or optionally substituted -C1-6 aliphatic, wherein R is as defined herein and described in embodiments herein. [00345] In some embodiments, R3 is –H. [00346] In some embodiments, R3 is -C(O)R. [00347] In some embodiments, R3 is optionally substituted -C1-6 aliphatic. [00348] In some embodiments, R3 is selected from H, -CH3, -CH2CH3, -C(O)CH3, and
Figure imgf000144_0001
. [00349] In some embodiments, R3 is selected from those depicted in Table C, below. [00350] As defined generally above, each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein. [00351] In some embodiments, R4 is -S(O)2NR2. [00352] In some embodiments, R4 is -S(O)2R. [00353] In some embodiments, R4 is -C(O)NR2. [00354] In some embodiments, R4 is -C(O)R. [00355] In some embodiments, R4 is -optionally substituted -C1-6 aliphatic. [00356] In some embodiments, R4 is selected from
Figure imgf000144_0002
, , , ,
Figure imgf000144_0003
[00357] In some embodiments, R4 is selected from:
Figure imgf000145_0001
, , and
Figure imgf000145_0002
. [00358] In some embodiments, R4 is selected from those depicted in Table C, below. [00359] As defined generally above, each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is independently as defined herein and as described in embodiments herein. [00360] In some embodiments, R5 is R. [00361] In some embodiments, R5 is -CN. [00362] In some embodiments, R5 is -C(O)R. [00363] In some embodiments, R5 is -C(O)NR2. [00364] In some embodiments, R5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00365] In some embodiments, each R5 is independently selected from: H, -CH3, -CD3,
Figure imgf000145_0003
Figure imgf000145_0004
-CH2CH3, -C(O)CH3, -CH2C(O)NHCH3,
Figure imgf000145_0005
[00366] In some embodiments, each R5 is independently selected from: -CH3, -CH2CH2OCH3, -CH2CF3, -CH2CH2Cl,
Figure imgf000146_0001
[00367] In some embodiments, R5 is selected from those depicted in Table C, below. [00368] As defined generally above, each m is independently 0, 1, or 2. [00369] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00370] In some embodiments, m is selected from those depicted in Table C, below. [00371] As defined generally above, each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00372] In some embodiments, R is H. [00373] In some embodiments, R is optionally substituted -C1-6 aliphatic. In some embodiments, R is unsubstituted -C1-6 aliphatic. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CH3. In some embodiments, R is –CH2CH3. In some embodiments, R is –CF3. In some embodiments, R is –CHF2. [00374] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO2, or -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F. [00375] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO2, or -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
[00376] In some embodiments, R is selected from
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0003
-CH3, -CD3, -CH2CH3, -CH2C(O)NHCH3,
Figure imgf000148_0004
[00377] In some embodiments, R is selected from those depicted in Table C, below. [00378] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
,
Figure imgf000149_0001
,
Figure imgf000150_0001
,
Figure imgf000151_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, Y, L1, m, n, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas C, and C-1 to C-85. [00379] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000151_0002
Figure imgf000152_0001
,
Figure imgf000153_0001
Figure imgf000154_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, Y, L1, n, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas C, and C-1 to C-85. [00380] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000155_0001
,
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, Y, L1, n, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas C, and C-1 to C-85. [00381] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000158_0002
Figure imgf000159_0001
, or a pharmaceutically acceptable salt thereof, wherein each of R, R1, L1, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas C, and C-1 to C-85. [00382] In some embodiments, TBM is a moiety set forth in Table C, or a pharmaceutically acceptable salt thereof. [00383] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table C. Table C. Exemplified TEAD Binding Moiety (TBM)
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0002
4. TEAD Binding Moiety (TBM) of Formulas D, and D-1 to D-85 [00384] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula D:
Figure imgf000172_0001
, thereby forming a compound of formula I-D or II-D:
Figure imgf000173_0001
or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from
Figure imgf000173_0003
, , , , , ,
Figure imgf000173_0004
each of which is optionally substituted;; Ring B is
Figure imgf000173_0005
each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000173_0002
; each Y is independently N or CR5; each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00385] As defined generally above, L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-. [00386] In some embodiments, L1 is a covalent bond. [00387] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-. [00388] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- . [00389] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-. [00390] In some embodiments, L1 is -NH-. In some embodiments, L1 is -NH-CH2-. In some embodiments, L1 is -NH-CH2-CH2-. In some embodiments, L1 is –CH2-. In some embodiments, L1 is 1 1
Figure imgf000174_0001
Figure imgf000174_0005
. In some embodiments, L is
Figure imgf000174_0006
. In some embodiments, L is . In some embodiments, L1 is
Figure imgf000174_0002
. In some embodiments, L1 is -CH=CH-. In some embodiments, L1 is
Figure imgf000174_0003
. In some embodiments, L1 is
Figure imgf000174_0004
. In some embodiments, L1 is -NH-C(O)-. [00391] In some embodiments, L1 is selected from those depicted in Table D, below. [00392] As defined generally above, Ring A is selected from
Figure imgf000175_0013
Figure imgf000175_0012
Figure imgf000175_0001
, each of which is optionally substituted. [00393] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0002
. [00394] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0003
. [00395] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0004
. [00396] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0005
. [00397] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0006
. [00398] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0007
. [00399] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0008
. [00400] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0009
. [00401] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0010
. [00402] In some embodiments, Ring A is optionally substituted
Figure imgf000175_0011
. [00403] In some embodiments, Ring A is optionally substituted
Figure imgf000176_0001
. [00404] In some embodiments, Ring A is optionally substituted
Figure imgf000176_0002
. [00405] In some embodiments, Ring A is selected from
Figure imgf000176_0003
Figure imgf000176_0004
Figure imgf000176_0005
, , wherein each R1 is independently R, halogen, -CN, -C(O)R, -C(O)NR2, -OR, -SR, -S(O)2NR2, or -S(O)2R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein. [00406] In some embodiments, R1 is R. In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments, R1 is -C(O)R. In some embodiments, R1 is - C(O)NR2. In some embodiments, R1 is -OR. In some embodiments, R1 is -SR. In some embodiments, R1 is -S(O)2NR2. In some embodiments, R1 is -S(O)2R. [00407] In some embodiments, each R1 is independently H, halogen, -C1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen. [00408] In some embodiments, each R1 is independently H, -CF3, -C(O)NH2, -CH3, -CH2CH3, -OCH3, -CHF2, -OCF3, -OCHF2, -SCF3, -Cl, -S(O)2-NH2, -OCH2CH3, -F, -C(O)NHCH3, -CN, - S(O)2-CH3, -OCH(CH3)2, -CH(CH3)2, -C(CH3)3, -CH2OH,
Figure imgf000177_0001
[00409] In some embodiments, each R1 is independently selected from those depicted in Table D, below. [00410] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [00411] In some embodiments, Ring A is selected from
Figure imgf000177_0002
and , wh 1
Figure imgf000177_0003
erein each of R is as defined herein and described in embodiments herein, both singly and in combination. [00412] In some embodiments, Ring A is selected from
Figure imgf000177_0004
and
Figure imgf000177_0005
wherein each R1 is as defined herein and described in embodiments herein, both singly and in combination. [00413] In some embodiments, Ring A is
Figure imgf000177_0006
Figure imgf000177_0007
Figure imgf000178_0001
Figure imgf000179_0001
[00414] In some embodiments, Ring A is selected from those depicted in Table D, below. [00415] As defined generally above, Ring B is
Figure imgf000179_0002
, wherein each of R2 and R4 is as defined herein and as described in embodiments herein, both singly and in combination. [00416] In some embodiments, Ring B is 2 4
Figure imgf000179_0003
, wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00417] In some embodiments, Ring B is , whe 2 4
Figure imgf000179_0004
rein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00418] In some embodiments, Ring B is 5
Figure imgf000179_0005
, wherein each of R, Y, m, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is , wherein 5
Figure imgf000180_0001
each of Y, R, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000180_0002
, wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. [00419] In some embodiments, Ring B is 5
Figure imgf000180_0003
, wherein each of m, R, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000180_0004
, wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B
is
Figure imgf000181_0001
, wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000181_0002
, wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000181_0003
wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. [00420] In some embodiments, Ring B is 5
Figure imgf000181_0004
, wherein each of m, R, and R is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000182_0001
, wherein each R is independently as defined herein and described in embodiments herein. In some embodiments, Ring B is
Figure imgf000182_0002
, wherein R is as defined above and described in embodiments herein. [00421] In some embodiments, Ring B is
Figure imgf000182_0003
, wherein each of m, R, and R5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000182_0004
, wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000183_0001
, wherein each of R and R5 is as defined herein and described in embodiments herein, both singly and in combination. [00422] In some embodiments, Ring B is
Figure imgf000183_0002
Figure imgf000183_0003
, wherein each of R, Y, m, and R5 is as defined
Figure imgf000183_0004
herein and described in embodiments herein, both singly and in combination. [00423] In some embodiments, Ring B is selected from those depicted in Table D, below. [00424] As defined generally above, each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000184_0005
, and , wherein 5
Figure imgf000184_0004
Figure imgf000184_0006
each of Y, m, and R is as defined herein and described in embodiments herein, both singly and in combination. [00425] In some embodiments, R2 is -OR. In some embodiments, R2 is -C(O)NR2. In some embodiments, R2 is optionally substituted -C1-6 aliphatic. In some embodiments, R2 is
Figure imgf000184_0007
. In some embodiments, R2 is
Figure imgf000184_0003
. In some embodiments, R2 is
Figure imgf000184_0008
. In some embodiments, R2 is
Figure imgf000184_0002
. In some embodiments, R2 is
Figure imgf000184_0009
. In some embodiments, R2 is 2
Figure imgf000184_0001
. In some embodiments, R is
Figure imgf000184_0010
[00426] In some embodiments, R2 is . In some embodim 2
Figure imgf000185_0015
ents, R is
Figure imgf000185_0008
In some embodiments, R2 is . In some embo 2 2
Figure imgf000185_0014
diments, R is
Figure imgf000185_0009
In some embodiments, R is . In some em 2 2
Figure imgf000185_0013
bodiments, R is
Figure imgf000185_0010
. In some embodiments, R is
Figure imgf000185_0007
In some embodiments, R2 is
Figure imgf000185_0011
. In some embodiments, R2 is
Figure imgf000185_0006
. In some embodiments, R2 is
Figure imgf000185_0012
. In some embodiments, R2 is
Figure imgf000185_0005
In some embodiments, R2 is
Figure imgf000185_0003
In some embodiments, R2 is
Figure imgf000185_0004
In some embodiments, R2 is 2
Figure imgf000185_0002
In some embodiments, R is
Figure imgf000185_0001
[00427] In some embodiments, R2 is selected from:
Figure imgf000186_0001
Figure imgf000186_0002
Figure imgf000187_0001
[00428] In some embodiments, R2 is selected from
Figure imgf000187_0002
Figure imgf000187_0003
, and -OCH3. [00429] In some embodiments, R2 is selected from those depicted in Table D, below. [00430] As defined generally above, each Y is independently N or CR5, wherein R5 is as defined herein and as described in embodiments herein. [00431] In some embodiments, Y is N. In some embodiments, Y is CR5. In some embodiments, Y is CH. [00432] In some embodiments, both Y are N. In some embodiments, both Y are CR5. In some embodiments, both Y are CH. In some embodiments, one Y is N, and the other Y is CR5. In some embodiments, one Y is N, and the other Y is CH. [00433] In some embodiments, Y is selected from those depicted in Table D, below. [00434] As defined generally above, each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein. [00435] In some embodiments, R4 is -S(O)2NR2. [00436] In some embodiments, R4 is -S(O)2R. [00437] In some embodiments, R4 is -C(O)NR2. [00438] In some embodiments, R4 is -C(O)R. [00439] In some embodiments, R4 is -optionally substituted -C1-6 aliphatic. [00440] In some embodiments, R4 is selected from
Figure imgf000188_0002
Figure imgf000188_0003
[00441] In some embodiments, R4 is selected from:
Figure imgf000188_0004
and
Figure imgf000188_0001
[00442] In some embodiments, R4 is selected from those depicted in Table D, below. [00443] As defined generally above, each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is as defined herein and as described in embodiments herein. [00444] In some embodiments, R5 is R. [00445] In some embodiments, R5 is -CN. [00446] In some embodiments, R5 is -C(O)R. [00447] In some embodiments, R5 is -C(O)NR2. [00448] In some embodiments, R5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00449] In some embodiments, each R5 is independently selected from: H, -CH3, -CD3,
Figure imgf000189_0001
Figure imgf000189_0003
, -CH2CH3, -C(O)CH3, -CH2C(O)NHCH3,
Figure imgf000189_0002
[00450] In some embodiments, each R5 is independently selected from: -CH3, -CH2CH2OCH3, -CH2CF3, -CH2CH2Cl,
Figure imgf000189_0004
[00451] In some embodiments, R5 is selected from those depicted in Table D, below. [00452] As defined generally above, each m is independently 0, 1, or 2. [00453] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00454] In some embodiments, m is selected from those depicted in Table D, below. [00455] As defined generally above, each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00456] In some embodiments, R is H. [00457] In some embodiments, R is optionally substituted -C1-6 aliphatic. In some embodiments, R is unsubstituted -C1-6 aliphatic. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CH3. In some embodiments, R is –CH2CH3. In some embodiments, R is –CF3. In some embodiments, R is –CHF2. [00458] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO2, or -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F. [00459] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO2, or -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F. [00460] In some embodiments, R is selected from
Figure imgf000191_0001
Figure imgf000191_0002
-CH3, -CD3, -CH2CH3, -CH2C(O)NHCH3,
Figure imgf000191_0003
, ,
Figure imgf000192_0001
[00461] In some embodiments, R is selected from those depicted in Table D, below. [00462] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: , ,
Figure imgf000192_0002
Figure imgf000193_0001
Figure imgf000194_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, Y, L1, m, n, and R5 is independently as defined above and described in embodiments in the section of TBM of Formulas D, and D-1 to D-85. [00463] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following
Figure imgf000195_0001
,
Figure imgf000196_0001
,
Figure imgf000197_0001
,
Figure imgf000198_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, Y, L1, n, and R5 is independently as defined above and described in embodiments in the section of TBM of Formulas D, and D-1 to D-85. [00464] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000198_0002
Figure imgf000199_0001
,
Figure imgf000200_0001
, ,
Figure imgf000201_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, Y, L1, n, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas D, and D-1 to D-85. [00465] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
Figure imgf000202_0001
Figure imgf000203_0001
, or a pharmaceutically acceptable salt thereof, wherein each of R, R1, L1, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas D, and D-1 to D-85. [00466] In some embodiments, TBM is a moiety set forth in Table D, or a pharmaceutically acceptable salt thereof. [00467] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table D. Table D: Exemplified TEAD Binding Moiety (TBM)
Figure imgf000203_0002
Figure imgf000204_0004
5. TEAD Binding Moiety (TBM) of Formulas E, and E-1 to E-204 [00468] In certain embodiments, the present invention provides a compound of formula I or formula II, wherein TBM is a moiety of Formula E:
Figure imgf000204_0002
thereby forming a compound of formula I-E or II-E:
Figure imgf000204_0001
or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from
Figure imgf000204_0003
Figure imgf000205_0003
, , , , , , each of which is optionally substituted; Ring B is selected from
Figure imgf000205_0004
Figure imgf000205_0005
each Rw is independently selected from
Figure imgf000205_0001
; each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000205_0002
; each Y is independently N or CR5; each R3 is independently H or optionally substituted -C1-6 aliphatic; each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; p is 0, 1, or 2, and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00469] As defined generally above, L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-. [00470] In some embodiments, L1 is a covalent bond. [00471] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-. [00472] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- . [00473] In some embodiments, L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-. [00474] In some embodiments, L1 is -NH-. In some embodiments, L1 is -NH-CH2-. In some embodiments, L1 is -NH-CH2-CH2-. In some embodiments, L1 is –CH2-. In some embodiments, L1 is
Figure imgf000206_0001
. In some embodiments, L1 is
Figure imgf000206_0002
. In some embodiments, L1 is
Figure imgf000206_0003
. In some embodiments, L1 is
Figure imgf000206_0004
. In some embodiments, L1 is -CH=CH-. In some embodiments, L1 is
Figure imgf000206_0005
. In some embodiments, L1 is
Figure imgf000206_0006
. In some embodiments, L1 is -NH-C(O)-. [00475] In some embodiments, L1 is selected from those depicted in Table E, below. [00476] As defined generally above, Ring A is selected from
Figure imgf000206_0007
, , ,
Figure imgf000206_0008
Figure imgf000206_0009
each of which is optionally substituted. [00477] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0001
. [00478] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0002
. [00479] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0003
. [00480] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0004
. [00481] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0005
. [00482] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0006
. [00483] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0007
. [00484] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0008
. [00485] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0009
. [00486] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0010
.
Figure imgf000207_0011
[00487] In some embodiments, Ring A is optionally substituted . [00488] In some embodiments, Ring A is optionally substituted
Figure imgf000207_0012
. [00489] In some embodiments, Ring A is selected from
Figure imgf000208_0001
, ,
Figure imgf000208_0002
Figure imgf000208_0003
wherein each R1 is independently R, halogen, -CN, -C(O)R, -C(O)NR2, -OR, -SR, -S(O)2NR2, or -S(O)2R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein. [00490] In some embodiments, R1 is R. In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments, R1 is -C(O)R. In some embodiments, R1 is - C(O)NR2. In some embodiments, R1 is -OR. In some embodiments, R1 is -SR. In some embodiments, R1 is -S(O)2NR2. In some embodiments, R1 is -S(O)2R. [00491] In some embodiments, each R1 is independently H, halogen, -C1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen. [00492] In some embodiments, each R1 is independently H, -CF3, -C(O)NH2, -CH3, -CH2CH3, -OCH3, -CHF2, -OCF3, -OCHF2, -SCF3, -Cl, -S(O)2-NH2, -OCH2CH3, -F, -C(O)NHCH3, -CN, - S(O)2-CH3, -OCH(CH3)2, -CH(CH3)2, -C(CH3)3, -CH2OH,
Figure imgf000208_0004
[00493] In some embodiments, each R1 is independently selected from those depicted in Table E, below. [00494] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. [00495] In some embodiments, Ring A is selected from
Figure imgf000209_0001
, , and
Figure imgf000209_0002
, wherein each of R1 is as defined above and described in embodiments herein, both singly and in combination. [00496] In some embodiments, Ring A is selected from
Figure imgf000209_0003
, , and
Figure imgf000209_0004
, wherein each R1 is as defined above and described in embodiments herein, both singly and in combination. [00497] In some embodiments, Ring A is
Figure imgf000209_0005
Figure imgf000209_0006
Figure imgf000210_0001
Figure imgf000211_0001
, , , [00498] In some embodiments, Ring A is selected from
Figure imgf000211_0002
Figure imgf000211_0003
[00499] In some embodiments, Ring A is selected from those depicted in Table E, below. [00500] As defined generally above, Ring B is selected from
Figure imgf000211_0004
Figure imgf000211_0005
wherein each of R2, R3, Rw, p, and R4 is as defined herein and described in embodiments herein, both singly and in combination. [00501] In some embodiments, Ring B is
Figure imgf000211_0006
wherein each of R2 and Rw is as defined herein and described in embodiments herein, both singly and in combination. [00502] In some embodiments, Ring B is 4 w
Figure imgf000211_0007
wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00503] In some embodiments, Ring B is
Figure imgf000212_0004
wherein each of R2 and Rw is as defined herein and described in embodiments herein, both singly and in combination. [00504] In some embodiments, Ring B is wherein e 2 w
Figure imgf000212_0005
ach of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00505] In some embodiments, Ring B is 4 w
Figure imgf000212_0006
wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00506] In some embodiments, Ring B is 2 w
Figure imgf000212_0007
wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [00507] In some embodiments, Ring B is 3
Figure imgf000212_0008
wherein each of R and p is as defined herein and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is
Figure imgf000212_0001
o . [00508] In some embodiments, Ring B is w
Figure imgf000212_0002
wherein R is as defined herein and described in embodiments herein. In some embodiments, Ring B is wherein Rw
Figure imgf000212_0003
is as defined herein and described in embodiments herein. [00509] In some embodiments, Ring B is selected from those depicted in Table E, below. [00510] As defined generally above, Rw is selected from
Figure imgf000213_0008
, , a d . [00511] In some embodiments, Rw is In some embodiments, Rw is
Figure imgf000213_0007
. In
Figure imgf000213_0009
some embodiments, Rw is w
Figure imgf000213_0010
In some embodiments, R is
Figure imgf000213_0006
In some embodiments, Rw is w
Figure imgf000213_0004
In some embodiments, R is
Figure imgf000213_0005
In some embodiments, Rw is
Figure imgf000213_0003
[00512] In some embodiments, Rw is selected from those depicted in Table E, below. [00513] As defined generally above, each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000213_0002
5
Figure imgf000213_0011
wherein each of Y, m, and R is as defined herein and described in embodiments herein, both singly and in combination.. [00514] In some embodiments, R2 is -OR. In some embodiments, R2 is -C(O)NR2. In some embodiments, R2 is optionally substituted -C1-6 aliphatic. In some embodiments, R2 is
Figure imgf000213_0001
. In some embodiments, R2 is
Figure imgf000214_0001
. In some embodiments, R2 is
Figure imgf000214_0002
In some embodiments, R2 is In som 2
Figure imgf000214_0015
e embodiments, R is
Figure imgf000214_0003
In some embodiments, R2 is 2
Figure imgf000214_0014
In some embodiments, R is
Figure imgf000214_0004
[00515] In some embodiments, R2 is 2
Figure imgf000214_0013
In some embodiments, R is
Figure imgf000214_0005
. In some embodiments, R2 is
Figure imgf000214_0012
. In some embodiments, R2 is 2
Figure imgf000214_0006
In some embodiments, R is
Figure imgf000214_0017
. In some embodiments, R2 is
Figure imgf000214_0016
In some embodiments, R2 is
Figure imgf000214_0007
. In some embodiments, R2 is
Figure imgf000214_0011
In some embodiments, R2 is
Figure imgf000214_0008
In some embodiments, R2 is In s 2
Figure imgf000214_0010
ome embodiments, R is
Figure imgf000214_0009
In some embodiments, R2 is In some embodime 2 2
Figure imgf000215_0001
nts, R is
Figure imgf000215_0002
In some embodiments, R is In 2
Figure imgf000215_0005
some embodiments, R is
Figure imgf000215_0006
[00516] In some embodiments, R2 is selected from:
Figure imgf000215_0004
Figure imgf000215_0003
Figure imgf000216_0001
[00517] In some embodiments, R2 is selected from
Figure imgf000216_0002
and -OCH3
Figure imgf000216_0003
. [00518] In some embodiments, R2 is selected from those depicted in Table E, below. [00519] As defined generally above, each Y is independently N or CR5. [00520] In some embodiments, Y is N. In some embodiments, Y is CR5. In some embodiments, Y is CH. [00521] In some embodiments, both Y are N. In some embodiments, both Y are CR5. In some embodiments, one Y is N, and the other Y is CR5. In some embodiments, both Y are CH. In some embodiments, one Y is N, and the other Y is CH. [00522] In some embodiments, Y is selected from those depicted in Table E, below. [00523] As defined generally above, each R3 is independently H, -C(O)R, or optionally substituted -C1-6 aliphatic, wherein R is as defined herein and described in embodiments herein. [00524] In some embodiments, R3 is H. [00525] In some embodiments, R3 is -C(O)R. [00526] In some embodiments, R3 is optionally substituted -C1-6 aliphatic. [00527] In some embodiments, R3 is selected from H, -CH3, -CH2CH3, -C(O)CH3, and
Figure imgf000217_0001
. [00528] In some embodiments, R3 is selected from those depicted in Table E, below. [00529] As defined generally above, each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein. [00530] In some embodiments, R4 is -S(O)2NR2. [00531] In some embodiments, R4 is -S(O)2R. [00532] In some embodiments, R4 is -C(O)NR2. [00533] In some embodiments, R4 is -C(O)R. [00534] In some embodiments, R4 is -optionally substituted -C1-6 aliphatic. [00535] In some embodiments, R4 is selected from
Figure imgf000217_0002
Figure imgf000217_0003
Figure imgf000218_0001
, [00536] In some embodiments, R4 is selected from:
Figure imgf000218_0002
and
Figure imgf000218_0003
[00537] In some embodiments, R4 is selected from those depicted in Table E, below. [00538] As defined generally above, each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is independently as defined herein and as described in embodiments herein. [00539] In some embodiments, R5 is R. [00540] In some embodiments, R5 is -CN. [00541] In some embodiments, R5 is -C(O)R. [00542] In some embodiments, R5 is -C(O)NR2. [00543] In some embodiments, R5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00544] In some embodiments, each R5 is independently selected from: H, -CH3, -CD3,
Figure imgf000219_0001
Figure imgf000219_0002
, -CH2CH3, -C(O)CH3, -CH2C(O)NHCH3,
Figure imgf000219_0003
[00545] In some embodiments, each R5 is independently selected from: -CH3, -CH2CH2OCH3, -CH2CF3, -CH2CH2Cl,
Figure imgf000219_0004
[00546] In some embodiments, R5 is selected from those depicted in Table E, below. [00547] As defined generally above, each m is independently 0, 1, or 2. [00548] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00549] In some embodiments, m is selected from those depicted in Table E, below. [00550] As defined generally above, p is 0, 1, or 2. [00551] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [00552] In some embodiments, p is selected from those depicted in Table E, below. [00553] As defined generally above, each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00554] In some embodiments, R is H. [00555] In some embodiments, R is optionally substituted -C1-6 aliphatic. In some embodiments, R is unsubstituted -C1-6 aliphatic. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CH3. In some embodiments, R is –CH2CH3. In some embodiments, R is –CF3. In some embodiments, R is –CHF2. [00556] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO2, or -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F. [00557] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO2, or -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F. [00558] In some embodiments, R is selected from
Figure imgf000221_0001
Figure imgf000221_0002
-CH3, -CD3, -CH2CH3, -CH2C(O)NHCH3,
Figure imgf000221_0003
, ,
Figure imgf000222_0001
[00559] In some embodiments, R is selected from those depicted in Table E, below. [00560] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000222_0002
Figure imgf000223_0001
Figure imgf000224_0002
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, Y, m, n, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204. [00561] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000224_0001
, ,
Figure imgf000225_0001
Figure imgf000226_0001
,
Figure imgf000227_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, Y, n, and R5 is independently as defined above and as described in the section of TBM of Formulas E, and E-1 to E-204. [00562] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
Figure imgf000227_0002
Figure imgf000228_0001
,
Figure imgf000229_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, n, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204. [00563] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following: ,
Figure imgf000230_0001
Figure imgf000231_0001
, or a pharmaceutically acceptable salt thereof, wherein each of R1, Rw, L1, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204. [00564] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000231_0002
Figure imgf000232_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, L1, Rw, and n is independently as defined and as described in the section of TBM of Formulas E, and E-1 to E-204. [00565] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
,
Figure imgf000233_0001
,
Figure imgf000234_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, R1, L1, Rw, and n is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204. [00566] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000234_0002
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, and n is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204. [00567] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000235_0001
Figure imgf000236_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, Y, m, n, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204. [00568] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, Y, n, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204. [00569] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000240_0001
,
Figure imgf000241_0001
,
Figure imgf000242_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, n, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E-204. [00570] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from the following:
Figure imgf000243_0001
Figure imgf000244_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, and R5 is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204. [00571] In some embodiments, TBM is a moiety set forth in Table E, or a pharmaceutically acceptable salt thereof. [00572] In some embodiments, the present invention provides a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein TBM is a moiety selected from those listed in Table E. Table E: Exemplified TEAD binding moiety (TBM)
Figure imgf000244_0002
Figure imgf000245_0001
Figure imgf000246_0001
Linker (L) [00573] As defined above and described herein, L is a bivalent moiety that connects TBM to LBM or TBM to DIM. L is attached to a modifiable carbon, oxygen, or nitrogen atom within DIM or LBM including substitution or replacement of a defined group in DIM or LBM. L is also attached to a modifiable carbon, oxygen, or nitrogen atom within TBM including substitution or replacement of a defined group in TBM. [00574] In some embodiments, L is a bivalent moiety that connects TBM to LBM. In some embodiments, L is a bivalent moiety that connects TBM to DIM. In some embodiments, L is a bivalent moiety that connects TBM to a lysine mimetic. [00575] In some embodiments, L is a bivalent moiety as described in WO 2018/237026, WO 2019/099926, WO 2019/199816, WO 2019/160915, WO 2019/060693, WO 2019/140387, or WO 2020/010177, the content of each of which is herein incorporated by reference in its entirety. [00576] In some embodiments, L is a covalent bond, or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 1-6 methylene units of L are independently and optionally replaced by –Cy-, -O-, -N(RI)-, -S-, -C(O)-, -S(O)-, -S(O)2-,
Figure imgf000247_0001
, wherein each –Cy– is independently an optionally substituted bivalent ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, and a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each RI is independently H or optionally substituted -C1-6 aliphatic, and wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. [00577] In some embodiments, each –Cy– is independently an optionally substituted 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, each –Cy– is independently an optionally substituted 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00578] In some embodiments, -Cy- is
Figure imgf000247_0002
. In some embodiments, -Cy- is
Figure imgf000248_0011
. In some embodiments, -Cy- is
Figure imgf000248_0001
. In some embodiments, -Cy- is
Figure imgf000248_0012
. In some embodiments, -Cy- is
Figure imgf000248_0003
[00579] In some embodiments, RI is H. In some embodiments, RI is optionally substituted -C1- 6 aliphatic. In some embodiments, RI is optionally substituted -C1-6 alkyl. In some embodiments, RI is optionally substituted -C1-6 alkenyl. In some embodiments, RI is unsubstituted -C1-6 aliphatic. In some embodiments, RI is unsubstituted -C1-6 alkyl. In some embodiments, RI is unsubstituted - C1-6 alkenyl. In some embodiments, RI is -CH3. In some embodiments, RI is -CH2CH3. [00580] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10. [00581] In some embodiments, L is a covalent bond. [00582] In some embodiments, L is
Figure imgf000248_0010
. In some embodiments, L is
Figure imgf000248_0006
In some embodiments, L is In some
Figure imgf000248_0004
embodiments, L is
Figure imgf000248_0007
In some embodiments, L is
Figure imgf000248_0005
. In some embodiments, L is
Figure imgf000248_0002
. In some embodiments, L is In some embodiments, L is
Figure imgf000248_0008
In some
Figure imgf000248_0009
embodiments, L is
Figure imgf000249_0001
. In some embodiments, L is
Figure imgf000249_0002
In some embodiments, L is
Figure imgf000249_0003
[00583] In some embodiments, L is selected from
Figure imgf000249_0004
, ,
Figure imgf000249_0005
[00584] In some embodiments, L is selected from
Figure imgf000249_0006
,
Figure imgf000249_0007
. [00585] In some embodiments, L is selected from
Figure imgf000250_0001
,
Figure imgf000250_0002
[00586] In some embodiments, L is selected from those depicted in Table 1, below. [00587] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000250_0003
or
Figure imgf000250_0007
and TBM is a moiety of Formulas A, or A-1 to A-50, and L is as defined above and described in embodiments herein. [00588] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000250_0004
or
Figure imgf000250_0005
, TBM is a moiety selected from the compounds set forth in Table A above, and L is as defined above and described in embodiments herein. [00589] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000250_0006
or
Figure imgf000251_0002
, , and L is as defined above and described in embodiments herein. [00590] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000251_0003
Figure imgf000251_0004
L is as defined above and described in embodiments herein. [00591] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000251_0001
,
Figure imgf000251_0005
Figure imgf000252_0003
L is as defined above and described in embodiments herein. [00592] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000252_0001
or
Figure imgf000252_0004
, , and L is as defined above and described in embodiments herein. [00593] In some embodiments, the present invention provides a compound of formula I, or a ,
Figure imgf000252_0002
, and L is as defined above and described in embodiments herein. [00594] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000253_0001
, ,
Figure imgf000253_0002
, and L is as defined above and described in embodiments herein. [00595] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000253_0003
,
Figure imgf000253_0004
Figure imgf000254_0002
Figure imgf000254_0003
and L is as defined above and described in embodiments herein. [00596] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000254_0001
or
Figure imgf000254_0004
TBM is
Figure imgf000254_0005
, L is as defined above and described in embodiments herein, and RI is H or optionally substituted -C1-6 aliphatic, for example, selected from the embodiments of RI as defined and described in the section of Linker(L). [00597] In some embodiments, the present invention provides a compound of formula I, or a , ,
Figure imgf000255_0001
, and L is as defined above and described in embodiments herein, and RI is H or optionally substituted -C1-6 aliphatic, for example, selected from the embodiments of RI as defined and described in the section of Linker(L). [00598] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000255_0002
, ,
Figure imgf000255_0003
, and L is as defined above and described in embodiments herein, and RI is H or optionally substituted -C1-6 aliphatic, for example, selected from the embodiments of RI as defined and described in the section of Linker(L). [00599] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000256_0001
or
Figure imgf000256_0007
TBM is a moiety selected from Formulas B, or B-1 to B-34, and L is as defined above and described in embodiments herein. [00600] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000256_0002
or
Figure imgf000256_0003
, TBM is a moiety selected from the compounds set forth in Table B above, and L is as defined above and described in embodiments herein. [00601] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000256_0004
or
Figure imgf000256_0006
, TBM is a moiety selected from Formulas C, or C-1 to C-85, and L is as defined above and described in embodiments herein. [00602] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000256_0005
or
Figure imgf000257_0001
, TBM is a moiety selected from the compounds set forth in Table C above, and L is as defined above and described in embodiments herein. [00603] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000257_0002
or
Figure imgf000257_0007
, TBM is a moiety selected from Formulas D, or D-1 to D-85, and L is as defined above and described in embodiments herein. [00604] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000257_0003
or
Figure imgf000257_0004
, TBM is a moiety selected from the compounds set forth in Table D above, and L is as defined above and described in embodiments herein. [00605] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000257_0005
or
Figure imgf000257_0006
, TBM is a moiety selected from Formulas E, or E-1 to E-204, and L is as defined above and described in embodiments herein. [00606] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000258_0001
or
Figure imgf000258_0002
, TBM is a moiety selected from the compounds set forth in Table E above, and L is as defined above and described in embodiments herein. [00607] In some embodiments, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein LBM is
Figure imgf000258_0003
Figure imgf000258_0004
Figure imgf000259_0001
, or
Figure imgf000259_0002
, TBM is a moiety selected from the compounds set forth in Tables A-E above, for example, TBM is
Figure imgf000259_0003
Figure imgf000259_0004
and L is as defined above and described in embodiments herein. [00608] Exemplary compounds of the invention are set forth in Table 1 below. Table 1. Exemplary Compounds
Figure imgf000259_0005
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
[00609] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4. General Methods of Providing the Present Compounds [00610] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. [00611] In the Schemes below, where a particular protecting group, leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference. [00612] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy- crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta- (trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl. [00613] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like. [00614] In the schemes below, where a final degrader is formed having a free amine DIM moiety, it is not shown but it is generally appreciated and well known by those having ordinary skill in the art that the reactivity of said free amine may be masked by employing a suitable amino protecting group that can thereafter be removed in situ or during a separate synthetic step to form the final degrader product. [00615] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 1 set forth below: Scheme 1: Synthesis of Compounds of the Invention
Figure imgf000268_0001
[00616] As depicted in Scheme 1, above, amine 1-A is coupled to acid 1-B using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond,
Figure imgf000268_0002
, represents the portion of the linker between TBM and the terminal amino group of 1-A or the portion of the linker between DIM and the terminal carboxyl group of 1-B, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU. [00617] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 2 set forth below: Scheme 2: Synthesis of Compounds of the Invention
Figure imgf000269_0001
[00618] As depicted in Scheme 2, above, amine 1-A is coupled to acid 1-B using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond,
Figure imgf000269_0004
, represents the portion of the linker between TBM and the terminal amino group of 1-A or the portion of the linker between DIM and the terminal carboxyl group of 1-B, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU. [00619] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 3 set forth below: Scheme 3: Synthesis of Compounds of the Invention
Figure imgf000269_0002
[00620] As depicted in Scheme 3, above, acid 2-A is coupled to amine 2-B using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond,
Figure imgf000269_0003
, represents the portion of the linker between TBM and the terminal carboxyl group of 2-A or the portion of the linker between DIM and the terminal amino group of 2-B, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU. [00621] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 4 set forth below: Scheme 4: Synthesis of Compounds of the Invention
Figure imgf000270_0001
[00622] As depicted in Scheme 4, above, acid 2-A is coupled to amine 2-B using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising an amide bond. The squiggly bond,
Figure imgf000270_0005
, represents the portion of the linker between TBM and the terminal carboxyl group of 2-A or the portion of the linker between DIM and the terminal amino group of 2-B, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU. [00623] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 5 set forth below: Scheme 5: Synthesis of Compounds of the Invention
Figure imgf000270_0002
[00624] As depicted in Scheme 5, above, an SNAr displacement of fluoride 3-B by amine 3-A is effected in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising a secondary amine. The squiggly bond,
Figure imgf000270_0004
, represents the portion of the linker between TBM and the terminal amino group of 3-A. [00625] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 6 set forth below: Scheme 6: Synthesis of Compounds of the Invention
Figure imgf000270_0003
[00626] As depicted in Scheme 6, above, an SNAr displacement of fluoride 4-A by amine 4-B is effected in the presence of the base DIPEA in DMF to form a compound of the invention with a linker comprising a secondary amine. The squiggly bond,
Figure imgf000271_0004
, represents the portion of the linker between DIM and the terminal amino group of 4-B. [00627] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 7 set forth below: Scheme 7: Synthesis of Compounds of the Invention
Figure imgf000271_0001
[00628] As depicted in Scheme 7, above, reductive alkylation of aldehyde 5-A by amine 5-B is effected in the presence of a mild hydride source (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to form a provided compound with a linker comprising a secondary amine. The squiggly bond,
Figure imgf000271_0005
, represents the portion of the linker between TBM and the terminal aldehyde group of 5-A or the portion of the linker between DIM and the terminal amino group of 5-B. [00629] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 8 set forth below: Scheme 8: Synthesis of Compounds of the Invention
Figure imgf000271_0002
[00630] As depicted in Scheme 8, above, reductive alkylation of aldehyde 6-B by amine 6-A is effected in the presence of a mild hydride source (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to form a provided compound with a linker comprising a secondary amine. The squiggly bond,
Figure imgf000271_0003
, represents the portion of the linker between TBM and the terminal amino group of 6-A or the portion of the linker between DIM and the terminal aldehyde group of 6-B. [00631] In some embodiments, the present invention provides a compound of formulas 1-A, 1- B, 2-A, 2-B, 3-A, 3-B, 4-A, 4-B, 5-A, 5-B, 6-A, or 6-B, or a pharmaceutically acceptable salt thereof. [00632] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See for example, “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of each of which is herein incorporated by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification. 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions [00633] According to another embodiment, the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [00634] The terms “patient” or “subject” as used herein, means an animal, preferably a mammal, and most preferably a human. [00635] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. [00636] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. [00637] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of TEAD, or a variant or mutant thereof. [00638] Compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00639] For this purpose, any bland fixed oil can be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation. [00640] Pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added. [00641] Alternatively, pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [00642] Pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00643] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used. [00644] For topical applications, provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00645] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum. [00646] Pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00647] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food. [00648] The amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form varies depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. [00649] It should also be understood that a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition also depends upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions The Hippo Signaling Network [00650] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co- activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un- phosphorylated/de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti- apoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer. [00651] Representative reference amino acid sequences of human TEAD1, human TEAD2, human TEAD3, and human TEAD4 include UniProt KB ID P28347-1 (SEQ ID NO: 1), UniProtKB ID Q15562 (SEQ ID NO: 2), UniProtKB ID Q99594 (SEQ ID NO: 3), and UniProtKB ID Q15561 (SEQ ID NO: 4), respectively. Below is the sequence alignments of TEAD coactivator binding domains, which is shown in Table 1 of “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072, the entire content of which is incorporated herein by reference.
Figure imgf000276_0001
Figure imgf000277_0001
[00652] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Lats1/2 (homologues of Warts/Wts), and their adaptor proteins Sav1 (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively. In general, MST1/2 kinase complexes with the scaffold protein Sav1, which in turn phosphorylates and activates Lats1/2 kinase. Lats1/2 is also activated by the scaffold protein Mob. The activated Lats1/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system. [00653] In some instances, Lats1/2 phosphorylates YAP at the [HXRXXS] (SEQ ID NO: 9) consensus motifs. YAP comprises five [HXRXXS] (SEQ ID NO: 9) consensus motifs, wherein X denotes any amino acid residue. In some instances, Lats1/2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Lats1/2 phosphorylates YAP at all five of the consensus motifs. In some instances, Lats1/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation. [00654] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK1δ/ε in the degradation motif, which then signals for interaction with the β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP. [00655] In some instances, Lats1/2 phosphorylates TAZ at the [HXRXXS] (SEQ ID NO: 9) consensus motifs. TAZ comprises four [HXRXXS] (SEQ ID NO: 9) consensus motifs, wherein X denotes any amino acid residues. In some instances, Lats1/2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Lats1/2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Lats1/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14- 3-3 and subsequently promotes nuclear translocation. [00656] In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCFβ-TRCP-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skp1, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, βTrCP1, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g. SCFβTrCP1) interacts with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate. Exemplary E1 ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome. [00657] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction. YAP/TAZ Interaction with TEAD [00658] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ interacts with the TEAD family of transcription factors (e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4)) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1. [00659] Proteomic and biochemical studies have shown that the TEAD (TEA Domain) transcription factors are palmitoylated at evolutionarily conserved cysteine residues. Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation. The C359S mutant showed the greatest loss of palmitoylation, and C327S and C53S also showed decreased palmitoylation. These results suggest that C359 plays a critical role in TEAD1 palmitoylation. Furthermore, combination mutation of all three cysteine residues, C53/327/359S (3CS), completely ablated TEAD1 palmitoylation, indicating that these residues are involved in TEAD1 palmitoylation. It has been found that TEADs undergo PAT-independent autopalmitoylation, under physiological concentrations of palmitoy 1-CoA. Furthermore, autopalmitoylation plays critical roles in regulating TEAD-YAP association and their physiological functions in vitro and in vivo. Chan, et al. Nature Chem. Biol. 12, pages 282–289 (2016); Noland, et al. Structure, 24, 1–8 (2016); Gibault et al. J. Med. Chem. 61, 5057-5072 (2018). Therefore, palmitoylation of TEADs play important roles in regulating Hippo pathway transcriptional complexes. [00660] In some embodiments, the TBM of the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD. [00661] In some embodiments, the TBM of the compounds described herein reversibly inhibit a TEAD transcription factor. In some embodiments, the transcription factor is TEAD1. In some embodiments, the transcription factor is TEAD2. In some embodiments, the transcription factor is TEAD3. In some embodiments, the transcription factor is TEAD4. In some embodiments, the TBM of the compounds described herein reversibly inhibit the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). [00662] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 and disrupt or inhibit the interaction between YAP and TEAD4. [00663] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. [00664] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C353, and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, C53, and C405. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, C53, and C405. [00665] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD, prevent TEAD palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. [00666] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 at C380, and disrupt or inhibit the interaction between YAP and TEAD2. [00667] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380. [00668] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2, prevent TEAD2 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380, and disrupt or inhibit the interaction between YAP and TEAD2. [00669] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3. [00670] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368 and C371. [00671] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3, prevent TEAD3 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3. [00672] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 at C367, and disrupt or inhibit the interaction between YAP and TEAD4. [00673] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367. [00674] In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4, prevent TEAD4 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD4. In some embodiments, the TBM of the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367, and disrupt or inhibit the interaction between YAP and TEAD4. YAP/TAZ regulation mediated by G-proteins/GPCRs [00675] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins. G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of alpha (Gα), beta (Gβ), and gamma (Gγ) subunits. In some cases, there are several classes of Gα subunits: Gq/11α, G12/13α, Gi/oα (G inhibitory, G other), and Gsα (G stimulatory). [00676] In some instances, Giα (G inhibitory), Goα (G other), Gq/11α, and G12/13α coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other instances, Gsα (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation. [00677] In some cases, Giα (G inhibitory), Goα (G other), Gq/11α, and G12/13α coupled GPCRs activate YAP/TAZ through repression of Lats1/2 activities. In contrast, Gsα, in some embodiments, induces Lats1/2 activity, thereby promoting YAP/TAZ degradation. Gq Family [00678] Gqα (also known as Gq/11 protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca2+) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca2+ channel. In some cases, the binding triggers the opening of the Ca2+ channel, and thereby increases the release of Ca2+ into the cytoplasm. [00679] In some embodiments, the GPCRs that interact with Gqα include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptor; histamine H1 receptor; metabotropic glutamate receptor, group I; muscarinic receptors M1, M3, and M5; and trace amine-associated receptor 1. [00680] In some instances, there are several types of Gqα: Gq, Gq/11, Gq/14, and Gq/15. The Gq protein is encoded by GNAQ. Gq/11 is encoded by GNA11. Gq/14 is encoded by GNA14. Gq/15 is encoded by GNA15. [00681] In some instances, mutations or modifications of the Gqα genes have been associated with cancer. Indeed, studies have shown that mutations in Gqα promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11. [00682] In some instances, mutations or modifications of the Gqα genes have been associated with congenital diseases. In some instances, mutations of Gqα have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge- Weber Syndrome harbors a mutation in GNAQ. G12/13 Family [00683] G12/13α modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g., Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport. [00684] In some embodiments, the GPCRs that interact with G12/13α include, but are not limited to, purinergic receptors (e.g., P2Y1, P2Y2, P2Y4, P2Y6); muscarinic acetylcholine receptors M1 and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1-phosphate (e.g., S1P2, S1P3, S1P4 and S1P5); lysophosphatidic acid (e.g., LPA1, LPA2, LPA3); angiotensin II (AT1); serotonin (5-HT2c and 5-HT4); somatostatin (sst5); endothelin (ETA and ETB); cholecystokinin (CCK1); V1a vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; A1 adenosine receptors; α1 adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NK1 tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors. [00685] In some instances, G12/13α is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively. Gi/o Family [00686] Gi/oα (G inhibitory, G other) (also known as Gi/Go or Gi protein) suppresses the production of 3’, 5’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP. [00687] In some embodiments, the GPCRs that interact with Giα include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT1 and 5-HT5; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as A1 and A3; adrenergic receptors such as α2A, α2B, and α2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GABAB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H3 and H4 receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as δ, κ, μ, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EP1), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sst1, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8. [00688] In some instances, there are several types of Giα: Giα1, Giα2, Giα3, Giα4, Goα, Gt, Ggust, and Gz. Giα1 is encoded by GNAI1. Giα2 is encoded by GNAI2. Giα3 is encoded by GNAI3. Goα, the αo subunit, is encoded by GNAO1. Gt is encoded by GNAT1 and GNAT2. Ggust is encoded by GNAT3. Gz is encoded by GNAZ. Gs Family [00689] Gsα (also known as G stimulatory, Gs alpha subunit, or Gs protein) activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’,5’-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with Gsα include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HT6, and 5-HT7; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and A2b; arginine vasopressin receptor 2 (AVPR2); β-adrenergic receptors β1, β2, and β3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor D1-like family receptors such as D1 and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin. [00690] In some instances, there are two types of Gsα: Gs and Golf. Gs is encoded by GNAS. Golf is encoded by GNAL. Additional Regulators of the Hippo signaling network [00691] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization. [00692] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1. [00693] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E-cad-associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Lats1/2 kinase activity, thereby preventing inactivation of YAP/TAZ. [00694] In some embodiments, additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2. [00695] In some embodiments, the TBM of the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the TBM of the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the TBM of the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). [00696] In some embodiments, the TBM of the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the Gqα family proteins such as Gq, Gq/11, Gq/14, and Gq/15; the G12/13α family of proteins such as G12 and G13; or the Giα family of proteins such as Giα1, Giα2, Giα3, Giα4, Goα, Gt, Ggust, and Gz. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/11. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/14. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/15. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Giα4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goα. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gz. [00697] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Sav1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD. [00698] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g., 26S proteasome). [00699] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42. [00700] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein. [00701] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease. USP47 is a member of the ubiquitin-specific protease (USP/UBP) superfamily of cysteine proteases. In some embodiments, the TBM of the compounds disclosed herein are inhibitors of USP47. [00702] In some embodiments, the present invention provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder. [00703] The activity of a TBM of a compound utilized in this invention as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, can be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof. Detailed conditions for assaying a TBM of a compound utilized in this invention as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are set forth in the Examples below. See, for example, Examples 2 and 5. [00704] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence. [00705] The provided compounds are degraders and/or inhibitors of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) and are therefore useful for treating one or more disorders associated with activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). Thus, in certain aspects and embodiments, the present invention provides a method for treating a TEAD- mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof. [00706] As used herein, the term “TEAD-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, is known to play a role. Accordingly, another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are known to play a role. [00707] As used herein, the term “a therapeutically effective amount of” refers to the amount of a TEAD degrader, and/or TEAD inhibitor or a pharmaceutically acceptable salt thereof, which is effective to reduce or attenuate the biological activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof, provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition in a biological sample or in a patient. In some embodiments, “a therapeutically effective amount of” refers to the amount of a TEAD degrader and/or a TEAD inhibitor or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, or any TEAD-mediated activity. The term “therapeutically effective amount” can encompass, in some embodiments, 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. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibition of a TEAD transcription factor. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease. [00708] In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of the Hippo pathway is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof. [00709] In some aspects and embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a TEAD degrader compound and/or a TEAD inhibitor compound as described herein, or a pharmaceutical salt or composition thereof. In some embodiments, a cellular proliferative disorder is cancer. In some embodiments, the cancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity. [00710] As used herein, the terms "increased," “elevated,” or “enhanced,” are used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration. For example, an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration. [00711] As used herein, the terms “increased expression” and/or “increased activity” of a substance, such as TEAD, in a sample or cancer or patient, refers to an increase in the amount of the substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as TEAD, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an “increased expression” or “increased activity” of TEAD if the expression and/or activity of TEAD is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of TEAD in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples. [00712] As used herein, 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 can 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. Exemplary proliferative diseases include cancers (i.e.,“malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. Cancer [00713] The cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer. [00714] In some embodiments of the methods and uses described herein, a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP). In some embodiments of the methods and uses described herein, a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). In some embodiments of the methods and uses described herein, the cancer is characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity. In some embodiments of the methods and uses described herein, the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells. [00715] In some embodiments of the methods and uses described herein, the cancer is characterized or associated with a genetic alteration in one or more Hippo pathway genes. As used herein, the term “genetic alteration in one or more Hippo pathway genes” refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes. As used herein, a genetic alteration in a gene, such as a Hippo pathway gene, can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1-TFE3 fusion. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes, at least about thirteen copies of genetically altered Hippo pathway genes, at least about fourteen copies of genetically altered Hippo pathway genes, at least about fifteen copies of genetically altered Hippo pathway genes, at least about twenty copies of genetically altered Hippo pathway genes, or more. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes. In some embodiments, a Hippo pathway gene is NF2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is NF2 deficiency. In some embodiments, NF2 deficiency refers to NF2 loss of function mutations. In some embodiments, NF2 deficiency refers to NF2 copy losses or deletions. In some embodiments, NF2 deficiency refers to absent or very low NF2 mRNA expression. In some embodiments, a Hippo pathway gene is YAP1. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion. In some embodiments, a Hippo pathway gene is TAZ. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is TAZ amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion. In some embodiments, a Hippo pathway gene is LATS 1/2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion. In some embodiments, a Hippo pathway gene is MST1/2. In some embodiments, a Hippo pathway gene is BAP1. [00716] In some embodiments, a cancer is characterized by a mutant Gα-protein. In some embodiments, a mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, a mutant Gα-protein is G12. In some embodiments, a mutant Gα-protein is G13. In some embodiments, a mutant Gα-protein is Gq. In some embodiments, a mutant Gα-protein is G11. In some embodiments, a mutant Gα-protein is Gi. In some embodiments, a mutant Gα-protein is Go. In some embodiments, a mutant Gα-protein is Gs. [00717] In some embodiments of the methods and uses described herein, a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor. In some embodiments of the methods and uses described herein, a cancer is treated by inhibiting or reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment. In some embodiments of the methods and uses described herein, a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of the cancers or tumors prior to treatment. [00718] In some embodiments, a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated. In some embodiments, a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated. [00719] In some embodiments, a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. [00720] In some embodiments of the methods and uses described herein, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma. In some embodiments, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, mesothelioma, sarcoma, or epithelioid hemangioendothelioma (EHE). In some embodiments, the cancer is mesothelioma, such as malignant mesothelioma. In some embodiments, the cancer is EHE. [00721] In some embodiments, cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). [00722] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. [00723] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient. [00724] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. [00725] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00726] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00727] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma. [00728] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00729] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. [00730] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma. [00731] In some embodiments, a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https://clinicaltrials.gov/ct2/show/study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/ NCT02426892) [00732] In some embodiments, a cancer is melanoma cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is lung cancer. In some embodiments, a cancer is small cell lung cancer (SCLC). In some embodiments, a cancer is non-small cell lung cancer (NSCLC). [00733] The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer. The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The terms “patient” or “subject,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00734] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00735] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00736] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00737] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00738] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00739] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. [00740] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00741] Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00742] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00743] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Co-Administration with One or More Other Therapeutic Agent(s) [00744] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” [00745] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. [00746] A compound of the current invention can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. [00747] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides, or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible, as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. [00748] One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart. [00749] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00750] The amount of a compound of the invention and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered. [00751] In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and a compound of the invention can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 – 1,000 μg/kg body weight/day of the one or more other therapeutic agent(s) can be administered. [00752] The amount of one or more other therapeutic agent(s) present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert. [00753] The compounds of this invention, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. Exemplary Other Therapeutic Agents [00754] In some embodiments, one or more other therapeutic agent is a MEK inhibitor. As used herein, a “MEK inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits mitogen-activated protein kinase enzymes MEK1 and/or MEK2. In some embodiments, an MEK inhibitor is selected from those as described in Cheng et al., “Current Development Status of MEK Inhibitors,” Molecules 2017, 22, 1551, the contents of which are incorporated herein by reference in its entirety. In certain embodiments, the MEK inhibitor is selected from binimetinib (MEK162, ARRY-438162, ARRAY BIOPHARMA INC.), cobimetinib(COTELLIC®, Exelexis/Genentech/Roche), refametinib (BAY 86–9766, RDEA119; Bayer AG), selumetinib (AZD6244, ARRY-142886; ASTRAZENECA), trametinib(MEKINIST®, Novartis), mirdametinib(PD-0325901, Spring Works Therapeutics), pimasertib (AS703026, MSC1936369B, Merck KGaA)or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. In certain embodiments, the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, mirdametinib, pimasertib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing. Other examples of MEK inhibitors for use as an other therapeutic agent in the methods and uses described herein include, but are not limited to, E6201 (Eisai Co Ltd./Strategia Theraputics), GDC-0623 (RG 7421, Genentech, Inc.), CH5126766 (RO5126766, Chugai Pharmaceutical Co., Roche), HL-085 (Shanghai Kechow Pharma, Inc.), SHR7390 (HENGRUI MEDICINE), TQ-B3234 (CHIATAI TIANQING), CS-3006 (CSTONE Pharmaceuticals), FCN- 159 (FosunPharmaceuticals), VS-6766 (Verastem Oncology), and IMM-1-104 (Immuneering Corp.). Other examples of MEK inhibitors for use as second anti-cancer agents in the methods and uses described herein include, but are not limited to, those described in WO2005/121142, WO2014/169843, WO2016/035008, WO2016/168704, WO2020/125747, WO2021/142144, WO2021/142345, WO2021/149776, the contents of each of which are herein incorporated by reference in their entireties. [00755] In some embodiments, one or more other therapeutic agent is an EGFR inhibitor. As used herein, an "EGFR inhibitor" refers to any inhibitor or blocker or antagonist that binds to and/or inhibits epidermal growth factor receptor (EGFR). In some embodiments, an EGFR inhibitor is selected from those as described in Ayati et al., "A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy," Bioorganic Chemistry 2020, 99: 103811, the contents of which are incorporated herein by reference in its entirety. In some embodiments, an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab. In some embodiments, an EGFR inhibitor is cetuximab. In some embodiments, an EGFR inhibitor is necitumumab. In some embodiments, an EGFR inhibitor is panitumumab. In some embodiments, an EGFR inhibitor is zalutumumab. In some embodiments, an EGFR inhibitor is nimotuzumab. In some embodiments, an EGFR inhibitor is matuzumab. [00756] In some embodiments, an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, an EGFR inhibitor is osimertinib. In some embodiments, an EGFR inhibitor is gefitinib. In some embodiments, an EGFR inhibitor is erlotinib. In some embodiments, an EGFR inhibitor is lapatinib. In some embodiments, an EGFR inhibitor is neratinib. In some embodiments, an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib. [00757] In some embodiments, an EGFR inhibitor is a "1st generation EGFR tyrosine kinase inhibitor" (1st generation TKI). A 1st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation. [00758] In some embodiments, an EGFR inhibitor is a "2nd generation EGFR tyrosine kinase inhibitor" (2nd generation TKI). A 2nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation. [00759] In some embodiments, an EGFR inhibitor is a "3rd generation EGFR tyrosine kinase inhibitor" (3rd generation TKI). A 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR. [00760] In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.). [00761] In some embodiments, one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China). [00762] In some embodiments, one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics). [00763] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics). [00764] In some embodiments, one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. In some embodiments, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix). [00765] In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008). [00766] In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. [00767] In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon/Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine- based nucleoside analog and thymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology). [00768] In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech/Roche/Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech/Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRUVICA®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin (RYDAPT®, Novartis). [00769] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/Takeda). [00770] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer). [00771] In some embodiments, one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda). [00772] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca). [00773] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis). [00774] In some embodiments, one or more other therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma. [00775] In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly). [00776] In some embodiments, one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan). [00777] In some embodiments, one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010). [00778] In some embodiments, one or more other therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences). [00779] In some embodiments, one or more other therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences). [00780] In some embodiments, one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (RITUXAN®, Genentech/BiogenIdec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline); obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, KADCYLA®, Genentech); and pertuzumab (anti-HER2, PERJETA®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, ADCETRIS®, Seattle Genetics). [00781] In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma). [00782] In some embodiments, one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740). [00783] In some embodiments, one or more other therapeutic agent is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals). [00784] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (EVISTA®, Eli Lilly). [00785] In some embodiments, one or more other therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis). [00786] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613). [00787] In some embodiments, one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFß). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD- L1/TGFß trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ“trap.” [00788] In some embodiments, one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize. [00789] In some embodiments, one or more other therapeutic agents is an antiproliferative compound. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17- DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, TEMODAL CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. [00790] The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name AROMASIN™. Formestane is marketed under the trade name LENTARON™. Fadrozole is marketed under the trade name AFEMA™. Anastrozole is marketed under the trade name ARIMIDEX™. Letrozole is marketed under the trade names FEMARA™ or FEMAr™. Aminoglutethimide is marketed under the trade name ORIMETEN™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors. [00791] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name NOLVADEX™. Raloxifene hydrochloride is marketed under the trade name EVISTA™. Fulvestrant can be administered under the trade name FASLODEX™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors. [00792] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEX™. [00793] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR™. Topotecan is marketed under the trade name HYCAMPTIN™. [00794] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYX™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name ETOPOPHOS™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name ACRIBLASTIN™ or ADRIAMYCIN™. Epirubicin is marketed under the trade name FARMORUBICIN™. Idarubicin is marketed. under the trade name ZAVEDOS™. Mitoxantrone is marketed under the trade name NOVANTRON™. [00795] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name TAXOL™. Docetaxel is marketed under the trade name TAXOTERE™. Vinblastine sulfate is marketed under the trade name VINBLASTIN R.P™. Vincristine sulfate is marketed under the trade name FARMISTIN™. [00796] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTIN™. Ifosfamide is marketed under the trade name HOLOXAN™. [00797] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA). [00798] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name XELODA™. Gemcitabine is marketed under the trade name GEMZAR™. [00799] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN™. [00800] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the AxI receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC™) or tyrphostin such as Tyrphostin A23/RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (HERCEPTIN™), cetuximab (ERBITUX™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3- d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c- Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan- JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL- 719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib). [00801] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K- C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib. [00802] The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic. [00803] The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib. [00804] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib. [00805] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference. [00806] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference. [00807] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference. [00808] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference. [00809] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition e.g., thalidomide (THALOMID™) and TNP-470. [00810] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708. [00811] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof. [00812] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ- tocopherol or α- γ- or δ-tocotrienol. [00813] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib. [00814] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name DIDRONEL™. Clodronic acid is marketed under the trade name BONEFOS™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name AREDIA™. Alendronic acid is marketed under the trade name FOSAMAX™. Ibandronic acid is marketed under the trade name BONDRANAT™. Risedronic acid is marketed under the trade name ACTONEL™. Zoledronic acid is marketed under the trade name ZOMETA™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICAN™), CCI-779 and ABT578. [00815] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons. [00816] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (ZARNESTRA™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin. [00817] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof. [00818] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADE™) and MLN 341. [00819] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MMI270B or AAJ996. [00820] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase. [00821] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518. [00822] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors. [00823] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DM1, erbitux, bevacizumab (AVASTIN™), rituximab (RITUXAN®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. [00824] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412. [00825] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol.1 , pp.248-275 (1993). [00826] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1 ,3-dione derivatives. [00827] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATIN™; ENDOSTATIN™; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTIN™). [00828] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNE™ and porfimer sodium. [00829] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone. [00830] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone. [00831] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action. [00832] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications). Exemplary Immuno-Oncology agents [00833] In some embodiments, one or more other therapeutic agent is an immuno-oncology agent. As used herein, the term “an immuno-oncology agent” refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject. In some embodiments, the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer. [00834] An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human. [00835] In some embodiments, an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses. [00836] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR. [00837] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response. [00838] In some embodiments, a combination of a compound of the invention and an immuno- oncology agent can stimulate T cell responses. In some embodiments, an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM- 4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. [00839] In some embodiments, an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonist of KIR, such as lirilumab. [00840] In some embodiments, an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357). [00841] In some embodiments, an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites. [00842] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab. [00843] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immuno- oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, an immuno-oncology agent may be pidilizumab (CT- 011). In some embodiments, an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224. [00844] In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. In some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS- 936559 (WO2007/005874), and MSB0010718C (WO2013/79174). [00845] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. In some embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273). [00846] In some embodiments, an immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO12/32433). [00847] In some embodiments, an immuno-oncology agent is a GITR agonist. In some embodiments, a GITR agonist is an agonistic GITR antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116), or MK- 4166 (WO11/028683). [00848] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)- dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237). [00849] In some embodiments, an immuno-oncology agent is an OX40 agonist. In some embodiments, an OX40 agonist is an agonistic OX40 antibody. In some embodiments, an OX40 antibody is MEDI-6383 or MEDI-6469. [00850] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879). [00851] In some embodiments, an immuno-oncology agent is a CD40 agonist. In some embodiments, a CD40 agonist is an agonistic CD40 antibody. In some embodiments, an immuno- oncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab. [00852] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab. [00853] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11/109400). [00854] In some embodiments, an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab. [00855] In some embodiments, an immuno-oncology agent is an immunostimulatory agent. For example, antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor- reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol.14, 1212–1218; Zou et al. (2016) Sci. Transl. Med.8. The anti-PD-1 antibody nivolumab (OPDIVO®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy. [00856] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma). [00857] In some embodiments, an immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non- small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL- ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta- galactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818). [00858] In some embodiments, an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5- fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNFα-IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8+ T cell response. [00859] In some embodiments, an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells. [00860] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex. [00861] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al.; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1]. [00862] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor γ (ROR γt). ROR γt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. In some embodiments, an activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862). [00863] In some embodiments, an immunostimulatory agent is an agonist or activator of a toll- like receptor (TLR). Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559). [00864] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol- Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody. [00865] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of ROR γt. [00866] In some embodiments, an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124. [00867] In some embodiments, an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol.14, pages 603-622, the content of which is incorporated herein by reference in its entirety. In some embodiments, an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al. [00868] In some embodiments, an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol.28, pages 319-329, the content of which is incorporated herein by reference in its entirety. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood. [00869] In some embodiments, an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BITE® ) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390, the content of which is incorporated herein by reference in its entirety. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, the bystander cells being lysed are in proximity to the BITE®-activated T cells. In some embodiment, the bystander cells comprises tumor-associated antigen (TAA) negative cancer cells. In some embodiment, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immuno- oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell. In some embodiments, an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs). Exemplary Immune Checkpoint Inhibitors [00870] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein. [00871] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions. [00872] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed. [00873] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti-tumor immune response. [00874] In some embodiments, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine. [00875] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, γδ, and memory CD8+ (αβ) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS- 936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3. [00876] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech). [00877] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab. [00878] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822). [00879] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268). [00880] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428). [00881] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS- 986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934). [00882] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol- Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475). [00883] Checkpoint inhibitors that can be used in the present invention include CD137 (also called 4-1BB) agonists. CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488). [00884] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038). [00885] Checkpoint inhibitors that can be used in the present invention include glucocorticoid- induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165). [00886] Checkpoint inhibitors that can be used in the present invention include inducible T-cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226). [00887] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045). [00888] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgG1, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC- 90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509). [00889] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti- CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141). [00890] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936). [00891] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4- [2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723). [00892] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516). [00893] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. EXEMPLIFICATION [00894] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. [00895] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. For example, Ligase Binding Moiety (LBM), Degradation Inducing Moiety (DIM), TEAD Binding Moiety (TBM), and degraders can be prepared as described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed.2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO 2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO 2012/003281, US 2013/0190340, US 2016/0022642, WO 2014/063061, US 2015/0274738, WO 2016/118666, US 2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US 2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US 2017/0008904, WO 2017/011590, US 2017/0037004, WO 2017/079267, US 2017/0121321, WO 2017/117473, WO 2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, WO 2017/197046, WO 2017/197051, WO 2017/197055, WO 2017/197056, WO 2019/060693, WO 2019/140387, WO 2020/010177, Pobbati et al., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy,” Structure 2015, 23, 2076–2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem.2018, 61, 5057-5072; Bum-Erdene et al., “Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD•Yap Protein-Protein Interaction,” Cell Chemical Biology 2019, 26, 1–12; Holden et al., “Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of HippoPathway Signaling,” Cell Reports 2020, 31, 107809; WO 2017/053706, WO 2017/111076, WO 2018/204532, WO 2018/235926, US 20190010136, WO 2019/040380, WO 2019/113236, WO 2019/222431, WO 2019/232216, WO 2020/051099, WO 2020/081572, WO 2020/097389, WO 2020/190774, WO 2020/214734, PCT/US2020/35098, and PCT/US2020/35111, the contents of each of which are herein incorporated by reference in their entireties. Example 1A: Synthesis of Exemplary Compounds [00896] Certain exemplary compounds are prepared as described below. I-1
Figure imgf000340_0001
Step 1: N-[2-[2-[2-[(3S)-2,6-Dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyethoxy]ethyl]-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000341_0001
[00897] To a stirred solution of (3S)-3-[5-[2-(2-aminoethoxy)ethoxy]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (20 mg, 57.58 µmol, N/A purity, 1 eq) and 3-(1-methylimidazol-4-yl)-4- [[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (27.64 mg, 63.33 µmol, 86.0% purity, 1.1 eq) in DMF (1 mL) was added DIEA (18.60 mg, 143.94 µmol, 25.07 µL, 2.5 eq) and HATU (24.08 mg, 63.33 µmol, 1.1 eq). The reaction mixture was stirred under N2 atmosphere at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5µm; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 53%-83%, 10 min) to yield N-[2-[2-[2- [(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyethoxy]ethyl]-3-(1-methylimidazol-4-yl)- 4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide (11.78 mg, 15.99 µmol, 27.8% yield, 95.7% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 9.17 (t, J = 5.9 Hz, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.72-7.64 (m, 3H), 7.61-7.53 (m, 3H), 7.49 (d, J = 8.6 Hz, 1H), 7.17-7.11 (m, 1H), 7.07-6.96 (m, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.06 (dd, J = 5.0, 13.3 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 4.43-4.28 (m, 1H), 4.18 (s, 2H), 3.78 (s, 2H), 3.74 (s, 3H), 3.61-3.55 (m, 2H), 3.49 (s, 2H), 2.95-2.82 (m, 1H), 2.70-2.53 (m, 2H), 2.43-2.31 (m, 1H), 1.95 (d, J = 5.4 Hz, 1H); ES-LCMS m/z 705.3 [M+H]+. I-2
Figure imgf000341_0002
Step 1: N-[6-[2-[(3S)-2,6-Dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyhexyl]-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000342_0001
[00898] To a stirred solution of (3S)-3-[5-(6-aminohexoxy)-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione (20 mg, 55.65 µmol, 1 eq) and 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (26.72 mg, 61.22 µmol, 86.0% purity, 1.1 eq) in DMF (1 mL) was added DIEA (17.98 mg, 139.12 µmol, 24.23 µL, 2.5 eq) and HATU (23.27 mg, 61.22 µmol, 1.1 eq). The reaction mixture was stirred under N2 atmosphere at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5µm; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 50%-80%, 10 min) to yield N-[6-[2-[(3S)- 2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxyhexyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (8.94 mg, 12.03 µmol, 21.6% yield, 96.4% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 9.14 (t, J = 6.0 Hz, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.71-7.65 (m, 3H), 7.61-7.53 (m, 3H), 7.48 (d, J = 10.3 Hz, 1H), 7.13 (s, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 8.6 Hz, 1H), 5.06 (dd, J = 5.3, 13.3 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.38-4.19 (m, 2H), 4.04 (t, J = 6.2 Hz, 2H), 3.75 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H), 2.96-2.83 (m, 1H), 2.68-2.59 (m, 1H), 2.40-2.31 (m, 1H), 1.97 (d, J = 5.9 Hz, 1H), 1.81-1.69 (m, 2H), 1.56-1.48 (m, 2H), 1.45 (s, 2H), 1.37 (d, J = 7.1 Hz, 2H); ES-LCMS m/z 717.3 [M+H]+. I-3
Figure imgf000343_0001
Step 1: (S)-3-(1-Oxo-5-(4-(piperidin-4-yl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione
Figure imgf000343_0002
[00899] To a solution of tert-butyl 4-[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5- yl]piperazin-1-yl]piperidine-1-carboxylate (45.00 mg, 87.96 µmol, 1 eq) in DCM (1 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 30.71 eq) at 20 °C. The mixture was stirred under N2 atmosphere at 20 °C for 1 h. The mixture was concentrated to yield (3S)-3-[1-oxo-5-[4-(4- piperidyl)piperazin-1-yl]isoindolin-2-yl]piperidine-2,6-dione (40 mg, 76.12 µmol, 86.5% yield, N/A purity, TFA) as yellow oil, which was used in the next step without further purification. ES- LCMS m/z 412.3 [M+H]+. Step 2: (S)-3-(5-(4-(1-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)piperazin-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione
Figure imgf000344_0001
[00900] To a solution of (3S)-3-[1-oxo-5-[4-(4-piperidyl)piperazin-1-yl]isoindolin-2- yl]piperidine-2,6-dione (40 mg, 76.12 µmol, N/A purity, 1 eq, TFA) in DMF (1 mL) was added HATU (28.94 mg, 76.12 µmol, 1.0 eq), 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (33.22 mg, 76.12 µmol, 86% purity, 1 eq) and DIEA (19.67 mg, 152.23 µmol, 26.52 µL, 2 eq). The mixture was stirred under N2 atmosphere at 20 °C for 1 h. The mixture was filtered and washed with DCM (5 mL x 2). The filtrate was concentrated to yield a residue which was purified by preparative HPLC ([water (10mM NH4HCO3)-ACN]; B%: 43%-63%), followed by lyophilization to yield (S)-3-(5-(4-(1-(3-(1- methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzoyl)piperidin-4- yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20 mg, 25.29 µmol, 33.2% yield, 97.2% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 7.77 (s, 1H), 7.70 (d, J = 5.9 Hz, 3H), 7.57 (d, J = 7.8 Hz, 2H), 7.53-7.50 (m, 2H), 7.07-7.02 (m, 3H), 6.50 (d, J = 8.6 Hz, 1H), 5.04 (dd, J = 5.1, 13.3 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.36-4.29 (m, 1H), 4.22-4.17 (m, 1H), 3.73 (s, 3H), 3.26 (s, 4H), 2.90 (t, J = 12.7 Hz, 3H), 2.64 (s, 4H), 2.56 (s, 1H), 2.42-2.28 (m, 1H), 2.06-1.76 (m, 3H), 1.45-1.30 (m, 2H), 0.99 (s, 1H); ES-LCMS m/z 769.3 [M+H]+. I-4
Figure imgf000345_0001
Step 1: (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1- yl)isoindoline-1,3-dione
Figure imgf000345_0002
[00901] To a solution of tert-butyl 4-[2-[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (20 mg, 36.12 µmol, 1 eq) in DCM (1 mL) was added TFA (308.00 mg, 2.70 mmol, 0.2 mL, 74.78 eq). The mixture was stirred under N2 atmosphere at 20 °C for 1 h. The mixture was concentrated to yield 2-[(3S)-2,6-dioxo-3- piperidyl]-5-[4-[2-(4-piperidyl)ethyl]piperazin-1-yl]isoindoline-1,3-dione (20 mg, 35.24 µmol, 97.6% yield, N/A purity, TFA) as yellow oil, which was used in the next step without further purification. ES-LCMS m/z 454.3 [M+H]+. Step 2: (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-(1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3- dione
Figure imgf000346_0001
[00902] To a solution of 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[4-[2-(4-piperidyl)ethyl]piperazin-1- yl]isoindoline-1,3-dione (20 mg, 35.24 µmol, N/A purity, 1 eq, TFA) in DMF (1 mL) was added HATU (13.40 mg, 35.24 µmol, 1 eq), DIEA (4.55 mg, 35.24 µmol, 6.14 µL, 1 eq) and 3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (15.38 mg, 35.24 µmol, 86% purity, 1 eq). The mixture was stirred under N2 atmosphere at 20 °C for 1 h. The mixture was filtered and washed with DCM (5 mL x 2). The filtrate was concentrated to yield a residue which was purified by preparative HPLC ([water (10 mM NH4HCO3)-ACN]; B%: 43%- 63%), followed by lyophilization to yield 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[4-[2-[1-[3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoyl]-4- piperidyl]ethyl]piperazin-1-yl]isoindoline-1,3-dione (5.03 mg, 6.09 µmol, 17.3% yield, 98.1% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.09 (s, 1H), 9.09-8.98 (m, 1H), 7.77 (s, 1H), 7.73-7.65 (m, 4H), 7.56 (d, J = 7.8 Hz, 2H), 7.50 (s, 1H), 7.33 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H), 5.07 (dd, J = 4.9, 12.7 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.09 (s, 1H), 3.73 (s, 3H), 3.42 (br s, 5H), 2.86 (d, J = 12.5 Hz, 3H), 2.70- 2.55 (m, 2H), 2.34 (d, J = 8.2 Hz, 3H), 2.01 (d, J = 10.2 Hz, 1H), 1.68 (s, 2H), 1.57 (s, 1H), 1.43 (s, 2H), 1.09 (d, J = 14.5 Hz, 3H); ES-LCMS m/z 811.4 [M+H]+. I-5
Figure imgf000346_0002
Step 1: (S)-N-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)propyl)-3-(1-methyl- 1H-imidazol-4-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzamide
Figure imgf000347_0001
[00903] To a solution of 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (28.88 mg, 66.18 µmol, 86% purity, 1.05 eq) in DMF (1 mL) was added HATU (26.36 mg, 69.33 µmol, 1.1 eq), (3S)-3-[5-(3-aminopropoxy)- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione (20 mg, 63.02 µmol, 1 eq) and DIEA (16.29 mg, 126.05 µmol, 21.95 µL, 2.0 eq) at 20 °C. The mixture was stirred under N2 atmosphere at 20 °C for 1 h. The mixture was purification by preparative HPLC ([water (0.05%HCl)-ACN]; B%: 30- 50%), followed by lyophilization to yield N-[3-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin- 5-yl]oxypropyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (11 mg, 16.30 µmol, 25.9% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.97 (s, 1H), 8.25 (s, 1H), 7.83 (s, 2H), 7.71-7.60 (m, 4H), 7.57 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 5.07 (dd, J = 5.0, 13.3 Hz, 1H), 4.54 (s, 2H), 4.40-4.32 (m, 1H), 4.28-4.20 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 2.94-2.82 (m, 1H), 2.67 (s, 1H), 2.61 (s, 2H), 2.33 (s, 2H), 2.02-1.92 (m, 3H); ES-LCMS m/z 675.2 [M+H]+. I-7
Figure imgf000347_0002
Step 1: N-[4-[2-[(3S)-2,6-Dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxybutyl]-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000348_0001
[00904] To a solution of (3S)-3-[5-(4-aminobutoxy)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (40 mg, 120.71 µmol, 1 eq) and 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (55.32 mg, 126.75 µmol, 1.05 eq) in DMF (1 mL) was added HATU (48.19 mg, 126.75 µmol, 1.05 eq) and DIEA (31.20 mg, 241.43 µmol, 42.05 µL, 2 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with EtOAc (15 mL), concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5µm;mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 47%-67%, 10min), followed by lyophilization to yield N-[4-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxybutyl]-3-(1-methylimidazol-4- yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide (7.53 mg, 10.61 µmol, 8.8% yield, 97.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.97 (s, 1H), 9.15 (s, 1H), 8.15 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.73-7.64 (t, 3H), 7.61 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 9.4 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.52 (d, J=9.0 Hz, 1H), 5.06 (dd, J = 5.3, 13.5 Hz, 1H), 4.62 (d, J = 5.1 Hz, 2H), 4.41-4.30 (m, 1H), 4.27-4.18 (m, 1H), 4.09 (t, 2H), 3.75 (s, 3H), 3.30 (m, J = 5.5 Hz, 1H), 2.95-2.85 (m, 1H), 2.60 (s, 2H), 2.37- 2.32 (m, 1H), 1.97 (s, 1H), 1.78 (s, 2H), 1.66 (s, 2H); LCMS m/z 689.3 [M+H]+. I-8
Figure imgf000348_0002
Step 1: N-[5-[2-[(3S)-2,6-Dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxypentyl]-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000349_0001
[00905] To a solution of (3S)-3-[5-(5-aminopentoxy)-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (50 mg, 144.76 µmol, 1 eq) and 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (66.34 mg, 152.00 µmol, 1.05 eq) in DMF (2 mL) was added HATU (57.80 mg, 152.00 µmol, 1.05 eq) and DIEA (37.42 mg, 289.53 µmol, 50.43 µL, 2 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with EtOAc (15 mL) and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30mm*5µm; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 53%-83%, 10 min), followed by lyophilization to yield N-[5-[2-[(3S)-2,6-dioxo-3-piperidyl]-1-oxo-isoindolin-5-yl]oxypentyl]-3-(1-methylimidazol-4- yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide (6.42 mg, 9.14 µmol, 6.3% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.94 (s, 1H), 7.97 (d, J = 2.0 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.59-7.53 (m, 2H), 7.50-7.46 (m, 3H), 7.34 (dd, J = 2.0, 8.6 Hz, 1H), 7.30 (s, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.45 (d, J = 8.6 Hz, 1H), 6.02 (s, 1H), 5.19 (dd, J = 5.3, 13.1 Hz, 1H), 4.59 (s, 2H), 4.44-4.37 (m, 1H), 4.30-4.22 (m, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.76 (s, 3H), 3.46 (q, J = 6.5 Hz, 2H), 2.97-2.73 (m, 2H), 2.38-2.27 (m, 1H), 2.24-2.16 (m, 1H), 1.89-1.83 (m, 2H), 1.67 (s, 2H), 1.56 (s, 2H); LCMS m/z 703.5 [M+H]+. I-9
Figure imgf000350_0001
Step 1: 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3- dione
Figure imgf000350_0002
[00906] To a solution of tert-butyl 4-[[1-[2-[(3S)-2,6-dioxo-3-piperidyl]-1,3-dioxo-isoindolin- 5-yl]-4-piperidyl]methyl]piperidine-1-carboxylate (70 mg, 129.96 µmol, 1 eq) in DCM (1 mL) was added TFA (14.82 mg, 129.96 µmol, 9.62 µL, 1 eq). The mixture was stirred under N2 atmosphere at 20°C for 1 h. The mixture was concentrated to yield 2-[(3S)-2,6-dioxo-3-piperidyl]- 5-[4-(4-piperidylmethyl)-1-piperidyl]isoindoline-1,3-dione (60 mg, 108.59 µmol, 83.6% yield, N/A purity, TFA) as yellow oil, which was used in the next step without further purification. ES- LCMS m/z 439.5 [M+H]+. Step 2: (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(4-((1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline- 1,3-dione
Figure imgf000351_0001
[00907] To a solution of 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[4-(4-piperidylmethyl)-1- piperidyl]isoindoline-1,3-dione (60 mg, 108.59 µmol, N/A purity, 1 eq, TFA) in DMF (1 mL) was added HATU (41.29 mg, 108.59 µmol, 1 eq), DIEA (28.07 mg, 217.18 µmol, 37.83 µL, 2 eq) and 3-(1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (47.39 mg, 108.59 µmol, 86% purity, 1 eq). The mixture was stirred under N2 atmosphere at 20 °C for 1 h. The mixture was filtered, washed with DCM (5 mL x 2). The filtrate was concentrated to yield the residue which was purified by preparative HPLC ([water (0.05%HCl)-ACN]; B%: 40%-60%), followed by lyophilization to yield 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[4-[[1-[3-(1-methylimidazol- 4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoyl]-4-piperidyl]methyl]-1- piperidyl]isoindoline-1,3-dione (23 mg, 25.41 µmol, 23.4% yield, 100.0% purity, 3HCl) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (s, 1H), 9.21 (s, 1H), 7.95 (s, 1H), 7.76- 7.56 (m, 5H), 7.35-7.18 (m, 4H), 6.50 (d, J = 8.6 Hz, 1H), 5.05 (dd, J = 5.3, 12.8 Hz, 1H), 4.48 (s, 2H), 4.03 (d, J = 12.5 Hz, 2H), 3.92 (s, 3H), 3.42-3.39 (m, 2H), 3.05-2.75 (m, 5H), 2.58 (d, J = 17.1 Hz, 2H), 2.10-1.91 (m, 1H), 1.79-1.53 (m, 6H), 1.25-0.88 (m, 6H); ES-LCMS m/z 811.4 [M+H]+. I-10
Figure imgf000351_0002
Step 1: (S)-2-(2,6-Dioxopiperidin-3-yl)-5-(3-((1-(3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)oxy)azetidin-1-yl)isoindoline-1,3- dione
Figure imgf000352_0001
[00908] To a stirred solution of 2-[(3S)-2,6-dioxo-3-piperidyl]-5-[3-(4-piperidyloxy)azetidin- 1-yl]isoindoline-1,3-dione (20 mg, 46.63 µmol, 96.2% purity, 1 eq), HATU (18.62 mg, 48.97 µmol, 1.05 eq) and DIEA (12.05 mg, 93.27 µmol, 16.25 µL, 2 eq) in DMF (1.5 mL) was added 3- (1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (17.86 mg, 46.63 µmol, 98.0% purity, 1 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 x 3 mL). The organic phase was separated, washed with saturated brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30 mm*5 µm; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)- ACN]; B%: 52%-67%, 14 min), followed by lyophilization to yield 2-[(3S)-2,6-dioxo-3- piperidyl]-5-[3-[[1-[3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoyl]-4-piperidyl]oxy]azetidin-1-yl]isoindoline-1,3- dione (6.88 mg, 8.94 µmol, 19.2% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (s, 1H), 7.82 (s, 1H), 7.68-7.61 (m, 3H), 7.55 (d, J = 7.8 Hz, 3H), 7.36 (s, 1H), 7.12 (s, 1H), 6.77 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 5.09-4.93 (m, 1H), 4.60 (s, 1H), 4.50 (s, 2H), 4.32-4.20 (m, 2H), 3.81 (s, 7H), 3.64 (s, 1H), 3.14 (d, J = 9.3 Hz, 2H), 2.84 (s, 1H), 2.58-2.56 (m, 1H), 1.95 (s, 2H), 1.79 (s, 2H), 1.42 (s, 2H); ES-LCMS m/z 770.3 [M+H]+. I-11
Figure imgf000352_0002
Step 1: (S)-3-(5-(4-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione
Figure imgf000353_0001
[00909] To a stirred solution of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6- dione (20 mg, 59.79 µmol, 98.2% purity, 1 eq), HATU (23.87 mg, 62.78 µmol, 1.05 eq) and DIEA (15.46 mg, 119.58 µmol, 20.83 µL, 2 eq) in DMF (1.5 mL) was added 3-(1-methylimidazol-4-yl)- 4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (27.40 mg, 62.78 µmol, 86.0% purity, 1.05 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 x 3 mL). The organic phase was separated, washed with saturated brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 µm; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 44%-59%, 14 min), followed by lyophilization to yield (3S)-3-[5-[4-[3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione (6.25 mg, 9.11 µmol, 15.2% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 9.16-9.06 (m, 1H), 7.77 (s, 1H), 7.70 (d, J = 6.4 Hz, 3H), 7.61- 7.52 (m, 4H), 7.13-7.04 (m, 3H), 6.53 (d, J = 8.6 Hz, 1H), 5.04 (dd, J = 4.9, 13.0 Hz, 1H), 4.61 (d, J = 5.4 Hz, 2H), 4.37-4.29 (m, 1H), 4.24-4.18 (m, 1H), 3.78-3.62 (m, 9H), 2.97-2.81 (m, 1H), 2.69- 2.54 (m, 3H), 2.43-2.25 (m, 1H), 1.97 (s, 1H); ES-LCMS m/z 770.3 [M+H]+. I-25
Figure imgf000354_0001
Step 1: 3-Bromo-4-fluoro-benzenesulfonamide
Figure imgf000354_0002
[00910] To a solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (5 g, 18.28 mmol, 1 eq) in THF (100 mL) was added NH3·H2O (6.87 g, 54.84 mmol, 7.54 mL, 28.0%, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.34) indicated the starting material was consumed completely and one new spot formed. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 3- bromo-4-fluoro-benzenesulfonamide (4.6 g, 18.10 mmol, 99.0% yield, 100.0% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO- d6) δ ppm 8.11 (dd, J = 2.3, 6.7 Hz, 1H), 7.88-7.84 (m, 1H), 7.59 (t, J = 8.6 Hz, 1H), 7.54 (s, 2H). Step 2: tert-Butyl N-(3-bromo-4-fluoro-phenyl)sulfonylcarbamate
Figure imgf000354_0003
[00911] To a solution of 3-bromo-4-fluoro-benzenesulfonamide (4.6 g, 18.10 mmol, 100.0%, 1 eq) in DCM (40 mL) was added DMAP (2.21 g, 18.10 mmol, 1 eq), (Boc)2O (11.85 g, 54.31 mmol, 12.48 mL, 3 eq) and DIEA (7.02 g, 54.31 mmol, 9.46 mL, 3 eq). The mixture was stirred at 25 °C for 1 h. TLC (PE/EtOAc = 5/1, Rf = 0.15) indicated the starting material was consumed completely and one new spot formed. The mixture was diluted with water (80 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.60) to yield tert-butyl N-(3-bromo-4-fluoro-phenyl)sulfonylcarbamate (2.2 g, 4.97 mmol, 27.5% yield, 80.0% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 8.26 (dd, J = 2.3, 6.3 Hz, 1H), 8.04-8.01 (m, 1H), 7.65 (t, J = 8.7 Hz, 1H), 1.40 (s, 9H). Step 3: tert-Butyl N-[3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]sulfonylcarbamate
Figure imgf000355_0001
[00912] To a solution of 5-(trifluoromethyl)pyridin-2-amine (1.24 g, 7.62 mmol, 1 eq) in DMF (20 mL) was added NaH (914.76 mg, 22.87 mmol, 60.0%, 3 eq) at 0 °C. After being stirring for 0.5 h, tert-butyl N-(3-bromo-4-fluoro-phenyl)sulfonylcarbamate (2.7 g, 7.62 mmol, 1 eq) was added. The mixture was stirred at 25 °C for 1.5 h. TLC (PE/EtOAc = 3/1, Rf = 0.58) indicated the starting material was consumed completely and one new spot formed. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by preparative TLC (PE/EtOAc = 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.38) to yield tert-butyl N-[3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]sulfonylcarbamate (2.8 g, 4.51 mmol, 59.2% yield, 80.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.58 (s, 1H), 8.53 (d, J = 8.9 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 2.1, 8.9 Hz, 1H), 7.84 (dd, J = 2.2, 8.8 Hz, 1H), 7.65-7.55 (m, 1H), 6.96 (d, J = 8.7 Hz, 1H), 1.50 (s, 9H); ES-LCMS m/z 495.2, 497.2 [M+H]+. Step 4: 3-Bromo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000355_0002
[00913] To a solution of tert-butyl N-[3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]sulfonylcarbamate (200 mg, 322.39 µmol, 80.0%, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was quenched with sat. aq. NaHCO3 (30 mL) dropwise and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (150 mg, crude) as a white solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.46 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.98-7.94 (m, 1H), 7.76 (dd, J = 2.1, 8.5 Hz, 1H), 7.43 (s, 2H), 7.17 (d, J = 8.9 Hz, 1H); ES-LCMS m/z 396.0, 398.0 [M+H]+. Step 5: 3-(1-Methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000356_0001
[00914] To a solution of 3-bromo-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (1.3 g, 2.79 mmol, 85.0%, 1 eq) and tributyl-(1- methylimidazol-4-yl)stannane (1.73 g, 4.18 mmol, 90.0%, 1.5 eq) in DMF (10 mL) was added Pd(dppf)Cl2 (204.08 mg, 278.91 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 3 h. TLC (PE/EtOAc = 1/1, Rf = 0.48) indicated the starting material was consumed completely and two new spots formed. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.27) to yield 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (1 g, 2.26 mmol, 81.2% yield, 90.0% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (s, 1H), 8.63 (d, J = 9.0 Hz, 1H), 8.59 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.98-7.91 (m, 2H), 7.77 (s, 1H), 7.64 (dd, J = 2.2, 8.8 Hz, 1H), 7.24 (s, 2H), 7.05 (d, J = 8.6 Hz, 1H), 3.78 (s, 3H). Step 6: 3-(1-Methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonyl chloride
Figure imgf000357_0001
[00915] A mixture of 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (1 g, 2.26 mmol, 90.0%, 1 eq) in HSO3Cl (12 mL) was stirred at 80 °C for 2 h. The reaction mixture was added dropwise to ice-water (50 mL), adjusted pH = 7~8 with Na2CO3 and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonyl chloride (600 mg, 1.44 mmol, 63.6% yield, 100.0% purity) as a yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ ppm 9.22 (s, 1H), 9.11 (s, 1H), 8.37 (s, 1H), 7.87-7.84 (m, 2H), 7.81 (d, J = 2.0 Hz, 1H), 7.73-7.70 (m, 1H), 7.69-7.65 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H); ES-LCMS m/z 417.1, 419.1 [M+H]+. Step 7: N-[2-[2-[(2S)-2-(2,6-Dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]oxyethoxy]ethyl]-3-(1- methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000357_0002
[00916] To a stirred solution of 3-[(2S)-5-[2-(2-aminoethoxy)ethoxy]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (20.00 mg, 57.58 µmol, N/A purity, 1 eq) and 3-(1-methylimidazol-4-yl)- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonyl chloride (24.00 mg, 57.58 µmol, 100.0% purity, 1 eq) in THF (2 mL) was added DIEA (22.32 mg, 172.73 µmol, 30.09 µL, 3 eq). The reaction mixture was stirred under N2 atmosphere at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5µm; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 45%-75%, 10min) to yield N-[2-[2-[(2S)-2-(2,6-dioxo-3-piperidyl)-1- oxo-isoindolin-5-yl]oxyethoxy]ethyl]-3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (5.58 mg, 7.34 µmol, 12.8% yield, 95.7% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.26 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.58 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.98-7.91 (m, 2H), 7.83 (d, J = 1.0 Hz, 1H), 7.65-7.49 (m, 3H), 7.10-7.03 (m, 2H), 6.98 (dd, J = 2.2, 8.6 Hz, 1H), 5.06 (dd, J = 5.0, 13.3 Hz, 1H), 4.40-4.31 (m, 1H), 4.29- 4.16 (m, 1H), 4.12-4.04 (m, 2H), 3.76 (s, 3H), 3.69-3.64 (m, 2H), 3.49-3.46 (m, 2H), 2.97 (t, J = 5.6 Hz, 2H), 2.61-2.54 (m, 2H), 2.41-2.33 (m, 1H), 2.03-1.90 (m, 1H); ES-LCMS m/z 728.2 [M+H]+. I-31
Figure imgf000358_0001
Step 1: 3-Aminopiperidine-2,6-dione
Figure imgf000358_0002
[00917] To a solution of tert-butyl N-(2,6-dioxo-3-piperidyl)carbamate (1 g, 3.78 mmol, 1 eq, HCl) in DCM (6 mL) was added TFA (5.31 g, 46.58 mmol, 3.45 mL, 12.33 eq). The mixture was stirred under N2 atmosphere at 25 °C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.45) showed the starting material was consumed completely. The reaction mixture was concentrated to yield 3- aminopiperidine-2,6-dione (1.5 g, crude, N/A yield, N/A purity, HCl) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (s, 1H), 8.79 (s, 2H), 3.36 (s, 1H), 2.80-2.50 (m, 3H), 2.05 (q, J = 12.8 Hz, 1H). Step 2: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione
Figure imgf000359_0001
[00918] To a solution of 3-aminopiperidine-2,6-dione (1.5 g, 9.11 mmol, 1 eq, HCl), 5- fluoroisobenzofuran-1,3-dione (1.48 g, 8.90 mmol, 9.77e-1 eq) and NaOAc (1.09 g, 13.29 mmol, 1.46 eq) was added AcOH (10 mL). The mixture was stirred under N2 atmosphere at 110 °C for 12 h. TLC (PE/EtOAc = 1/1, Rf = 0.35) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (30 mL), stirred for 30 min, filtered and washed with water (10 mL x 2). The filtrate was concentrated under reduced pressure to yield 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3- dione (2.3 g, 7.99 mmol, 87.71% yield, 96% purity) as a white solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ ppm 11.15 (s, 1H), 8.01 (dd, J = 4.4, 8.2 Hz, 1H), 7.85 (dd, J = 2.3, 7.5 Hz, 1H), 7.75-7.70 (m, 1H), 5.16 (dd, J = 5.3, 13.0 Hz, 1H), 2.89 (ddd, J = 5.3, 13.9, 17.2 Hz, 1H), 2.64-2.53 (m, 2H), 2.10-2.04 (m, 1H); ES-LCMS m/z 277.1 [M+H]+. Step 3: 5-Fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure imgf000359_0002
[00919] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (2.30 g, 7.99 mmol, 96%, 1 eq) in DMF (15 mL) was added NaH (383.66 mg, 9.59 mmol, 60.0%, 1.2 eq) at 0 °C under N2 atmosphere. After being stirred for 30 min, CH3I (1.25 g, 8.79 mmol, 547.40 µL, 1.1 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.34) showed the starting material was remained and one new spot formed. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 5-fluoro-2-(1-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1.4 g, 4.44 mmol, 55.5% yield, 92.0% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.01 (dd, J = 4.6, 8.3 Hz, 1H), 7.95 (s, 1H), 7.85 (dd, J = 2.3, 7.5 Hz, 1H), 5.23 (dd, J = 5.4, 13.2 Hz, 1H), 3.02 (s, 3H), 2.51-2.50 (m, 2H), 2.50- 2.49 (m, 2H); ES-LCMS m/z 290.6 [M+H]+. Step 4: tert-Butyl 4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazine-1-carboxylate
Figure imgf000360_0001
[00920] To a solution of 5-fluoro-2-(1-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1.4 g, 4.44 mmol, 92.0%, 1 eq) in DMSO (8 mL) was added DIEA (1.15 g, 8.88 mmol, 1.55 mL, 2 eq) and tert-butyl piperazine-1-carboxylate (909.16 mg, 4.88 mmol, 1.1 eq). The mixture was stirred under N2 atmosphere at 110 °C for 16 h. TLC (PE/EtOAc = 1/1, Rf = 0.35) showed the starting material was consumed completely and one major new spot was detected. The reaction mixture was acidified by the addition of 1 N HCl (2 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with saturated NaHCO3 (20 mL x 3) and brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.35) to yield tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]piperazine-1-carboxylate (1.8 g, 3.75 mmol, 84.4% yield, 95.0% purity) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ ppm 7.65 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 2.4, 8.6 Hz, 1H), 5.10 (dd, J = 5.3, 13.1 Hz, 1H), 3.43 (s, 8H), 2.97 (s, 2H), 2.67-2.66 (m, 1H), 2.46-2.45 (m, 4H), 1.38 (s, 9H); ES-LCMS m/z 456.8 [M+H]+. Step 5: 2-(1-Methyl-2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione
Figure imgf000360_0002
[00921] To a solution of tert-butyl 4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin- 5-yl]piperazine-1-carboxylate (1.8 g, 3.75 mmol, 95.0%, 1 eq) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3.00 mL, 10.82 eq). The mixture was stirred under N2 atmosphere at 25°C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.40) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to yield 2-(1-methyl-2,6-dioxo-3- piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (870 mg, 2.44 mmol, 65.2% yield, 100.0% purity) as a yellow solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 7.26 (dd, J = 1.7, 8.6 Hz, 1H), 5.13 (dd, J = 5.3, 13.1 Hz, 1H), 3.01 (s, 3H), 3.00-2.86 (m, 6H), 2.75 (d, J = 17.4 Hz, 2H), 2.60- 2.51 (m, 4H), 2.08-1.99 (m, 1H); ES-LCMS m/z 356.8 [M+H]+. Step 6: tert-Butyl 4-(2-(4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate
Figure imgf000361_0001
[00922] To a soluiton of 2-(1-methyl-2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3- dione (820 mg, 2.30 mmol, 100.0%, 1 eq) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (523.00 mg, 2.30 mmol, 1 eq) in MeOH (10 mL) was added 2 drops of AcOH at 25 °C under N2 atmosphere. After being stirred for 30 min, NaBH3CN (722.96 mg, 11.50 mmol, 5 eq) was added. The mixture was stirred at 25 °C for 1 h. TLC (EtOAc, Rf = 0.20) showed the starting material was consumed completely. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 10/1 to 0/1, TLC: PE/EtOAc = 0/1, Rf = 0.20) to yield tert-butyl 4-[2-[4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (700 mg, 1.22 mmol, 53.1% yield, 99.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 5.15 (dd, J = 5.3, 13.1 Hz, 1H), 3.91 (d, J = 11.7 Hz, 3H), 3.03-2.55 (m, 12H), 1.69-1.42 (m, 6H), 1.38 (s, 9H), 1.28-1.13 (m, 5H), 1.07-0.95 (m, 2H); ES-LCMS m/z 568.1 [M+H]+. Step 7: 2-(1-Methyl-2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1- yl)isoindoline-1,3-dione
Figure imgf000362_0001
[00923] To a solution of tert-butyl 4-[2-[4-[2-(1-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (50 mg, 87.20 µmol, 99.0%, 1 eq) in DCM (1.5 mL) was added TFA (385.00 mg, 3.38 mmol, 250.00 µL, 38.72 eq). The mixture was stirred under N2 atmosphere at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to yield 2-(1-methyl-2,6-dioxo-3-piperidyl)-5-[4-[2-(4- piperidyl)ethyl]piperazin-1-yl]isoindoline-1,3-dione (50 mg, 81.67 µmol, 93.7% yield, 95.0% purity, TFA) as a yellow solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 4.22 (s, 1H), 3.26 (s, 8H), 3.17 (s, 3H), 2.84 (d, J = 9.5 Hz, 5H), 2.74 (s, 5H), 2.04 (s, 1H), 1.81 (d, J = 12.5 Hz, 2H), 1.69-1.62 (m, 2H), 1.60-1.53 (m, 1H), 1.32-1.25 (m, 2H); ES-LCMS m/z 445.7[M+H]+. Step 8: 5-(4-(2-(1-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)-2-(1-methyl- 2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure imgf000362_0002
[00924] To a solution of 3-(4-methylimidazol-1-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (38.91 mg, 101.59 µmol, 98.0%, 1 eq) in DCM (3 mL) and DIEA (367.14 mg, 2.84 mmol, 494.79 µL, 27.96 eq) was added HATU (77.26 mg, 203.18 µmol, 2 eq) at 25 °C under N2 atmosphere. After being stirred for 15 min, 2-(1-methyl-2,6- dioxo-3-piperidyl)-5-[4-[2-(4-piperidyl)ethyl]piperazin-1-yl]isoindoline-1,3-dione (50 mg, 101.59 µmol, 95.0%, 1 eq) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. The solvent was filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC: ([water (0.05%HCl)-ACN]; B%: 25%-45%, 10 min) and lyophilized to yield 2-(1-methyl-2,6-dioxo-3-piperidyl)-5-[4-[2-[1-[3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoyl]-4-piperidyl]ethyl]piperazin-1-yl]isoindoline-1,3- dione (21.8 mg, 26.43 µmol, 26.0% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 1H), 8.93 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.73-7.67 (m, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.48 (s, 1H), 7.38-7.32 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.6 Hz, 1H), 5.16 (dd, J = 5.1, 13.0 Hz, 1H), 4.51 (s, 2H), 4.20 (d, J = 13.0 Hz, 2H), 3.89 (s, 3H), 3.56 (s, 2H), 3.20-3.04 (m, 6H), 3.01 (s, 3H), 2.99-2.90 (m, 2H), 2.88-2.82 (m, 1H), 2.76 (d, J = 16.4 Hz, 1H), 2.62-2.54 (m, 2H), 2.05 (dd, J = 5.3, 10.9 Hz, 1H), 1.68 (d, J = 9.3 Hz, 2H), 1.61 (s, 1H), 1.45-1.19 (m, 2H), 1.18-0.84 (m, 3H); ES-LCMS m/z 413.5[M+H]+. I-32
Figure imgf000363_0001
Step 1: Methyl 5-hydroxy-2-methyl-benzoate
Figure imgf000364_0001
[00925] To a solution of 5-hydroxy-2-methyl-benzoic acid (5 g, 32.86 mmol, 1 eq) in MeOH (100 mL) was added SOCl2 (8.20 g, 68.92 mmol, 5 mL, 2.10 eq). The mixture was stirred at 85 °C for 5 h. TLC (PE/EtOAc = 3/1, Rf = 0.10) showed the starting material was not remained and one new spot was detected. The mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yield methyl 5-hydroxy-2-methyl-benzoate (5.4 g, 32.50 mmol, 98.9% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 7.42 (d, J = 2.7 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.91 (dd, J = 2.6, 8.2 Hz, 1H), 5.18 (s, 1H), 3.89 (s, 3H), 2.53-2.48 (m, 1H); LCMS m/z 167.1 [M+H]+. Step 2: Methyl 5-[tert-butyl(dimethyl)silyl]oxy-2-methyl-benzoate
Figure imgf000364_0002
[00926] A mixture of methyl 5-hydroxy-2-methyl-benzoate (5.4 g, 32.50 mmol, 100% purity, 1 eq), TBSCl (5.88 g, 39.00 mmol, 4.78 mL, 1.2 eq) and imidazole (4.42 g, 64.99 mmol, 2 eq) in DMF (50 mL) was stirred at 20 °C for 12 h. TLC (PE/EtOAc = 10/1, Rf = 0.70) showed the starting material was consumed completely. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (150 mL x 3). The organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from pure PE to PE/EtOAc = 20/1, TLC: PE/EtOAc = 10/1, Rf = 0.70) to yield methyl 5-[tert-butyl(dimethyl)silyl]oxy-2-methyl-benzoate (9 g, 30.49 mmol, 93.8% yield, 95.0% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 7.38 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.89 (dd, J = 2.4, 8.3 Hz, 1H), 3.89 (s, 3H), 2.52 (s, 3H), 0.99 (s, 9H), 0.20 (s, 6H). Step 3: Methyl 2-(bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-benzoate
Figure imgf000365_0001
[00927] A mixture of methyl 5-[tert-butyl(dimethyl)silyl]oxy-2-methyl-benzoate (2 g, 6.78 mmol, 95% purity, 1 eq), NBS (1.21 g, 6.78 mmol, 1 eq) and AIBN (100 mg, 608.98 umol, 8.99e- 2 eq) in CCl4 (50 mL) was stirred under N2 atmosphere at 70 °C for 12 h. TLC (PE/EtOAc = 10/1, Rf = 0.66) showed the starting material was consumed completely. The mixture was concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 20/1, TLC: PE/EtOAc = 10/1, Rf = 0.66) to yield methyl 2- (bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-benzoate (2.4 g, 6.35 mmol, 93.7% yield, 95.0% purity) as colorless oil.1H NMR (500 MHz, CDCl3) δ ppm 7.42 (d, J = 2.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 2.6, 8.4 Hz, 1H), 4.93 (s, 2H), 3.94 (s, 3H), 0.99 (s, 9H), 0.23 (s, 6H). Step 4: 3-[6-[tert-Butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-1-methyl-piperidine-2,6- dione
Figure imgf000365_0002
[00928] A mixture of methyl 2-(bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-benzoate (1.8 g, 4.76 mmol, 95% purity, 1 eq), 3-amino-1-methyl-piperidine-2,6-dione (1.22 g, 4.76 mmol, N/A purity, 1 eq, TFA) and DIEA (3.08 g, 23.79 mmol, 4.14 mL, 5 eq) in MeCN (40 mL) was stirred at 80 °C for 12 h. TLC (PE/EtOAc = 10/1, Rf = 0.03) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 2/3, Rf = 0.40) to yield 3-[6-[tert-butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-1-methyl- piperidine-2,6-dione (600 mg, 1.49 mmol, 31.3% yield, 96.3% purity) as a green solid.1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.29 (m, 2H), 7.06 (dd, J = 2.3, 8.2 Hz, 1H), 5.19 (dd, J = 5.1, 13.7 Hz, 1H), 4.45-4.24 (m, 2H), 3.20 (s, 3H), 3.06-2.97 (m, 1H), 2.93-2.79 (m, 1H), 2.32 (dq, J = 4.7, 13.2 Hz, 1H), 2.24-2.16 (m, 1H), 1.00 (s, 9H), 0.22 (s, 6H); ES-LCMS m/z 389.2 [M+H]+. Step 5: 3-(6-Hydroxy-1-oxo-isoindolin-2-yl)-1-methyl-piperidine-2,6-dione
Figure imgf000366_0001
[00929] To a solution of 3-[6-[tert-butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-1-methyl- piperidine-2,6-dione (600 mg, 1.49 mmol, 96.3% purity, 1 eq) in MeCN (20 mL) was added HCl/H2O (2 M, 10 mL, 13.45 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 0/1, TLC: EtOAc, Rf = 0.20) to yield 3-(6-hydroxy- 1-oxo-isoindolin-2-yl)-1-methyl-piperidine-2,6-dione (250 mg, 911.51 μmol, 61.3% yield, 100.0% purity) as a brown solid.1H NMR (500 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.07-7.01 (m, 2H), 5.14 (dd, J = 5.1, 13.4 Hz, 1H), 4.37-4.15 (m, 2H), 3.00 (s, 3H), 2.99-2.91 (m, 1H), 2.75 (d, J = 16.8 Hz, 1H), 2.42-2.36 (m, 1H), 2.06-1.96 (m, 1H); ES-LCMS m/z 275.2 [M+H]+. Step 6: tert-Butyl N-[2-[2-[2-(1-methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5- yl]oxyethoxy]ethyl]carbamate
Figure imgf000366_0002
[00930] A mixture of 3-(6-hydroxy-1-oxo-isoindolin-2-yl)-1-methyl-piperidine-2,6-dione (80 mg, 291.68 μmol, 100% purity, 1 eq), tert-butyl N-[2-(2-bromoethoxy)ethyl]carbamate (100.00 mg, 372.93 μmol, 1.28 eq) and Na2CO3 (150.00 mg, 1.42 mmol, 4.85 eq) in DMF (4 mL) was stirred at 80 °C for 36 h. The reaction mixture was quenched with aqueous citric acid (1%, 50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 0/1, TLC: EtOAc, Rf = 0.30) to yield tert-butyl N-[2- [2-[2-(1-methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]oxyethoxy]ethyl]carbamate (100 mg, 197.40 μmol, 67.7% yield, 91.1% purity) as a colorless gum.1H NMR (500 MHz, CD3OD) δ ppm 7.50 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 2.4, 8.4 Hz, 1H), 5.18 (dd, J = 5.0, 13.4 Hz, 1H), 4.50-4.37 (m, 2H), 4.27-4.18 (m, 2H), 3.90-3.83 (m, 2H), 3.61-3.59 (m, 2H), 3.27 (t, J = 5.6 Hz, 2H), 3.16 (s, 3H), 2.99-2.90 (m, 2H), 2.49 (dq, J = 5.3, 12.9 Hz, 1H), 2.21-2.13 (m, 1H), 1.44 (s, 9H); ES-LCMS m/z 462.3 [M+H]+. Step 7: 3-[6-[2-(2-Aminoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-1-methyl-piperidine-2,6- dione
Figure imgf000367_0001
[00931] A mixture of tert-butyl N-[2-[2-[2-(1-methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin- 5-yl]oxyethoxy]ethyl]carbamate (50 mg, 98.70 μmol, 91.1% purity, 1 eq) and HCl/1,4-dioxane (4 M, 3 mL, 121.58 eq) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to yield 3-[6-[2-(2-aminoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-1-methyl- piperidine-2,6-dione (40 mg, 91.69 μmol, 92.9% yield, 91.2% purity, HCl) as a colorless gum, which was used in the next step without further purification. ES-LCMS m/z 362.2 [M+H]+. Step 8: N-[2-[2-[2-(1-Methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]oxyethoxy]ethyl]- 3-(1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000367_0002
[00932] A mixture of 3-[6-[2-(2-aminoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-1-methyl- piperidine-2,6-dione (40 mg, 91.69 μmol, 91.2% purity, 1 eq, HCl), 3-(1-methylimidazol-4-yl)-4- [[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (40 mg, 104.44 μmol, 98% purity, 1.14 eq), HATU (50.90 mg, 133.87 μmol, 1.46 eq) and DIEA (50.90 mg, 393.85 μmol, 68.60 μL, 4.30 eq) in DMF (1 mL) was stirred at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (0.05%HCl)-ACN]; B%: 30%-45%, 10 min) and lyophilized. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*30mm*4um; mobile phase: [water (0.05%HCl)-ACN]; B%: 28%-58%, 9 min) and lyophilized to yield N-[2-[2-[2-(1-methyl-2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5- yl]oxyethoxy]ethyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (4.69 mg, 6.53 μmol, 7.1% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CD3OD) δ ppm 9.01 (s, 1H), 7.77 (dd, J = 1.7, 10.5 Hz, 2H), 7.70 (dd, J = 2.2, 8.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.58-7.55 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 2.4, 8.3 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 5.17 (dd, J = 5.0, 13.4 Hz, 1H), 4.56 (s, 2H), 4.48-4.34 (m, 2H), 4.22-4.19 (m, 2H), 4.02 (s, 3H), 3.91- 3.87 (m, 2H), 3.76-3.72 (m, 2H), 3.60-3.57 (m, 2H), 3.15 (s, 3H), 2.98-2.91 (m, 2H), 2.54-2.40 (m, 1H), 2.21-2.13 (m, 1H); ES-LCMS m/z 719.1 [M+H]+. Step 9: tert-Butyl N-(1-methyl-2,6-dioxo-3-piperidyl)carbamate
Figure imgf000368_0001
[00933] To a solution of tert-butyl N-(2,6-dioxo-3-piperidyl)carbamate (3 g, 13.14 mmol, 1 eq) in DMF (50 mL) was added NaH (630.84 mg, 15.77 mmol, 1.2 eq) at 0 °C under N2 atmosphere. After being stirred for 30 min, CH3I (2.05 g, 14.46 mmol, 900.07 uL, 1.1 eq) was added at 0 °C. The mixture was stirred under N2 atmosphere at 25 °C for 1.5 h. The mixture was quenched by sat.aq NaHCO3, diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl N-(1-methyl-2,6-dioxo-3-piperidyl)carbamate (3.5 g, 12.24 mmol, 93.1% yield, 84.7% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (d, J = 8.6 Hz, 1H), 4.36-4.24 (m, 1H), 2.97-2.97 (m, 1H), 2.97 (s, 2H), 2.85-2.73 (m, 2H), 1.98- 1.85 (m, 2H), 1.40 (s, 9H); LCMS m/z 243.2 [M+H]+. Step 10: 3-Amino-1-methyl-piperidine-2,6-dione
Figure imgf000368_0002
[00934] To a solution of tert-butyl N-(1-methyl-2,6-dioxo-3-piperidyl)carbamate (1.6 g, 5.59 mmol, 84.7% purity, 1 eq) in DCM (10 mL) was added TFA (7.70 g, 67.53 mmol, 5 mL, 12.07 eq). The mixture was stirred at 20 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.04) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to yield 3-amino-1-methyl-piperidine-2,6-dione (1.43 g, 5.58 mmol, 100.0% yield, N/A purity, TFA) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ ppm 4.25 (dd, J = 5.3, 13.6 Hz, 1H), 3.13 (s, 3H), 2.88-2.85 (m, 1H), 2.83-2.75 (m, 1H), 2.29 (dtd, J = 2.7, 5.2, 12.6 Hz, 1H), 2.05 (dq, J = 5.9, 12.9 Hz, 1H). I-37
Figure imgf000369_0001
Step 1: N-(2-(2,2-Dimethoxyethoxy)ethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((5- (trifluoromethyl)pyridin-2-yl)amino)benzamide
Figure imgf000369_0002
[00935] To a stirred solution of 2-(2,2-dimethoxyethoxy)ethanamine (71.67 mg, 480.42 μmol, 1.2 eq) in DCM (10 mL) was added 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzoic acid (150 mg, 400.35 μmol, 96.7% purity, 1 eq), HATU (182.67 mg, 480.42 μmol, 1.2 eq), DIEA (155.22 mg, 1.20 mmol, 209.20 μL, 3 eq), the mixture was stirred at 20 °C for 2 h. The mixture was concentrated and then water (20 mL) was added, extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by preparative TLC (PE/EtOAc = 0/1, Rf = 0.2) to yield N-[2-(2,2-dimethoxyethoxy)ethyl]-3-(1-methylimidazol-4-yl)- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzamide (100 mg, 101.32 μmol, 25.3% yield, 50.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 8.46 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.88 (br s, 1H), 7.70 (d, J = 6.7 Hz, 2H), 7.47-7.37 (m, 1H), 6.98 (d, J = 7.8 Hz, 1H), 4.57-4.54 (m, 1H), 3.83 (s, 3H), 3.74 (d, J = 5.1 Hz, 2H), 3.68 (br s, 2H), 3.60-3.56 (m, 2H), 3.40 (s, 6H); ES-LCMS m/z 494.3 [M+H]+. Step 2: 3-(1-Methyl-1H-imidazol-4-yl)-N-(2-(2-oxoethoxy)ethyl)-4-((5- (trifluoromethyl)pyridin-2-yl)amino)benzamide
Figure imgf000370_0001
[00936] To a stirred mixture of N-[2-(2,2-dimethoxyethoxy)ethyl]-3-(1-methylimidazol-4-yl)- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzamide (100.00 mg, 101.32 μmol, 50% purity, 1 eq) in THF (4 mL), H2O (1 mL) was added TsOH (8.72 mg, 50.66 μmol, 0.5 eq). The mixture was stirred at 70 °C for 2 h. The mixture was added water (10 mL), extracted with EtOAc (20 mL x 3). The desired fraction was washed with 2 N NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated to yield 3-(1-methylimidazol-4-yl)-N-[2-(2-oxoethoxy)ethyl]-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzamide (40 mg, 89.4 μmol, 88.2% yield, N/A purity) as yellow oil, which was used in the next step without further purification. ES-LCMS m/z 448.3 [M+H]+. Step 3: (2S,4R)-1-((S)-3,3-Dimethyl-2-((2-(2-(3-(1-methyl-1H-imidazol-4-yl)-4-((5- (trifluoromethyl)pyridin-2-yl)amino)benzamido)ethoxy)ethyl)amino)butanoyl)-4-hydroxy- N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
Figure imgf000371_0001
[00937] To a stirred solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N- [(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (39.75 mg, 89.40 μmol, N/A purity, 1 eq) in MeOH (5 mL) was added 3-(1-methylimidazol-4-yl)-N-[2-(2- oxoethoxy)ethyl]-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzamide (40 mg, 89.40 μmol, N/A purity, 1 eq) the mixture was stirred for 0.5 h, NaBH3CN (56.18 mg, 894.04 μmol, 10 eq) was added to the mixture. The mixture was stirred at 20 °C for 16 h. The mixture was concentrated and water (10 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by preparative TLC (DCM/MeOH = 5/1, Rf = 0.3) to yield (2S,4R)-1-[(2S)-3,3-dimethyl-2-[2-[2-[[3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzoyl]amino]ethoxy]ethylamino]butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4- methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (5.21 mg, 5.95 μmol, 6.7% yield, 100.0% purity) as white solid.1H NMR (400 MHz, CD3OD) δ ppm 8.85 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.48 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 7.88-7.83 (m, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.29 (m, 2H), 7.01 (d, J = 9.3 Hz, 1H), 4.77 (d, J = 6.8 Hz, 1H), 4.69 (t, J = 8.4 Hz, 1H), 4.45 (br s, 1H), 3.83 (s, 3H), 3.80 (s, 1H), 3.71-3.60 (m, 5H), 3.57 (br s, 3H), 3.48 (br s, 1H), 2.76 (br s, 2H), 2.45 (s, 3H), 2.22 (d, J = 7.6 Hz, 1H), 1.95 (s, 1H), 1.27 (d, J = 7.1 Hz, 3H), 1.02 (s, 9H); ES-LCMS m/z 876.2 [M+H]+. Example 2A: Synthesis of Exemplary TEAD Binding Moieties (TBMs) [00938] Certain exemplary compounds are prepared as described below. T-C-3
Figure imgf000372_0001
Step 1: 2-Bromo-4-isopropenyl-pyridine
Figure imgf000372_0002
[00939] A mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (660 mg, 3.93 mmol, 1 eq), 2-bromo-4-iodo-pyridine (2 g, 7.04 mmol, 1.8 eq), Cs2CO3 (3.82 g, 11.73 mmol, 3 eq) and Pd(dppf)Cl2 (143.09 mg, 195.56 μmol, 0.05 eq) in dioxane (45 mL) and H2O (15 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 12 h. TLC (PE/EtOAc = 5/1, Rf = 0.50) indicated 10% of starting material was remained and one major new spot with lower polarity was detected. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 10/1, TLC: PE/EtOAc = 5/1, Rf = 0.50) to yield 2-bromo-4-isopropenyl-pyridine (650 mg, 3.15 mmol, 80.6% yield, 96.0% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 1.0 Hz, 1H), 7.29 (dd, J = 1.5, 5.1 Hz, 1H), 5.65-5.50 (m, 1H), 5.35-5.25 (m, 1H), 2.13 (s, 3H); ES-LCMS m/z 198.1 [M+H]+. Step 2: 3-(4-Isopropenyl-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000373_0001
[00940] A mixture of 2-bromo-4-isopropenyl-pyridine (60 mg, 290.82 μmol, 96% purity, 1 eq), tert-butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (211.16 mg, 290.46 μmol, 93.2% purity, 9.99e-1 eq), Pd(dppf)Cl2 (19.20 mg, 26.24 μmol, 9.02e-2 eq), Cs2CO3 (288.00 mg, 883.93 μmol, 3.04 eq) in 1,4-dioxane (6 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 4/1, TLC: PE/EtOAc = 5/1, Rf = 0.20) to yield 3-(4-isopropenyl-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4- [[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (140 mg, 233.90 μmol, 80.4% yield, 95.0% purity) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 12.24 (s, 1H), 8.82 (d, J = 8.9 Hz, 1H), 8.67 (d, J = 5.3 Hz, 1H), 8.56 (s, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 2.1, 8.9 Hz, 1H), 7.81-7.79 (m, 1H), 7.75 (dd, J = 2.4, 8.8 Hz, 1H), 7.40 (dd, J = 1.7, 5.3 Hz, 1H), 7.26- 7.23 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.89-6.85 (m, 2H), 5.68-5.60 (m, 1H), 5.42-5.34 (m, 1H), 4.14 (s, 2H), 3.83-3.77 (m, 3H), 2.65-2.60 (m, 3H), 2.22 (s, 3H); ES-LCMS m/z 569.2 [M+H]+. Step 3: 3-(4-Isopropyl-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000374_0001
[00941] To a solution of 3-(4-isopropenyl-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (140 mg, 233.90 μmol, 95% purity, 1 eq) in MeOH (50 mL) was added Pd/C (140 mg, 132.08 μmol, 10% purity, 0.5 eq). The mixture was degassed and purged with H2 for 3 times, and then the mixture was stirred at 20 °C for 12 h under H2 atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was added DCM (10 mL) and TFA (1 mL) and stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure and added NH3·H2O until pH = 8 to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 60%-90%, 10 min), followed by lyophilization to yield 3-(4-isopropyl-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (20.41 mg, 45.31 μmol, 19.4% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 12.28 (br s, 1H), 8.74 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.52 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 2.1, 8.9 Hz, 1H), 7.73 (dd, J = 2.4, 8.7 Hz, 1H), 7.67 (s, 1H), 7.27-7.24 (m, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.35 (d, J = 5.5 Hz, 1H), 3.03 (spt, J = 6.9 Hz, 1H), 2.72 (d, J = 5.5 Hz, 3H), 1.34 (d, J = 6.9 Hz, 6H); ES-LCMS m/z 451.1 [M+H]+. T-C-4
Figure imgf000375_0001
Step 1: 2-Bromo-5-isopropenyl-pyridine
Figure imgf000375_0002
[00942] A mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.98 mmol, 1 eq), 2-bromo-5-iodo-pyridine (1.52 g, 5.35 mmol, 1.80 eq), Cs2CO3 (2.90 g, 8.92 mmol, 3 eq)and Pd(dppf)Cl2 (215.86 mg, 295.01 μmol, 9.91e-2 eq) in 1,4-dioxane (60 mL) and H2O (20 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 12 h. TLC (PE/EtOAc = 5/1, Rf = 0.65) indicated starting material was consumed completely. The mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 10/1, TLC: PE/EtOAc = 5/1, Rf = 0.65) to yield 2-bromo-5-isopropenyl-pyridine (390 mg, 1.87 mmol, 62.9% yield, 95.0% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 2.6, 8.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 5.45-5.40 (m, 1H), 5.23-5.20 (m, 1H), 2.17-2.13 (m, 3H). Step 2: 3-(5-Isopropenyl-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000376_0001
[00943] A mixture of 2-bromo-5-isopropenyl-pyridine (40 mg, 191.86 μmol, 95% purity, 1 eq), tert-butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (140 mg, 185.97 μmol, 90% purity, 1 eq), Cs2CO3 (190.00 mg, 583.14 μmol, 3.04 eq) and Pd(dppf)Cl2 (14 mg, 19.13 μmol, 0.1 eq) in dioxane (3 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.40) to yield 3-(5-isopropenyl-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4- [[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (80 mg, 137.88 μmol, 71.9% yield, 98.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 12.53 (br s, 1H), 8.83 (dd, J = 3.2, 5.5 Hz, 2H), 8.56 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 2.4, 8.5 Hz, 1H), 7.85-7.80 (m, 2H), 7.76 (dd, J = 2.3, 8.7 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 5.58-5.54 (m, 1H), 5.33-5.27 (m, 1H), 4.14 (s, 2H), 3.80 (s, 3H), 2.63 (s, 3H), 2.25 (s, 3H); ES-LCMS m/z 569.2 [M+H]+. Step 3: 3-(5-Isopropyl-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000377_0001
[00944] To a solution of 3-(5-isopropenyl-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (70 mg, 120.65 μmol, 98% purity, 1 eq) in MeOH (35 mL) was added Pd/C (70 mg, 10% purity). The mixture was degassed and purged with H2 for 3 times and the mixture was stirred under H2 atmosphere at 20 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and TFA (1 mL) and stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure and added NH3·H2O until pH = 8 to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150 * 25 mm * 5 um; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 65%-95%, 10 min), followed by lyophilization to yield 3-(5- isopropyl-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (15.68 mg, 34.81 μmol, 28.9% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 12.45 (br s, 1H), 8.75 (d, J = 8.9 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 2.3, 8.9 Hz, 1H), 7.83-7.80 (m, 1H), 7.80-7.76 (m, 1H), 7.74 (dd, J = 2.4, 8.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.32 (d, J = 5.0 Hz, 1H), 3.05 (td, J = 7.0, 13.9 Hz, 1H), 2.71 (d, J = 5.5 Hz, 3H), 1.36 (d, J = 6.9 Hz, 6H); ES-LCMS m/z 451.2 [M+H]+. T-C-5
Figure imgf000377_0002
Step 1: tert-Butyl N-[2-bromo-4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]phenyl]-N-[5- (trifluoromethyl)-2-pyridyl]carbamate
Figure imgf000378_0002
[00945] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (2 g, 3.69 mmol, 97.8%, 1 eq) in THF (35 mL) was added DMAP (450.57 mg, 3.69 mmol, 1 eq) and (Boc)2O (2.41 g, 11.06 mmol, 2.54 mL, 3 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.60) to yield tert-butyl N-[2-bromo-4-[(4- methoxyphenyl)methyl-methyl-sulfamoyl]phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (2.42 g, 3.68 mmol, 99.8% yield, 95.9% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.46 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 2.1, 8.9 Hz, 1H), 7.83 (dd, J = 2.0, 8.3 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.17 (s, 2H), 3.82 (s, 3H), 2.67 (s, 3H), 1.45 (s, 9H); ES-LCMS m/z 630.0, 632.0 [M+H]+. Step 2: tert-Butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate
Figure imgf000378_0001
[00946] To a solution of tert-butyl N-[2-bromo-4-[(4-methoxyphenyl)methyl-methyl- sulfamoyl]phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (2.1 g, 3.19 mmol, 95.9%, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.06 g, 15.97 mmol, 5 eq) in 1,4-dioxane (20 mL) was added K2CO3 (882.93 mg, 6.39 mmol, 2 eq) and Pd(PPh3)4 (369.12 mg, 319.43 µmol, 0.1 eq). The mixture was degassed and purged with N2 for three times and stirred under N2 atmosphere at 90 °C for 12 h. The reaction mixture was diluted with EtOAc (50 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was added to water (50 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.65) to yield tert-butyl N-[4-[(4- methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (1.5 g, 2.06 mmol, 64.6% yield, 93.2% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.42 (s, 1H), 8.34-8.25 (m, 2H), 7.98- 7.88 (m, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.14 (s, 2H), 3.81 (s, 3H), 2.64 (s, 3H), 1.40 (s, 9H), 1.14 (s, 12H); ES-LCMS m/z 678.2 [M+H]+. Step 3: 3-(5-Cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000379_0001
[00947] To a solution of tert-butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2- pyridyl]carbamate (150 mg, 206.34 µmol, 93.2%, 1 eq) and 6-bromopyridine-3-carbonitrile (43.72 mg, 226.97 µmol, 95%, 1.1 eq) in 1,4-dioxane (6 mL) and water (2 mL) was added Cs2CO3 (134.46 mg, 412.67 µmol, 2 eq), Pd(dppf)Cl2 (15.10 mg, 20.63 µmol, 0.1 eq) and 6-bromopyridine-3- carbonitrile (43.72 mg, 226.97 µmol, 95%, 1.1 eq). The mixture was bubbled with N2 for 3 min and stirred under microwave at 100 °C for 30 min. The reaction mixture was added to saturated NaHCO3 solution (30 mL), and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.45) to yield 3-(5-cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (40 mg, 66.19 µmol, 32.1% yield, 91.6% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 11.90 (s, 1H), 9.02 (s, 1H), 8.83 (d, J = 9.0 Hz, 1H), 8.58 (s, 1H), 8.18-8.14 (m, 2H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 1.8, 8.9 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.3 Hz, 2H), 4.15 (s, 2H), 3.81 (s, 3H), 2.65 (s, 3H); ES-LCMS m/z 554.4 [M+H]+. Step 4: 3-(5-Cyano-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000380_0001
[00948] To a stirred solution of 3-(5-cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N- methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (40 mg, 66.19 µmol, 91.6%, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 204.05 eq). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was added to saturated NaHCO3 solution (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 50%-80%, 10min). The desired fraction was lyophilized to yield 3-(5-cyano-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (15.13 mg, 34.91 µmol, 52.7% yield, 100.0% purity) as a light yellow solid.1H NMR (500 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 9.18 (d, J = 1.4 Hz, 1H), 8.44 (s, 1H), 8.41 (dd, J = 2.3, 8.4 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 2.4, 8.9 Hz, 1H), 7.85 (dd, J = 2.3, 8.7 Hz, 1H), 7.44 (d, J = 5.3 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 2.45 (d, J = 4.7 Hz, 3H); ES-LCMS m/z 434.2 [M+H]+. T-C-7
Figure imgf000381_0001
Step 1: 3-(4-Cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000381_0002
[00949] To a solution of tert-butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2- pyridyl]carbamate (300 mg, 412.67 µmol, 93.2%, 1 eq) in 1,4-dioxane (6 mL) and water (2 mL) was added Cs2CO3 (268.91 mg, 825.34 µmol, 2 eq), Pd(dppf)Cl2 (30.20 mg, 41.27 µmol, 0.1 eq) and 2-bromopyridine-4-carbonitrile (90.63 mg, 495.20 µmol, 1.2 eq). The mixture was bubbled with N2 for 3 min and stirred under microwave at 100 °C for 30 min. The reaction mixture was added to saturated NaHCO3 solution (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.35) to yield 3-(4-cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]- N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (200 mg, 325.17 µmol, 78.8% yield, 90.0% purity) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ ppm 11.02 (s, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.56-8.48 (m, 2H), 8.43 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 2.3, 8.9 Hz, 1H), 7.93-7.89 (m, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 4.12 (s, 2H), 3.73 (s, 3H), 2.57 (s, 3H); ES-LCMS m/z 554.4 [M+H]+. Step 2: 3-(4-Cyano-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000382_0001
[00950] To a stirred solution of 3-(4-cyano-2-pyridyl)-N-[(4-methoxyphenyl)methyl]-N- methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (200 mg, 325.17 µmol, 90%, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 41.54 eq). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was added to saturated NaHCO3 solution (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 39%-69%, 10 min). The desired fraction was lyophilized to yield 3-(4-cyano-2-pyridyl)-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (18.1 mg, 41.76 µmol, 12.8% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 11.84 (s, 1H), 8.91 (d, J = 4.9 Hz, 1H), 8.76 (d, J = 8.9 Hz, 1H), 8.56 (s, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 7.92 (dd, J = 2.1, 9.0 Hz, 1H), 7.78 (dd, J = 2.3, 8.7 Hz, 1H), 7.59 (dd, J = 1.2, 5.0 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.53 (q, J = 5.3 Hz, 1H), 2.74 (d, J = 5.3 Hz, 3H); ES-LCMS m/z 434.1 [M+H]+. T-C-12
Figure imgf000382_0002
Step 1: 2-Cyclohexyl-N-methyl-7-(1-methyl-1H-imidazol-4-yl)-1H-benzo[d]imidazole-5- sulfonamide
Figure imgf000383_0001
[00951] To a solution of 3,4-diamino-N-methyl-5-(1-methylimidazol-4-yl)benzenesulfonamide (80 mg, 255.92 µmol, 90% purity, 1 eq) in DMF (1 mL) was added sodium hydrogen sulphite (7.99 mg, 76.78 µmol, 0.3 eq), cyclohexanecarbaldehyde (30.14 mg, 268.72 µmol, 32.34 µL, 1.05 eq). The mixture was stirred under N2 atmosphere at 140 °C for 2 h. The crude material was purified preparative HPLC ([water (10mM NH4HCO3)-ACN]; B%: 26%-56%), followed by lyophilization to yield 2-cyclohexyl-N-methyl-7-(1-methylimidazol-4-yl)-1H-benzimidazole-5- sulfonamide (27.23 mg, 72.25 µmol, 28.2% yield, 99.1% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 8.21 (s, 2H), 7.70 (s, 2H), 6.98 (s, 1H), 3.78 (s, 3H), 2.56-2.51 (m, 1H), 2.45 (s, 3H), 2.14-2.06 (m, 2H), 1.86 (d, J = 3.5, 13.0 Hz, 2H), 1.78-1.65 (m, 3H), 1.50-1.41 (m, 2H), 1.40-1.32 (m, 1H); ES-LCMS m/z 374.2 [M+H]+. T-C-13 and T-C-14 (isomers of T-C-173)
Figure imgf000383_0003
Step 1: 5-(Trifluoromethyl)indan-1-ol
Figure imgf000383_0002
[00952] To a solution of 5-(trifluoromethyl)indan-1-one (500.00 mg, 2.50 mmol, 1 eq) in THF (6 mL) was added NaBH4 (141.75 mg, 3.75 mmol, 1.5 eq). After being stirring for 0.5 h, MeOH (2 mL) was added slowly. The mixture was stirred at 25 °C for 1 h. TLC (PE/EtOAc = 10/1, Rf = 0.48) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 5- (trifluoromethyl)indan-1-ol (500 mg, 2.37 mmol, 95.0% yield, 96.0% purity) as yellow oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 7.52 (s, 3H), 5.29 (t, J = 6.4 Hz, 1H), 3.19-3.04 (m, 1H), 2.92-2.84 (m, 1H), 2.61-2.53 (m, 1H), 2.05-1.95 (m, 1H); ES-LCMS: no desired ms was found. Step 2: 1-Bromo-5-(trifluoromethyl)indane
Figure imgf000384_0001
[00953] To a solution of 5-(trifluoromethyl)indan-1-ol (410 mg, 1.95 mmol, 96%, 1 eq) in THF (10 mL) was added PBr3 (1.58 g, 5.84 mmol, 782.92 µL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC (Pure PE, Rf = 0.10) indicated the starting material was consumed completely and two new spots formed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 1-bromo-5-(trifluoromethyl)indane (500 mg, 1.32 mmol, 67.8% yield, 70.0% purity) as yellow oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J = 7.1 Hz, 3H), 5.55 (d, J = 4.9 Hz, 1H), 3.27-3.22 (m, 1H), 2.96-2.93 (m, 1H), 2.72-2.62 (m, 1H), 2.57 (d, J = 6.8 Hz, 1H). Step 3: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[(1R)-5-(trifluoromethyl)indan-1- yl]amino]benzenesulfonamide
Figure imgf000384_0002
[00954] To a solution of 4-amino-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (263.74 mg, 792.25 µmol, 80%, 1.2 eq) in DMF (3 mL) was added DIEA (255.97 mg, 1.98 mmol, 344.98 µL, 3 eq), followed by the addition of 1-bromo-5-(trifluoromethyl)indane (250.00 mg, 660.20 µmol, 70%, 1 eq). The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10 mM NH4HCO3)-ACN]; B%: 50%-65%, 14 min), followed by lyophilization to yield product which was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 µm); mobile phase: [0.1% NH3·H2O MeOH]; B%: 35%- 35%, min) to yield peak 1 (Rt = 1.712 min) and peak 2 (Rt = 2.144 min). Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (20 mL) and H2O (40 mL) and lyophilized to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[(1R)-5- (trifluoromethyl)indan-1-yl]amino]benzenesulfonamide (9.05 mg, 20.09 µmol, 3.0% yield, 100.0% purity, SFC: Rt = 1.712, ee = 100%, [α]28.2D = -44.000 (MeOH, c = 0.05 g/100 mL)) as a green solid.1H NMR (500 MHz, CDCl3) δ ppm 9.12 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 2.1, 8.7 Hz, 1H), 7.54 (s, 1H), 7.52-7.46 (m, 2H), 7.39 (s, 1H), 7.28 (d, J = 1.1 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 5.16 (q, J = 7.0 Hz, 1H), 4.28-4.13 (m, 1H), 3.74 (s, 3H), 3.16-3.07 (m, 1H), 3.06-2.95 (m, 1H), 2.81-2.74 (m, 1H), 2.67 (d, J = 5.6 Hz, 3H), 2.11-2.02 (m, 1H); ES- LCMS m/z 451.2 [M+H]+. T-C-15
Figure imgf000385_0001
Step 1: 4-[(5-Bromo-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide
Figure imgf000386_0001
[00955] To a stirred solution of 5-bromopyridin-2-amine (319.86 mg, 1.85 mmol, 3 eq) in DMF (10 mL) was added NaH (221.83 mg, 5.55 mmol, 60%, 9 eq). The reaction mixture was stirred at 0 °C for 0.5 h. 4-Fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide (300 mg, 616.26 µmol, 80.0% purity, 1 eq) was added. The mixture was stirred under N2 atmosphere at 120 °C for 11.5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.28) to yield 4-[(5-bromo-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (180 mg, 321.87 µmol, 52.2% yield, 97.0% purity) as yellow oil.1H NMR (500 MHz, CDCl3) δ ppm 11.90 (s, 1H), 8.80 (d, J = 8.9 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.67-7.62 (m, 2H), 7.57 (s, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.26-7.21 (m, 2H), 6.90-6.81 (m, 3H), 4.08 (s, 2H), 3.81 (d, J = 1.1 Hz, 6H), 2.58 (s, 3H); ES-LCMS m/z 542.0, 544.0 [M+H]+. Step 2: 4-[(5-Isopropenyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide
Figure imgf000386_0002
[00956] To a stirred solution of 4-[(5-bromo-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]- N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (100 mg, 178.82 µmol, 97.0% purity, 1 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.07 mg, 268.23 µmol, 1.5 eq) in 1,4-dioxane (6 mL) and H2O (2 mL) was added Cs2CO3 (116.53 mg, 357.64 µmol, 2 eq) and Pd(dppf)Cl2 (13.08 mg, 17.88 µmol, 0.1 eq). The reaction mixture was stirred under N2 atmosphere at 100 °C for 3 h. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.41) to yield 4-[(5-isopropenyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide (80 mg, 155.67 µmol, 87.1% yield, 98.0% purity) as yellow oil.1H NMR (500 MHz, CDCl3) δ ppm 8.39 (s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.24 (d, J = 8.7 Hz, 3H), 6.96 (s, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.36 (s, 1H), 5.08 (s, 1H), 4.09 (s, 2H), 3.81 (s, 6H), 2.58 (s, 3H), 2.16 (s, 3H); ES-LCMS m/z 504.2 [M+H]+. Step 3: 4-[(5-Isopropyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide
Figure imgf000387_0001
[00957] To a stirred solution of 4-[(5-isopropenyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (80 mg, 155.67 µmol, 98.0% purity, 1 eq) in EtOAc (10 mL) was added Pd/C (100 mg, 10%). The reaction mixture was stirred under H2 atmosphere (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to yield 4-[(5-isopropyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (63 mg, 124.60 µmol, 80.1% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 11.55 (s, 1H), 8.73 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 2.2, 8.8 Hz, 1H), 7.56 (s, 1H), 7.47 (dd, J = 2.3, 8.4 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 4.07 (s, 2H), 3.80 (d, J = 3.7 Hz, 6H), 2.95- 2.85 (m, 1H), 2.57 (s, 3H), 1.27 (d, J=7.1 Hz, 6H); ES-LCMS m/z 506.2 [M+H]+. Step 4: 4-[(5-Isopropyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide
Figure imgf000388_0001
[00958] To a stirred solution of 4-[(5-isopropyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (63 mg, 124.60 µmol, 100.0% purity, 1 eq) in DCM (6 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 216.80 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 48%-78%, 10 min) to yield 4-[(5-isopropyl-2-pyridyl)amino]-N-methyl- 3-(1-methylimidazol-4-yl)benzenesulfonamide (21.17 mg, 54.92 µmol, 44.1% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 11.84 (s, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.97-7.90 (m, 2H), 7.80 (d, J = 1.1 Hz, 1H), 7.60 (dd, J = 2.4, 8.5 Hz, 1H), 7.53 (dd, J = 2.3, 8.9 Hz, 1H), 7.20-7.07 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 2.90-2.85 (m, 1H), 2.41 (d, J = 5.0 Hz, 3H), 1.21 (d, J = 6.9 Hz, 6H); ES-LCMS m/z 386.2 [M+H]+. T-C-17
Figure imgf000388_0002
Step 1: 2-(4-Bromoimidazol-1-yl)ethanol
Figure imgf000388_0003
[00959] To a solution of 2-bromoethanol (2.55 g, 20.41 mmol, 1.45 mL, 3 eq) in DMF (40 mL) was added KI (1.13 g, 6.80 mmol, 1 eq), Cs2CO3 (8.87 g, 27.22 mmol, 4 eq) and 4-bromo-1H- imidazole (1 g, 6.80 mmol, 1 eq). The mixture was stirred under N2 atmosphere at 100 °C for 12 h. TLC (PE/EtOAc = 0/1, Rf = 0.11) indicated starting material was consumed completely and one new spot formed. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (From PE/EtOAc=1/0 to 0/1, Rf = 0.11) to yield 2-(4-bromoimidazol-1-yl)ethanol (1.1 g, 3.46 mmol, 50.8% yield, 60.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.34 (d, J = 1.2 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 4.02-3.99 (m, 2H), 3.91-3.85 (m, 3H). Step 2: 3-[1-(2-Hydroxyethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000389_0001
[00960] To a solution of 2-(4-bromoimidazol-1-yl)ethanol (250 mg, 785.24 µmol, 60% purity, 1 eq) in H2O (5 mL) and 1,4-dioxane (15 mL) were added tert-butyl N-[4-[(4- methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (729.80 mg, 785.24 µmol, 72.9% purity, 1 eq), Cs2CO3 (767.53 mg, 2.36 mmol, 3 eq) and Pd(dppf)Cl2 (57.46 mg, 78.52 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 80 °C for 12 h. TLC (PE/EtOAc = 1/1, Rf = 0.10) indicated starting material was consumed completely and many new spots formed. The mixture was concentrated, diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (From PE/EtOAc = 1/0 to 1/1, Rf = 0.10) to yield 3-[1-(2-hydroxyethyl)imidazol-4-yl]-N-[(4- methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (50 mg, 74.61 µmol, 9.5% yield, 83.8% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 12.23 (s, 1H), 8.95 (d, J = 9.0 Hz, 1H), 8.56 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.75-7.65 (m, 3H), 7.47 (s, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 4.20 (t, J = 5.1 Hz, 2H), 4.02 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H), 2.60 (s, 3H); ES-LCMS m/z 562.1 [M+H]+. Step 3: 3-[1-(2-Hydroxyethyl)imidazol-4-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000390_0001
[00961] To a solution of 3-[1-(2-hydroxyethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]- N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (50 mg, 74.61 µmol, 83.8% purity, 1 eq) in DCM (4 mL) was added TFA (645.26 mg, 5.66 mmol, 419.00 µL, 75.85 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated, diluted with water (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 34%-64%, 10min) to yield 3-[1-(2- hydroxyethyl)imidazol-4-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (16.97 mg, 38.44 µmol, 51.5% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.09 (s, 1H), 8.89 (d, J = 9.0 Hz, 1H), 8.54 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.77-7.63 (m, 3H), 7.45 (s, 1H), 6.94 (d, J = 8.6 Hz, 1H), 4.52 (s, 1H), 4.15 (d, J = 4.7 Hz, 2H), 3.95 (s, 2H), 2.68 (d, J = 5.5 Hz, 3H); ES-LCMS m/z 442.2 [M+H]+. T-C-18
Figure imgf000390_0002
Step 1: tert-Butyl N-(5-bromo-2-pyridyl)carbamate
Figure imgf000391_0001
[00962] To a stirred solution of 5-bromopyridin-2-amine (4 g, 23.12 mmol, 1 eq) in DCM (60 mL) was added DMAP (4.24 g, 34.68 mmol, 1.5 eq) and (Boc)2O (6.06 g, 27.74 mmol, 6.37 mL, 1.2 eq). The reaction mixture was stirred under N2 atmosphere at 25 °C for 4 h. TLC (PE/EtOAc = 3/1, Rf = 0.57) showed start material was consumed completely and many new spots was detected. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 100/5, TLC: PE/EtOAc = 3/1, Rf = 0.57) to yield tert-butyl N-(5-bromo-2-pyridyl)carbamate (1.9 g, 6.96 mmol, 30.1% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (s, 1H), 8.27-8.09 (m, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.76 (dd, J = 2.3, 8.9 Hz, 1H), 1.55 (s, 9H); ES-LCMS m/z 273.2, 275.2 [M+H]+. Step 2: tert-Butyl N-[5-(1-hydroxycyclobutyl)-2-pyridyl]carbamate
Figure imgf000391_0002
[00963] To a solution of tert-butyl N-(5-bromo-2-pyridyl)carbamate (200 mg, 732.26 µmol, 100.0% purity, 1 eq) in THF (10 mL) was added i-PrMgCl (2 M, 366.13 µL, 1 eq) dropwise under N2 atmosphere at -10 °C and stirred for 5 min. n-BuLi (2.5 M, 732.26 µL, 2.5 eq) was added dropwise under N2 atmosphere at -30 °C and stirred for 5 min. A solution of cyclobutanone (76.99 mg, 1.10 mmol, 82.07 µL, 1.5 eq) in THF (1 mL) was added under N2 atmosphere at -30 °C. The mixture was stirred under N2 atmosphere at -30 °C for 10 min. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine ( 30 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.28) to yield tert-butyl N-[5-(1-hydroxycyclobutyl)-2- pyridyl]carbamate (130 mg, 477.07 µmol, 65.2% yield, 97.0% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 7.83-7.77 (m, 1H), 7.76-7.70 (m, 1H), 5.64-5.56 (m, 1H), 2.40-2.34 (m, 2H), 2.30-2.21 (m, 2H), 1.91-1.86 (m, 1H), 1.64-1.58 (m, 1H), 1.46 (s, 9H); ES-LCMS m/z 265.3 [M+H]+. Step 3: 5-Cyclobutylpyridin-2-amine
Figure imgf000392_0001
[00964] To a stirred solution of tert-butyl N-[5-(1-hydroxycyclobutyl)-2-pyridyl]carbamate (120 mg, 440.38 µmol, 97.0% purity, 1 eq) in triethylsilane (1.09 g, 9.39 mmol, 1.5 mL, 21.33 eq) was added TFA (2.31 g, 20.26 mmol, 1.5 mL, 46.00 eq). The reaction mixture was stirred under N2 atmosphere at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was diluted with H2O (10 mL), adjust pH to 9 by sat aq. NaOH and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.17) to yield 5-cyclobutylpyridin-2-amine (65 mg, 434.20 µmol, 98.6% yield, 99.0% purity) as yellow oil.1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (d, J = 1.7 Hz, 1H), 7.31 (dd, J = 2.3, 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.67 (s, 2H), 2.22-2.16 (m, 3H), 2.04-1.96 (m, 2H), 1.92-1.86 (m, 1H), 1.80-1.73 (m, 1H); ES-LCMS m/z 149.4 [M+H]+. Step 4: 3-Bromo-4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N- methyl-benzenesulfonamide
Figure imgf000392_0002
[00965] To a solution of 5-cyclobutylpyridin-2-amine (55 mg, 367.40 µmol, 99.0% purity, 1 eq) in DMF (4 mL) was added NaH (44.08 mg, 1.10 mmol, 60%, 3 eq) at 0 °C and stirred 0.5 h.3- Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (150.15 mg, 367.40 µmol, 95.0% purity, 1 eq) was added. The reaction mixture was stirred under N2 atmosphere at 25 °C for 11.5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.56) to yield 3-bromo-4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl- benzenesulfonamide (140 mg, 265.66 µmol, 72.3% yield, 98.0% purity) as colorless oil.1H NMR (500 MHz, CDCl3) δ ppm 8.48 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.02-7.97 (m, 1H), 7.71 (dd, J = 2.1, 8.8 Hz, 1H), 7.56 (dd, J = 2.3, 8.4 Hz, 1H), 7.26-7.22 (m, 2H), 7.15 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.89-6.88 (m, 1H), 6.88-6.86 (m, 1H), 4.09 (s, 2H), 3.81 (s, 3H), 3.57-3.50 (m, 1H), 2.60-2.58 (m, 3H), 2.43-2.34 (m, 1H), 2.45-2.28 (m, 1H), 2.20-2.09 (m, 2H), 2.09-2.02 (m, 1H), 1.95-1.87 (m, 1H); ES-LCMS m/z 516.1, 518.1 [M+H]+. Step 5: 4-[(5-Cyclobutyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide
Figure imgf000393_0001
[00966] To a stirred solution of 3-bromo-4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (100 mg, 189.76 µmol, 98.0% purity, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (284.56 mg, 759.03 µmol, 99.0% purity, 4 eq) in DMF (10 mL) was added Pd(dppf)Cl2 (13.88 mg, 18.98 µmol, 0.1 eq). The reaction mixture was stirred under N2 atmosphere at 130 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.21) to yield 4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (55 mg, 106.25 µmol, 56.0% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 11.56 (s, 1H), 8.74 (d, J = 8.9 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 2.2, 8.8 Hz, 1H), 7.57 (s, 1H), 7.48 (dd, J = 2.3, 8.4 Hz, 1H), 7.33 (d, J = 1.1 Hz, 1H), 7.25 (s, 1H), 7.23 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 4.07 (s, 2H), 3.80 (d, J = 2.9 Hz, 6H), 3.54-3.47 (m, 1H), 2.56 (s, 3H), 2.41-2.31 (m, 2H), 2.19-2.08 (m, 2H), 2.06-2.01 (m, 1H), 1.94-1.85 (m, 1H); ES-LCMS m/z 518.3 [M+H]+. Step 6: 4-[(5-Cyclobutyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide
Figure imgf000394_0001
[00967] To a stirred solution of 4-[(5-cyclobutyl-2-pyridyl)amino]-N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (50 mg, 96.59 µmol, 100.0% purity, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 279.66 eq). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)- ACN]; B%: 45%-75%, 10 min) to yield 4-[(5-cyclobutyl-2-pyridyl)amino]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide (34.31 mg, 86.32 µmol, 89.4% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.98-7.88 (m, 2H), 7.81 (d, J = 1.0 Hz, 1H), 7.63 (dd, J = 2.3, 8.4 Hz, 1H), 7.53 (dd, J = 2.1, 8.9 Hz, 1H), 7.20 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.77 (s, 3H), 3.52-3.43 (m, 1H), 2.41 (s, 3H), 2.33-2.22 (m, 2H), 2.16-2.04 (m, 2H), 2.01-1.90 (m, 1H), 1.89-1.76 (m, 1H); ES-LCMS m/z 398.3 [M+H]+. T-C-19
Figure imgf000395_0001
Step 1: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[(5-vinyl-2- pyridyl)amino]benzenesulfonamide
Figure imgf000395_0002
[00968] To a stirred solution of 4-[(5-bromo-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]- N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (150 mg, 251.64 µmol, 91%, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (58.13 mg, 377.46 µmol, 64.02 µL, 1.5 eq) in 1,4- dioxane (6 mL) and H2O (2 mL) was added Cs2CO3 (163.98 mg, 503.27 µmol, 2 eq) and Pd(dppf)Cl2 (18.41 mg, 25.16 µmol, 0.1 eq). The reaction mixture was stirred under N2 atmosphere at 100 °C for 3 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.44) to yield N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[(5- vinyl-2-pyridyl)amino]benzenesulfonamide (110 mg, 198.03 µmol, 78.7% yield, 88.1% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.82 (s, 1H), 8.86 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.68 (ddd, J = 2.2, 8.7, 13.0 Hz, 2H), 7.58 (s, 1H), 7.34 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.67 (dd, J = 11.0, 17.6 Hz, 1H), 5.67 (d, J = 17.6 Hz, 1H), 5.22 (d, J = 11.2 Hz, 1H), 4.08 (s, 2H), 3.80 (s, 6H), 2.57 (s, 3H); ES-LCMS m/z 490.2 [M+H]+. Step 2: 4-[(5-Ethyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1- methylimidazol-4-yl)benzenesulfonamide
Figure imgf000396_0001
[00969] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[(5-vinyl-2-pyridyl)amino]benzenesulfonamide (110 mg, 198.03 µmol, 88.1%, 1 eq) in EtOAc (15 mL) was added Pd/C (100 mg, 10%, 1.00 eq) under H2 atmosphere. The suspension was degassed and purged with H2 for 3 times and stirred under H2 at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to yield compound 4-[(5-ethyl-2- pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide (85 mg, 160.71 µmol, 81.1% yield, 92.9% purity) as a colorless oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 11.56 (br s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 2.2, 9.0 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J = 2.3, 8.4 Hz, 1H), 7.33 (d, J = 1.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 4.07 (s, 2H), 3.80 (d, J = 3.2 Hz, 6H), 2.64-2.58 (m, 2H), 2.56 (s, 3H), 1.27 (d, J = 2.0 Hz, 3H); ES-LCMS m/z 492.2 [M+H]+. Step 3: 4-[(5-Ethyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide
Figure imgf000396_0002
[00970] To a solution of 4-[(5-ethyl-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N- methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (80 mg, 151.26 µmol, 92.9%, 1 eq) in DCM (6 mL) was added TFA (2.86 g, 25.11 mmol, 1.86 mL, 165.99 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of sat. NaHCO3 (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; B%: 39%-69%, 10min), followed by lyophilization to yield 4-[(5-ethyl-2-pyridyl)amino]-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide(20 mg, 52.84 µmol, 34.9% yield, 98.1% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.54 (s, 1H), 8.68 (d, J = 9.0 Hz, 1H), 8.15 (s, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.65 (dd, J = 1.8, 8.9 Hz, 1H), 7.54 (s, 1H), 7.42 (dd, J = 1.7, 8.3 Hz, 1H), 7.32 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.36 (d, J = 5.4 Hz, 1H), 3.77 (s, 3H), 2.65 (d, J = 5.4 Hz, 3H), 2.59 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); ES-LCMS m/z 372.2 [M+H]+. T-C-20
Figure imgf000397_0002
Step 1: 4-(Cyclohexylmethylamino)-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide
Figure imgf000397_0001
[00971] A mixture of 4-amino-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (100 mg, 300.39 μmol, 80% purity, 1 eq) and cyclohexanecarbaldehyde (42 mg, 374.43 μmol, 45.06 μL, 1.25 eq) in MeOH (3 mL) and AcOH (0.05 mL) was stirred at 25 °C for 3 h. NaBH3CN (56.00 mg, 891.12 μmol, 2.97 eq) was added. The mixture was stirred at 25 °C for 12 h. The mixture was filtered. The solid was stirred in MeOH (4 mL) for 0.5 h and filtered. The solid was washed with MeOH (2 mL), dissolved in MeCN (50 mL) and water (50 mL) and lyophilized to yield 4- (cyclohexylmethylamino)-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (27.35 mg, 75.45 μmol, 25.1% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.63 (br s, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 2.2, 8.8 Hz, 1H), 7.48 (s, 1H), 7.25 (d, J = 1.1 Hz, 1H), 6.66 (d, J = 8.9 Hz, 1H), 4.16 (q, J = 5.5 Hz, 1H), 3.76 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.62 (d, J = 5.5 Hz, 3H), 1.87 (d, J = 12.8 Hz, 2H), 1.80-1.74 (m, 2H), 1.73-1.64 (m, 2H), 1.31- 1.18 (m, 3H), 1.05 (dq, J = 3.2, 12.1 Hz, 2H); ES-LCMS m/z 363.3 [M+H]+. T-C-22
Figure imgf000398_0001
Step 1: 4-Bromo-1-(oxetan-3-yl)imidazole
Figure imgf000398_0002
[00972] To a solution of 3-bromooxetane (700 mg, 5.11 mmol, 1 eq) in DMF (20 mL) was added Cs2CO3 (3.33 g, 10.22 mmol, 2 eq) and 4-bromo-1H-imidazole (1.13 g, 7.67 mmol, 1.5 eq). The mixture was stirred at 130 °C for 8 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 0/1, Rf =0.57) to yield 4-bromo-1-(oxetan-3-yl)imidazole (740 mg, 3.23 mmol, 63.1% yield, 88.5% purity) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 5.31-5.22 (m, 1H), 5.11 (t, J = 7.3 Hz, 2H), 4.85-4.79 (m, 2H); ES- LCMS m/z 204.9 [M+H]+. Step 2: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000399_0001
[00973] To a solution of 4-bromo-1-(oxetan-3-yl)imidazole (200 mg, 871.77 µmol, 88.5% purity, 1 eq) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (6.38 mg, 8.72 µmol, 0.01 eq), Cs2CO3 (568.08 mg, 1.74 mmol, 2 eq) and tert-butyl N-[4-[(4-methoxyphenyl)methyl- methyl-sulfamoyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[5- (trifluoromethyl)-2-pyridyl]carbamate (1.42 g, 1.05 mmol, 50% purity, 1.2 eq). The mixture was stirred at 100 °C for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 2/1, Rf = 0.21) to yield N-[(4-methoxyphenyl)methyl]-N-methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4- [[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (130 mg, 113.32 µmol, 13.0% yield, 50.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 12.05 (s, 1H), 8.93 (d, J = 9.0 Hz, 1H), 8.53 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 1.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.96-6.88 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.40-5.31 (m, 1H), 5.17 (t, J = 7.3 Hz, 2H), 4.90 (d, J = 6.0, 7.2 Hz, 2H), 4.09 (s, 2H), 3.78 (s, 3H), 2.59 (s, 3H); ES-LCMS m/z 574.2 [M+H]+. Step 3: N-Methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000400_0001
[00974] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-[1-(oxetan-3-yl)imidazol- 4-yl]-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (120 mg, 104.61 µmol, 50% purity, 1 eq) in DCM (3 mL) was added TFA (462.00 mg, 4.05 mmol, 300.00 µL, 38.74 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5um; mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 44%-59%,14min), followed by lyophilization to yield N-methyl-3-[1-(oxetan-3-yl)imidazol-4-yl]-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (19.77 mg, 43.60 µmol, 41.7% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 12.04 (s, 1H), 8.90 (d, J = 9.0 Hz, 1H), 8.55 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.78 (s, 2H), 7.74 (td, J = 2.8, 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 5.43-5.34 (m, 1H), 5.20 (t, J = 7.3 Hz, 2H), 4.96-4.89 (m, 2H), 4.31 (q, J = 5.3 Hz, 1H), 2.70 (d, J = 5.4 Hz, 3H) ; ES-LCMS m/z 454.2 [M+H]+. T-C-24
Figure imgf000400_0002
Step 1: 3-Bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide
Figure imgf000400_0003
[00975] To a solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (300 mg, 1.10 mmol, 1 eq) in THF (6 mL) was added DIEA (425.29 mg, 3.29 mmol, 573.16 µL, 3 eq) and N- methylmethanamine (185.44 mg, 1.65 mmol, 208.36 µL, 40%, 1.5 eq). The mixture was stirred at 20 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.40) indicated most of the starting material was consumed and one new spot formed. The reaction mixture was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.40) to yield 3-bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide (300 mg, 1.03 mmol, 94.0% yield, 97.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.01 (dd, J = 2.2, 6.4 Hz, 1H), 7.73 (m, 1H), 7.32-7.28 (m, 1H), 2.74 (s, 6H); ES-LCMS m/z 282.1, 284.1 [M+H]+. Step 2: 3-Bromo-N,N-dimethyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000401_0001
[00976] A mixture of 3-bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide (300 mg, 1.03 mmol, 97%, 1 eq), [4-(trifluoromethyl)phenyl]methanamine (361.32 mg, 2.06 mmol, 293.75 µL, 2 eq) in DMSO (15 mL) was degassed and purged with N2 for 3 times and stirred under N2 atmosphere at 140 °C for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.41) to yield 3-bromo-N,N-dimethyl-4- [[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (310 mg, 574.24 µmol, 55.6% yield, 81.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.88 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.52 (dd, J = 2.0, 8.6 Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H), 6.56 (d, J = 8.6 Hz, 1H), 5.35 (t, J = 5.3 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 2.69 (s, 6H); ES-LCMS m/z 437.1, 439.1 [M+H]+. Step 3: N,N-Dimethyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000402_0001
[00977] To a solution of 3-bromo-N,N-dimethyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (310 mg, 574.24 µmol, 81%, 1 eq) in DMF (4 mL) was added Pd(dppf)Cl2 (42.02 mg, 57.42 µmol, 0.1 eq) and tributyl-(1- methylimidazol-4-yl)stannane (538.20 mg, 1.44 mmol, 99%, 2.5 eq). The mixture was stirred under N2 atmosphere at 130 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 0/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.20) to yield N,N-dimethyl-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (135.21 mg, 302.20 µmol, 52.6% yield, 98.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.20 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 7.8 Hz, 3H), 7.43 (dd, J = 2.0, 8.6 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 4.60 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H), 2.67 (s, 6H); ES-LCMS m/z 439.2 [M+H]+. T-C-26 & T-C-27 (isomers of T-C-174)
Figure imgf000403_0001
Step 1: 4,4,5,5-Tetramethyl-2-[(Z)-1-methylprop-1-enyl]-1,3,2-dioxaborolane
Figure imgf000403_0002
[00978] A stirred solution of (E)-2-bromobut-2-ene (0.4 g, 2.96 mmol, 1 eq) in THF (10 mL) was cooled to –78 °C and t-BuLi (1.3 M, 4.10 mL, 1.8 eq) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (661.52 mg, 3.56 mmol, 725.35 µL, 1.2 eq) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes and warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 4,4,5,5-tetramethyl-2-[(Z)-1-methylprop-1-enyl]- 1,3,2-dioxaborolane (400 mg, 1.76 mmol, 59.3% yield, 80.0% purity) as a yellow oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 6.15 (d, J = 6.1 Hz, 1H), 1.88 (dd, J = 1.5, 6.8 Hz, 3H), 1.75 (s, 3H), 1.28 (s, 12H). Step 2: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(E)-1- methylprop-1-enyl]-2-pyridyl]amino]benzenesulfonamide
Figure imgf000404_0001
[00979] To a solution of 4-[(5-bromo-2-pyridyl)amino]-N-[(4-methoxyphenyl)methyl]-N- methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (220 mg, 369.07 µmol, 91%, 1 eq) in H2O (2 mL) and 1,4-dioxane (8 mL) was added Pd(dppf)Cl2 (27.01 mg, 36.91 µmol, 0.1 eq), 4,4,5,5- tetramethyl-2-[(E)-1-methylprop-1-enyl]-1,3-dioxolane (255.04 mg, 1.11 mmol, 80%, 3 eq) and Cs2CO3 (240.50 mg, 738.14 µmol, 2 eq). The mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.49) to yield N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(E)-1-methylprop-1-enyl]- 2-pyridyl]amino]benzenesulfonamide (175 mg, 328.81 µmol, 89.0% yield, 97.2% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 11.69-11.63 (m, 1H), 8.82-8.75 (m, 1H), 8.33- 8.15 (m, 1H), 7.91-7.87 (m, 1H), 7.66-7.60 (m, 1H), 7.54 (s, 1H), 7.42 (dd, J = 2.3, 8.4 Hz, 1H), 7.31 (d, J = 1.0 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.93-6.81 (m, 3H), 5.86-.56 (m, 1H), 4.05 (s, 2H), 3.78 (s, 6H), 2.54 (s, 3H), 2.00 (s, 3H), 1.22 (s, 3H); ES-LCMS m/z 518.2 [M+H]+. Step 3: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[(5-sec-butyl-2- pyridyl)amino]benzenesulfonamide
Figure imgf000404_0002
[00980] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[[5-[(E)-1-methylprop-1-enyl]-2-pyridyl]amino]benzenesulfonamide (170 mg, 299.71 µmol, 91.2%, 1 eq) in EtOAc (10 mL) was added Pd/C (100 mg, 10%) under H2 atmosphere. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to yield N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4- yl)-4-[(5-sec-butyl-2-pyridyl)amino]benzenesulfonamide (150 mg, 259.79 µmol, 86.6% yield, 90.0% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 11.56 (s, 1H), 8.76 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.91-7.90 (m, 1H), 7.66 (dd, J = 2.4, 5.6 Hz, 1H), 7.56 (s, 1H), 7.42 (dd, J = 2.3, 8.4 Hz, 1H), 7.35-7.33 (m, 2H), 7.29 (s, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.6 Hz, 1H), 4.07 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 2.64 (d, J = 5.6 Hz, 3H), 1.60-1.53 (m, 2H), 1.26-1.25 (m, 3H), 0.85 (t, J = 7.3 Hz, 3H); ES-LCMS m/z 520.3 [M+H]+. Step 4: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(1R)-1-methylpropyl]-2- pyridyl]amino]benzenesulfonamide and N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(1S)-1- methylpropyl]-2-pyridyl]amino]benzenesulfonamide
Figure imgf000405_0001
[00981] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[(5-sec-butyl-2-pyridyl)amino]benzenesulfonamide (140 mg, 242.47 µmol, 90%, 1 eq) in DCM (10 mL) was added TFA (2.77 g, 24.31 mmol, 1.80 mL, 100.26 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/2, TLC: PE/EtOAc = 1/1, Rf = 0.26) to yield a product which was separated by chiral SFC column: DAICEL CHIRALPAK IG (250mm*30mm, 10µm); mobile phase: [0.1% NH3H2O MeOH]; B%: 60%-60%, min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield the residue which was dissolved in MeCN (2 mL) and water (15 mL) and lyophilized to yield N-methyl-3-(1- methylimidazol-4-yl)-4-[[5-[(1R)-1-methylpropyl]-2-pyridyl]amino]benzenesulfonamide (15.03 mg, 37.62 µmol, 15.5% yield, 100.0% purity, SFC: Rt = 2.211, ee = 100%, [α]29.5D = + 12.5 (CH3OH, c = 0.016 g/100 mL)) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.53 (br s, 1H), 8.70 (d, J = 9.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 2.1, 8.9 Hz, 1H), 7.55 (s, 1H), 7.41 (dd, J = 2.2, 8.3 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.20 (d, J = 5.6 Hz, 1H), 3.79 (s, 3H), 2.66 (d, J = 5.6 Hz, 3H), 2.62-2.55 (m, 1H), 1.64-1.60 (m, 2H), 1.25 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H); ES-LCMS m/z 400.3 [M+H]+. Peak 2 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) and lyophilized to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[5-[(1S)-1- methylpropyl]-2-pyridyl]amino]benzenesulfonamide (15.26 mg, 38.20 µmol, 15.7% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 11.51 (br s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 2.2, 8.8 Hz, 1H), 7.53 (s, 1H), 7.38 (dd, J = 2.3, 8.4 Hz, 1H), 7.31 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.17 (d, J = 5.1 Hz, 1H), 3.77 (s, 3H), 2.63 (d, J = 5.6 Hz, 3H), 2.58-2.52 (m, 1H), 1.65-1.59 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 0.81 (t, J = 7.3 Hz, 3H); ES-LCMS m/z 400.3 [M+H]+. T-C-28
Figure imgf000406_0001
Step 1: 3-Bromo-N-methyl-4-(2-phenylethylamino)benzenesulfonamide
Figure imgf000406_0002
[00982] To a solution of 3-bromo-4-fluoro-N-methyl-benzenesulfonamide (150 mg, 559.49 µmol, 1 eq) in DMSO (5 mL) was added 2-phenylethanamine (135.60 mg, 1.12 mmol, 140.51 µL, 2 eq). The mixture was stirred at 140 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.43) to yield 3-bromo-N-methyl-4-(2- phenylethylamino)benzenesulfonamide (200 mg, 530.77 µmol, 94.8% yield, 98.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.90 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 1.8, 8.7 Hz, 1H), 7.39-7.31 (m, 2H), 7.31-7.26 (m, 1H), 7.26-7.21 (m, 2H), 6.67 (d, J = 8.8 Hz, 1H), 4.89 (br s, 1H), 4.29 (q, J = 5.1 Hz, 1H), 3.54-3.45 (m, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.64 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 369.1, 371.1 [M+H]+. Step 2: N-Methyl-3-(1-methylimidazol-4-yl)-4-(2-phenylethylamino)benzenesulfonamide
Figure imgf000407_0001
[00983] To a solution of 3-bromo-N-methyl-4-(2-phenylethylamino)benzenesulfonamide (200 mg, 530.77 µmol, 98%, 1 eq) in DMF (10 mL) was added tributyl-(1-methylimidazol-4- yl)stannane (397.97 mg, 1.06 mmol, 99%, 2 eq) and Pd(dppf)Cl2 (38.84 mg, 53.08 µmol, 0.1 eq) was degassed and purged with N2 for 3 times. The mixture was stirred under N2 atmosphere at 130 °C for 4 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/2, TLC: PE/EtOAc = 1/2, Rf = 0.43), followed by lyophilization to yield N-methyl-3-(1-methylimidazol-4-yl)-4-(2- phenylethylamino)benzenesulfonamide (133.67 mg, 353.45 µmol, 66.5% yield, 97.9% purity) as a gray solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (br s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 2.2, 8.8 Hz, 1H), 7.45 (s, 1H), 7.35-7.28 (m, 4H), 7.26-7.20 (m, 2H), 6.71 (d, J = 8.8 Hz, 1H), 4.13 (q, J = 5.3 Hz, 1H), 3.76 (s, 3H), 3.55-3.49 (m, 2H), 3.03 (t, J = 7.5 Hz, 2H), 2.63 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 371.2 [M+H]+. T-C-30
Figure imgf000408_0001
N-[2-(1-Methylimidazol-4-yl)-4-(methylsulfamoyl)phenyl]-3- (trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide
Figure imgf000408_0002
[00984] To a solution of 4-amino-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (100 mg, 300.39 µmol, 80% purity, 1 eq) and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1- carboxylic acid (54.11 mg, 300.39 µmol, 1 eq) in DMF (6 mL) were added HATU (148.48 mg, 390.51µmol, 1.3 eq) and DIPEA (77.65 mg, 600.78 µmol, 104.65 µL, 2 eq). The mixture was stirred under N2 atmosphere at 25 °C for 16 h. The solvent was removed to yield a residue which was purified by preparative TLC (PE/EtOAc = 0/1, Rf = 0.85) to yield N-[2-(1-methylimidazol-4- yl)-4-(methylsulfamoyl)phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide (41 mg, 95.70 µmol, 31.9% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 12.88 (s, 1H), 8.81 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 2.2, 8.8 Hz, 1H), 7.57 (s, 1H), 7.39 (d, J = 1.1 Hz, 1H), 4.29 (d, J = 5.3 Hz, 1H), 3.81 (s, 3H), 2.66 (d, J = 5.3 Hz, 3H), 2.37 (s, 6H); ES-LCMS m/z 429.2 [M+H]+. Step 2 N-Methyl-3-(1-methylimidazol-4-yl)-4-[[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]methylamino]benzenesulfonamide
Figure imgf000408_0003
[00985] To a solution of N-[2-(1-methylimidazol-4-yl)-4-(methylsulfamoyl)phenyl]-3- (trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide (130 mg, 300.40 µmol, 99% purity, 1 eq) in THF (5 mL) was added LiAlH4 (34.20 mg, 901.20 µmol, 3 eq) at 25 °C and stirred for 16 h. TLC (PE/EtOAc = 0/1, Rf = 0.76) indicated the starting material was consumed completely and one new spot formed. The mixture was quenched by aq.15% NaOH (1 mL). The mixture was filtered and the filter cake was washed with EtOAc (30 mL x 2). The filtrate was concentrated to yield a residue which was purified by preparative TLC (PE/EtOAc = 0/1, Rf = 0.76) to yield a product which was dissolved in MeCN (3 mL) and H2O (10 mL) and lyophilized to yield N-methyl- 3-(1-methylimidazol-4-yl)-4-[[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]methylamino]benzenesulfonamide (5.73 mg, 13.60 µmol, 4.5% yield, 98.4% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.76 (br s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 2.1, 8.7 Hz, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.31- 4.15 (m, 1H), 3.83-3.69 (m, 3H), 3.39 (d, J = 4.4 Hz, 2H), 2.69-2.54 (m, 3H), 2.00 (s, 6H); ES- LCMS m/z 415.2 [M+H]+. T-C-31
Figure imgf000409_0001
Step 1: 3-Imidazo[1,5-a]pyridin-1-yl-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000409_0002
[00986] To a solution of 1-bromoimidazo[1,5-a]pyridine (50 mg, 253.77 µmol, 1 eq) and N- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (159.13 mg, 304.52 µmol, 90% purity, 1.2 eq) in 1,4-dioxane (5 mL) and H2O (0.5 mL) were added Pd(dppf)Cl2 (18.57 mg, 25.38 µmol, 0.1 eq) and Cs2CO3 (165.36 mg, 507.53 µmol, 2 eq). The mixture was stirred under N2 atmosphere at 90 °C for 16 h. The solvent was removed and the residue was treated with EtOAc (20 mL). The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um;mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN];B%: 47%-77%,10min), followed by lyophilization to yield 3-imidazo[1,5-a]pyridin-1-yl-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (55.95 mg, 118.81µmol, 46.8% yield, 97.8% purity) as a gray solid.1H NMR (400 MHz, CDCl3) δ ppm 8.51 (t, J = 5.5 Hz, 1H), 8.20 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.63-7.54 (m, 3H), 7.49 (d, J = 8.1 Hz, 2H), 6.88 (dd, J = 6.5, 9.2 Hz, 1H), 6.70 (t, J = 6.7 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 4.59 (d, J = 5.4 Hz, 2H), 4.18 (br s, 1H), 2.64 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 460.9 [M+H]+. T-C-32
Figure imgf000410_0001
Step 1: 3-Bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide
Figure imgf000410_0002
[00987] To a solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (400 mg, 1.46 mmol, 1 eq) in THF (6 mL) was added DIEA (378.03 mg, 2.92 mmol, 509.48 µL, 2 eq) and 2-aminoethanol (134.00 mg, 2.19 mmol, 132.67 µL, 1.5 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-bromo-4-fluoro-N-(2- hydroxyethyl)benzenesulfonamide (400 mg, crude) as white oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 10.72 (s, 1H), 8.14 (dd, J = 2.3, 6.2 Hz, 1H), 7.88 (ddd, J = 2.2, 4.4, 8.6 Hz, 1H), 7.26-7.21 (m, 1H), 6.03 (s, 1H), 3.14-3.10 (m, 4H). Step 2: 3-Bromo-N-(2-hydroxyethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000411_0001
[00988] To a solution of 3-bromo-4-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (400 mg, 1.34 mmol, N/A purity, 1 eq) in DMSO (3 mL) was added [4- (trifluoromethyl)phenyl]methanamine (470.00 mg, 2.68 mmol, 382.11 µL, 2 eq). The mixture was stirred at 140 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 0/1, TLC: PE/EtOAc = 0/1, Rf = 0.40) to yield 3-bromo-N-(2-hydroxyethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (580 mg, 959.69 µmol, 71.5% yield, 75.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 8.6 Hz, 1H), 5.40-5.31 (m, 1H), 4.77 (t, J = 6.1 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.13 (q, J = 7.3 Hz, 1H), 3.74-3.71 (m, 2H), 3.13-3.05 (m, 2H), ES-LCMS m/z 453.0, 455.0 [M+H]+. Step 3: N-(2-Hydroxyethyl)-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000412_0001
[00989] A mixture of 3-bromo-N-(2-hydroxyethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (580 mg, 959.69 µmol, 75% purity, 1 eq), tributyl-(1-methylimidazol-4-yl)stannane (890.46 mg, 2.40 mmol, 2.5 eq), Pd(dppf)Cl2 (70.22 mg, 95.97 µmol, 0.1 eq), tributyl-(1-methylimidazol-4-yl)stannane (890.46 mg, 2.40 mmol, 2.5 eq) in DMF (6 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 130 °C for 8 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.49) and lyophilized to yield N-(2-hydroxyethyl)-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (274.08 mg, 583.18 µmol, 60.8% yield, 96.7% purity) as white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.28-9.20 (m, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.52-7.47 (m, 4H), 7.32 (d, J = 1.2 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.76 (t, J = 6.3 Hz, 1H), 4.60 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 3.69 (t, J = 5.1 Hz, 2H), 3.13-3.02 (m, 2H). ES-LCMS m/z 455.2 [M+H]+. T-C-33
Figure imgf000412_0002
Step 1: 3-Bromo-N-ethyl-4-fluoro-benzenesulfonamide
Figure imgf000413_0001
[00990] To a solution of ethanamine (238.51 mg, 2.92 mmol, 346.18 µL, 2 eq, HCl) in THF (6 mL) was added DIEA (472.54 mg, 3.66 mmol, 636.85 µL, 2.5 eq) and 3-bromo-4-fluoro- benzenesulfonyl chloride (400 mg, 1.46 mmol, 1 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-bromo-N-ethyl-4-fluoro-benzenesulfonamide (400 mg, 1.42 mmol, 96.9% yield, N/A purity) as a white oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.11 (dd, J = 2.2, 6.4 Hz, 1H), 7.83 (ddd, J = 2.2, 4.3, 8.6 Hz, 1H), 7.27-7.23 (m, 1H), 4.75 (s, 1H), 3.07-3.00 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). Step 2: 3-Bromo-N-ethyl-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000413_0002
[00991] To a solution of 3-bromo-N-ethyl-4-fluoro-benzenesulfonamide (400 mg, 1.42 mmol, N/A purity, 1 eq) in DMSO (4 mL) was added [4-(trifluoromethyl)phenyl]methanamine (496.65 mg, 2.84 mmol, 403.78 µL, 2 eq). The mixture was stirred at 140 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.40) to yield a 3-bromo-N-ethyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (217 mg, 397.01 µmol, 28.0% yield, 80.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 8.6 Hz, 1H), 5.41-5.27 (m, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.00 (dd, J = 6.4, 7.1 Hz, 2H), 2.91 (s, 2H), 1.14-1.11 (m, 3H), ES-LCMS m/z 437.0, 438.9 [M+H]+. Step 3: N-Ethyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000414_0001
[00992] A mixture of 3-bromo-N-ethyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (217 mg, 397.01 µmol, 80% purity, 1 eq), tributyl-(1-methylimidazol-4-yl)stannane (372.09 mg, 992.51 µmol, 99% purity, 2.5 eq), Pd(dppf)Cl2 (29.05 mg, 39.70 umol, 0.1 eq) in DMF (5 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 130 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.20) and by preparative HPLC(column: Agela DuraShell C18150 x 25mm x 5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)- ACN]; B%: 43%-73%, 10min) and lyophilized to yield N-ethyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (30.89 mg, 70.45 µmol, 17.6% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.23 (t, J = 5.7 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 6.4 Hz, 4H), 7.32 (s, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.11 (t, J = 6.2 Hz, 1H), 3.78 (s, 3H), 2.98 (q, J = 7.0 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H), ES-LCMS m/z 439.2 [M+H]+. T-C-36
Figure imgf000414_0002
Step 1: N-[(4-Methoxyphenyl)methyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000415_0001
[00993] To a stirred solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (1 g, 1.70 mmol, 90%, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (832.09 mg, 2.04 mmol, 91%, 1.2 eq) in DMF (10 mL) was added Pd(dppf)Cl2 (124.40 mg, 170.01 µmol, 0.1 eq). The reaction mixture bubbled with N2 for 1 min and stirred under microwave at 130 °C for 1.5 h. The reaction mixture was quenched by addition of water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.50) to yield N-[(4-methoxyphenyl)methyl]-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (695 mg, 1.05 mmol, 61.6% yield, 80.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.27 (t, J = 5.3 Hz, 1H), 7.88 (s, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.53-7.48 (m, 4H), 7.43 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.1 Hz, 2H), 6.55 (d, J = 8.8 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 4.03 (d, J = 6.1 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H); ES-LCMS m/z 531.1 [M+H]+. Step 2: 3-(1-Methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000415_0002
[00994] To a solution of N-[(4-methoxyphenyl)methyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (695 mg, 1.31 mmol, 1 eq) in DCM (10 mL) was added TFA (15.40 g, 135.06 mmol, 10.00 mL, 103.10 eq). The mixture was stirred at 25 °C for 48 h. The reaction mixture was quenched by addition of aq. NaHCO3 (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.20) to yield 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (162.21 mg, 375.79 µmol, 29.0% yield, 96.9% purity) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 9.22 (t, J = 6.3 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 2.1, 8.7 Hz, 1H), 6.94 (s, 2H), 6.58 (d, J = 8.7 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 3.75 (s, 3H); ES-LCMS m/z 411.1 [M+H]+. T-C-37
Figure imgf000416_0001
Step 1: 1-Cyclopropyl-4-iodo-imidazole
Figure imgf000416_0002
[00995] To a solution of 4-iodo-1H-imidazole (2.7 g, 13.92 mmol, 1 eq) in 1,2-dichloroethane (25 mL) was added 2-(2-pyridyl)pyridine (2.17 g, 13.92 mmol, 1 eq) ,Cu(OAc)2 (2.53 g, 13.92 mmol, 1 eq), K2CO3 (3.85 g, 27.84 mmol, 2 eq) and cyclopropylboronic acid (2.03 g, 23.66 mmol, 1.7 eq). The mixture was stirred under N2 atmosphere at 50 °C for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/DCM = 1/0 to 1/2, TLC: PE/DCM = 1/2, Rf = 0.60) to yield 1-cyclopropyl-4-iodo-imidazole (1.3 g, 2.22 mmol, 15.9% yield, 40.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 7.34 (d, J = 1.0 Hz, 1H), 7.31 (d, J= 1.0 Hz, 1H), 3.33 (tt, J = 3.7, 7.2 Hz, 1H), 1.04-0.90 (m, 4H); ES-LCMS m/z 235.1 [M+H]+. Step 2: 3-(1-Cyclopropylimidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000417_0001
[00996] To a solution of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (150 mg, 287.04 µmol, 90%, 1 eq) and 1-cyclopropyl-4-iodo-imidazole (201.54 mg, 344.45 µmol, 40%, 1.2 eq) in 1,4-dioxane (5 mL) and H2O (1.5 mL) was added Cs2CO3 (187.05 mg, 574.09 µmol, 2 eq) and Pd(dppf)Cl2 (21.00 mg, 28.70 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; B%: 47%-77%, 10min), followed by lyophilization to yield 3-(1- cyclopropylimidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (63.84 mg, 138.40 µmol, 48.2% yield, 97.6% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.21 (t, J = 5.1 Hz, 1H), 7.87- 7.83 (m, 1H), 7.57 (d, J = 8.3 Hz, 3H), 7.46 (d, J = 7.3 Hz, 3H), 7.38 (s, 1H), 6.51 (d, J = 8.8 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.11 (q, J = 5.2 Hz, 1H), 3.44-3.37 (m, 1H), 2.60 (d, J = 5.6 Hz, 3H), 1.10-0.99 (m, 4H); ES-LCMS m/z 451.2 [M+H]+. T-C-40
Figure imgf000418_0001
Step 1: 3-Bromo-N-cyclopropyl-4-fluoro-benzenesulfonamide
Figure imgf000418_0002
[00997] To a stirred solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (700 mg, 2.56 mmol, 1 eq) in THF (12 mL) was added cyclopropanamine (438.37 mg, 7.68 mmol, 532.01 µL, 3 eq) at -60 °C. The reaction mixture was stirred under N2 atmosphere -60 °C for 1 h. TLC (PE/EtOAc = 10/1, Rf = 0.16) showed start material was consumed completely and one new spot was detected. The reaction mixture was quenched by addition 1 N HCl (8 mL) at -60 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-bromo-N- cyclopropyl-4-fluoro-benzenesulfonamide (800 mg, 2.50 mmol, 97.8% yield, 92.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (dd, J = 2.3, 6.2 Hz, 1H), 7.86-7.82 (m, 1H), 7.29-7.25 (m, 1H), 4.85 (s, 1H), 2.31-2.24 (m, 1H), 0.64-0.60 (m, 4H); ES-LCMS m/z 294.1, 296.1 [M+H]+. Step 2: 3-Bromo-N-cyclopropyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000418_0003
[00998] To a stirred solution of 3-bromo-N-cyclopropyl-4-fluoro-benzenesulfonamide (200 mg, 625.55 µmol, 92.0% purity, 1 eq) in DMSO (5 mL) was added [4- (trifluoromethyl)phenyl]methanamine (219.13 mg, 1.25 mmol, 178.16 µL, 2 eq). The reaction mixture was stirred under N2 atmosphere at 140 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 5/1, TLC: PE/EtOAc = 1/1, Rf = 0.43) to yield 3-bromo-N-cyclopropyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (280 mg, 573.36 µmol, 91.7% yield, 92.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.46 (dd, J = 2.0, 8.6 Hz, 1H), 6.92 (t, J = 6.1 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 2.04-1.97 (m, 1H), 0.48-0.41 (m, 2H), 0.37-0.30 (m, 2H); ES-LCMS m/z 449.1, 451.1 [M+H]+. Step 3: N-Cyclopropyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000419_0001
[00999] To a stirred solution of 3-bromo-N-cyclopropyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (150 mg, 307.15 µmol, 92.0% purity, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (230.30 mg, 614.31 µmol, 99.0% purity, 2 eq) in DMF (4 mL) was added Pd(dppf)Cl2 (22.47 mg, 30.72 µmol, 0.1 eq). The reaction mixture was stirred under N2 atmosphere at 140 °C for 5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 50%-80%, 10min) to yield N- cyclopropyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (80.72 mg, 177.45 µmol, 57.8% yield, 99.0% purity) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (t, J = 5.9 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 7.74-7.66 (m, 3H), 7.56 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 7.37 (dd, J = 2.1, 8.7 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.65 (d, J = 5.9 Hz, 2H), 3.75 (s, 3H), 2.03 (s, 1H), 0.48-0.40 (m, 2H), 0.38-0.31 (m, 2H); ES-LCMS m/z 451.2 [M+H]+. T-C-46
Figure imgf000420_0001
Step 1: 3-Bromo-4-[[2-fluoro-4-(trifluoromethyl)phenyl]methylamino]-N-methyl- benzenesulfonamide
Figure imgf000420_0002
[001000] To a solution of [2-fluoro-4-(trifluoromethyl)phenyl]methanamine (200 mg, 1.04 mmol, 1 eq) in DMSO (10 mL) was added 3-bromo-4-fluoro-N-methyl-benzenesulfonamide (462.7 mg, 1.6 mmol, 90%, 1.5 eq). The mixture was stirred at 140 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.46) to yield a 3- bromo-4-[[2-fluoro-4-(trifluoromethyl)phenyl]methylamino]-N-methyl-benzenesulfonamide (380 mg, 790.8 µmol, 76.4% yield, 91.8% purity) as a colorless solid.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 1.6, 8.7 Hz, 1H), 7.44-7.37 (m, 3H), 6.57 (d, J = 8.6 Hz, 1H), 5.34 (t, J = 5.6 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H), 4.24 (d, J = 5.1 Hz, 1H), 2.65 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 441.0, 443.0 [M+H]+. Step 2: 4-[[2-Fluoro-4-(trifluoromethyl)phenyl]methylamino]-N-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
Figure imgf000421_0001
[001001] To a solution of 3-bromo-4-[[2-fluoro-4-(trifluoromethyl)phenyl]methylamino]-N- methyl-benzenesulfonamide (260 mg, 525.5 µmol, 89.2%, 1 eq) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (400.33 mg, 1.58 mmol, 3 eq) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (38.45 mg, 52.55 µmol, 0.1 eq) and KOAc (103.15 mg, 1.05 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.43) to yield 4-[[2-fluoro-4- (trifluoromethyl)phenyl]methylamino]-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzenesulfonamide (150 mg, 246.86 µmol, 47.0% yield, 80.4% purity) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J = 2.2 Hz, 1H), 7.67 (dd, J = 2.3, 8.7 Hz, 1H), 7.44-7.38 (m, 1H), 7.38-7.32 (m, 2H), 6.86 (t, J = 6.1 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 3.90 (br s, 1H), 2.59 (d, J = 5.4 Hz, 3H), 1.33 (s, 12H); ES-LCMS m/z 489.2 [M+H]+. Step 3: 3-(1-Cyclopropylimidazol-4-yl)-4-[[2-fluoro-4- (trifluoromethyl)phenyl]methylamino]-N-methyl-benzenesulfonamide
Figure imgf000422_0001
[001002] To a solution of 4-[[2-fluoro-4-(trifluoromethyl)phenyl]methylamino]-N-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (150 mg, 246.86 µmol, 80.4%, 1.16 eq) and 4-[[2-fluoro-4-(trifluoromethyl)phenyl]methylamino]-N-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (149.29 mg, 255.15 µmol, 40%, 1.2 eq) in H2O (1 mL) and 1,4-dioxane (5 mL) was added Cs2CO3 (138.55 mg, 425.25 µmol, 2 eq) and Pd(dppf)Cl2 (15.56 mg, 21.26 µmol, 0.1 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water (0.05%NH3·H2O+10mM NH4HCO3)-ACN]; B%: 52%-82%, 10min), followed by lyophilization to yield 3-(1- cyclopropylimidazol-4-yl)-4-[[2-fluoro-4-(trifluoromethyl)phenyl]methylamino]-N-methyl- benzenesulfonamide (13.56 mg, 28.95 µmol, 13.6% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.24 (t, J = 5.6 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.55-7.47 (m, 2H), 7.42 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 4.25 (q, J = 5.1 Hz, 1H), 3.47-3.39 (m, 1H), 2.63 (d, J = 5.6 Hz, 3H), 1.11-1.02 (m, 4H); ES-LCMS m/z 469.2 [M+H]+. T-C-47
Figure imgf000422_0002
Step 1: 3-(1H-Imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000423_0001
[001003] To a solution of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (500 mg, 956.81 µmol, 90%, 1 eq) and 4-iodo-1H-imidazole (222.71 mg, 1.15 mmol, 1.2 eq) in 1,4-dioxane (10 mL) and H2O (2 mL) was added Cs2CO3 (623.49 mg, 1.91 mmol, 2 eq) and Pd(dppf)Cl2 (70.01 mg, 95.68 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 100 °C for 12 h. The reaction mixture was quenched by addition of water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/2, TLC: PE/EtOAc = 1/1, Rf = 0.44) to yield 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (300 mg, 642.60 µmol, 67.1% yield, 87.9% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.19 (br s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.54-7.49 (m, 3H), 7.46 (s, 1H), 6.56 (d, J = 8.6 Hz, 1H), 4.61 (br s, 2H), 4.24 (d, J = 5.6 Hz, 1H), 2.63 (d, J = 5.6 Hz, 3H); ES-LCMS m/z 411.2 [M+H]+. Step 2: 3-[1-(2-Methoxyethyl)imidazol-4-yl]-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000423_0002
[001004] To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (50 mg, 107.10 µmol, 87.9%, 1 eq) in DMF (5 mL) was added K2CO3 (29.60 mg, 214.2 µmol, 2 eq) and 1-bromo-2-methoxy-ethane (17.86 mg, 128.52 µmol, 12.07 µL, 1.2 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; B%: 43%-73%, 10 min), followed by lyophilization to yield 3-[1-(2- methoxyethyl)imidazol-4-yl]-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (16.89 mg, 35.36 µmol, 33.0% yield, 98.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.35-9.29 (m, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.62-7.57 (m, 3H), 7.50 (d, J = 7.6 Hz, 3H), 7.41 (s, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.61 (d, J = 5.9 Hz, 2H), 4.19-4.10 (m, 3H), 3.70 (t, J = 5.0 Hz, 2H), 3.39 (s, 3H), 2.63 (d, J = 5.6 Hz, 3H); ES-LCMS m/z 469.2 [M+H]+. T-C-48
Figure imgf000424_0001
Step 1: 3-Bromo-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoate
Figure imgf000424_0002
[001005] To a solution of 4-(trifluoromethyl)benzaldehyde (3 g, 17.23 mmol, 2.31 mL, 1 eq) in MeOH (50 mL) was added AcOH (2.07 g, 34.46 mmol, 1.97 mL, 2 eq) and methyl 4-amino-3- bromo-benzoate (4.76 g, 20.68 mmol, 1.2 eq). The mixture was stirred at 20 °C for 5 h. NaBH3CN (2.17 g, 34.46 mmol, 2 eq) was added. The mixture was stirred at 20 °C for 17 h. The reaction mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.54) to yield methyl 3-bromo-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoate (1.1 g, 2.64 mmol, 15.3% yield, 93.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.17 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 1.6, 8.6 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 6.50 (d, J = 8.6 Hz, 1H), 5.30 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H); ES-LCMS m/z 388.1, 390.1 [M+H]+. Step 2: Methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate
Figure imgf000425_0001
[001006] To a solution of methyl 3-bromo-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate (600 mg, 1.44 mmol, 93%, 1 eq), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (730.06 mg, 2.87 mmol, 2 eq) in 1,4-dioxane (10 mL) was added KOAc (282.16 mg, 2.87 mmol, 2 eq) and Pd(PPh3)2Cl2 (100.90 mg, 143.75 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 80 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.54) to yield methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate (450 mg, 920.17 µmol, 64.0% yield, 89.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 2.0, 8.6 Hz, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 6.97 (t, J = 5.9 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H), 3.74 (s, 3H), 1.33 (s, 12H); ES-LCMS m/z 436.3 [M+H]+. Step 3: Methyl 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate
Figure imgf000426_0001
[001007] To a solution of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate (450 mg, 920.17 µmol, 89%, 1.2 eq), 4-iodo-1- methyl-imidazole (159.50 mg, 766.81 µmol, 1 eq) in 1,4-dioxane (10 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (56.11 mg, 76.68 µmol, 0.1 eq) and Cs2CO3 (249.84 mg, 766.81 µmol, 1 eq). The mixture was stirred under N2 atmosphere at 80 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.38) to yield methyl 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate (200 mg, 410.92 µmol, 53.5% yield, 80.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 9.18 (s, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.73 (dd, J = 2.0, 8.6 Hz, 1H), 7.60-7.55 (m, 2H), 7.49 (d, J = 10.8 Hz, 3H), 7.32 (d, J = 1.2 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.61 (d, J = 5.1 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H); ES-LCMS m/z 390.2 [M+H]+. Step 4: 3-(1-Methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid
Figure imgf000427_0001
[001008] To a solution of methyl 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoate (200 mg, 410.92 µmol, 80%, 1 eq) in THF (2 mL) and MeOH (2 mL) was added NaOH (109.58 mg, 410.92 µmol, 2 mL, 15%, 1 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated to yield a residue which was dissolved HCl (1M, 10 mL), adjusted pH to 5~6. The reaction mixture was quenched by addition of water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-(1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (100 mg, 242.44 µmol, 59.0% yield, 91.0% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 9.41-9.31 (m, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = 9.3 Hz, 3H), 7.55 (d, J = 8.6 Hz, 3H), 6.55 (d, J = 8.6 Hz, 1H), 4.65 (d, J = 5.4 Hz, 2H), 3.73 (s, 3H); ES-LCMS m/z 376.2 [M+H]+. Step 5: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000427_0002
[001009] To a solution of 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (70 mg, 169.71 µmol, 91%, 1 eq) in THF (3 mL) was added Et3N (51.52 mg, 509.13 µmol, 70.86 µL, 3 eq) and methanamine; hydrochloride (57.29 mg, 848.56 µmol, 5 eq) and HATU (129.06 mg, 339.42 µmol, 2 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water (0.05% NH3·H2O + 10 mM NH4HCO3)-ACN]; B%: 36%-66%, 10 min), followed by lyophilization to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (27.73 mg, 71.40 µmol, 42.0% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (t, J = 6.5 Hz, 1H), 8.05 (d, J = 4.3 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.65 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 3.75 (s, 3H), 2.74 (d, J = 4.3 Hz, 3H); ES-LCMS m/z 389.2 [M+H]+. T-C-49 & T-C-50 (isomers of T-C-175)
Figure imgf000428_0002
Step 1: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)cyclohexyl]methylamino]benzenesulfonamide and N-methyl-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)cyclohexyl]methylamino]benzenesulfonamide
Figure imgf000428_0001
[001010] To a stirred solution of 4-amino-N-methyl-3-(1-methylimidazol-4- yl)benzenesulfonamide (155.60 mg, 555.04 µmol, 95.0% purity, 1 eq) and 4- (trifluoromethyl)cyclohexanecarbaldehyde (200 mg, 777.06 µmol, 70.0% purity, 1.4 eq) in MeOH (10 mL) was added AcOH (6.67 mg, 111.01 µmol, 6.35 µL, 0.2 eq). The reaction mixture was stirred under N2 atmosphere at 25 °C for 1 h. NaBH3CN (174.39 mg, 2.78 mmol, 5 eq) was added and the reaction mixture was stirred under N2 atmosphere at 25 °C for 11 h. The reaction mixture was concentrated under reduced pressure, diluted with H2O (15 mL), adjust pH to 8 by sat aq NaHCO3 and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150*30mm*4µm; mobile phase: [water(0.05%HCl)-ACN]; B%: 30%-50%, 10min) to yield crude product which was separated by chiral SFC (column: Phenomenex-Cellulose-2 (250mm*30mm, 5µm); mobile phase: [0.1%NH3H2O ETOH]; B%: 40%-40%, min) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (20 mL) and H2O (40 mL) and lyophilized to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)cyclohexyl]methylamino]benzenesulfonamide (15.11 mg, 35.10 µmol, 6.3% yield, 100.0% purity, SFC: Rt = 4.596, ee = 100.0%) as a gray solid.1H NMR (500 MHz, DMSO- d6) δ ppm 8.80 (t, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 1.1 Hz, 1H), 7.40 (dd, J = 2.1, 8.7 Hz, 1H), 6.98 (d, J = 5.2 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 3.73 (s, 3H), 3.25- 3.17 (m, 2H), 2.36 (d, J = 5.0 Hz, 4H), 1.96 (s, 1H), 1.67-1.65 (m, 4H), 1.62-1.52 (m, 4H); ES- LCMS m/z 431.3 [M+H]+. Peak 2 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (20 mL) and H2O (40 mL) and lyophilized to yield N-methyl-3-(1- methylimidazol-4-yl)-4-[[4-(trifluoromethyl)cyclohexyl]methylamino]benzenesulfonamide (45.85 mg, 104.85 µmol, 18.9% yield, 98.4% purity, SFC: Rt = 4.950, ee = 98.2%) as a gray solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.88 (t, J = 5.5 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 0.9 Hz, 1H), 7.40 (dd, J = 2.1, 8.7 Hz, 1H), 6.97 (q, J = 5.0 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 3.73 (s, 3H), 3.10 (t, J = 6.0 Hz, 2H), 2.36 (d, J = 5.0 Hz, 3H), 2.27-2.15 (m, 1H), 1.93-1.89 (m, 4H), 1.66-1.58 (m, 1H), 1.31-1.22 (m, 2H), 1.15-1.06 (m, 2H); ES-LCMS m/z 431.1 [M+H]+. T-C-51
Figure imgf000429_0001
Step 1: N-Benzyl-2-fluoro-5-(methylsulfamoyl)benzamide
Figure imgf000430_0002
[001011] To a solution of phenylmethanamine (206.76 mg, 1.93 mmol, 210.33 µL, 1 eq) in DMF (3 mL) was added DIEA (748.12 mg, 5.79 mmol, 1.01 mL, 3 eq), 2-fluoro-5- (methylsulfamoyl)benzoic acid (500 mg, 1.93 mmol, 90% purity, 1 eq) and HATU (1.32 g, 3.47 mmol, 1.8 eq). The mixture was stirred at 25 °C for 0.5 h. The mixture was added water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 0/1, Rf = 0.7) to yield N-benzyl-2-fluoro-5-(methylsulfamoyl)benzamide (300 mg, 856.20 µmol, 44.4% yield, 92.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.61 (dd, J = 2.7, 7.0 Hz, 1H), 8.00 (ddd, J = 2.7, 4.7, 8.6 Hz, 1H), 7.38-7.34 (m, 4H), 7.33-7.30 (m, 1H), 7.29-7.26 (m, 1H), 7.00 (s, 1H), 4.72-4.68 (m, 3H), 2.67 (d, J = 5.5 Hz, 3H); ES-LCMS m/z 323.2 [M+H]+. Step 2: N-Benzyl-5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000430_0001
[001012] To a solution of N-benzyl-2-fluoro-5-(methylsulfamoyl)benzamide (150 mg, 428.10 µmol, 92.0% purity, 1 eq) in DMF (3 mL) was added [4- (trifluoromethyl)phenyl]methanamine (149.96 mg, 856.20 µmol, 121.92 µL, 2 eq). The mixture was stirred at 70 °C for 4 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150 * 25 mm * 5 µm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 53%-83%, 10 min), followed by lyophilization to yield N-benzyl-5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (76.67 mg, 160.57 µmol, 37.5% yield, 100% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.95 (t, J = 5.8 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 2.1, 8.9 Hz, 1H), 7.61 (s, 1H), 7.60 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.41-7.34 (m, 4H), 7.34-7.29 (m, 1H), 6.69 (s, 1H), 6.59 (d, J = 9.0 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.54 (d, J = 6.0 Hz, 2H), 4.24 (q, J = 5.4 Hz, 1H), 2.59 (d, J = 5.5 Hz, 3H); ES-LCMS m/z 478.2 [M+H]+. T-C-52
Figure imgf000431_0001
Step 1: 3-Bromo-N-methyl-4-[[3-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000431_0002
[001013] To a solution of 3-bromo-4-fluoro-N-methyl-benzenesulfonamide (400 mg, 1.49 mmol, 100% purity, 1 eq) in DMSO (6 mL) was added [3-(trifluoromethyl)phenyl]methanamine (522.64 mg, 2.98 mmol, 428.39 μL, 2 eq). The mixture was stirred at 140 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.30) to yield 3-bromo-N-methyl-4-[[3- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (590 mg, 1.32 mmol, 88.8% yield, 95.0% purity) as a brown oil.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 2.0 Hz, 1H), 7.65- 7.56 (m, 3H), 7.56-7.48 (m, 2H), 6.57 (d, J = 8.6 Hz, 1H), 5.40-5.25 (m, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.25 (q, J = 5.7 Hz, 1H), 2.65 (d, J = 5.5 Hz, 3H); ES-LCMS m/z 425.1 [M+H]+. Step 2: N-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[3- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000432_0001
[001014] A mixture of 3-bromo-N-methyl-4-[[3- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (200 mg, 448.91 μmol, 95% purity, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (136.80 mg, 538.72 μmol, 1.2 eq), KOAc (133.00 mg, 1.36 mmol, 3.02 eq) and Pd(PPh3)2Cl2 (31.51 mg, 44.89 μmol, 0.1 eq) in 1,4-dioxane (4 mL) was degassed and purged with N2 for 3 times and the mixture was stirred at 110 °C under N2 atmosphere for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 4/1, TLC: PE/EtOAc = 3/1, Rf = 0.70) to yield N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[3- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (100 mg, 138.21 μmol, 30.8% yield, 65.0% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.14 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 2.2, 8.8 Hz, 1H), 7.63 (s, 1H), 7.59-7.46 (m, 4H), 6.92-6.85 (m, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 2.62 (d, J = 5.6 Hz, 3H), 1.25 (s, 12H); ES-LCMS m/z 471.2 [M+H]+. Step 3: 3-(1-Cyclopropylimidazol-4-yl)-N-methyl-4-[[3- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000433_0001
[001015] A mixture of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[3- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (100 mg, 138.21 μmol, 65% purity, 1 eq), 1-cyclopropyl-4-iodo-imidazole (80.86 mg, 138.21 μmol, 40% purity, 1 eq), Cs2CO3 (135.09 mg, 414.62 μmol, 3 eq) and Pd(dppf)Cl2 (10.11 mg, 13.82 μmol, 0.1 eq) in 1,4-dioxane (1.5 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45%-75%, 10 min), followed by lyophilization to yield 3-(1-cyclopropylimidazol-4-yl)-N- methyl-4-[[3-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (11.42 mg, 25.35 μmol, 18.3% yield, 100.0% purity) as a gray solid.1H NMR (400 MHz, CDCl3) δ ppm 9.23 (t, J = 6.0 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J = 1.1 Hz, 1H), 7.57-7.44 (m, 4H), 7.40 (d, J = 1.2 Hz, 1H), 6.56 (d, J = 8.9 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.13 (q, J = 5.3 Hz, 1H), 3.48-3.39 (m, 1H), 2.63 (d, J = 5.6 Hz, 3H), 1.13-1.01 (m, 4H); ES-LCMS m/z 451.2 [M+H]+.
Figure imgf000433_0002
Figure imgf000433_0003
Step 1: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)-1- bicyclo[2.2.2]octanyl]methylamino]benzenesulfonamide
Figure imgf000434_0001
[001016] To a solution of 4-amino-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (55 mg, 196.19 µmol, 95% purity, 1 eq) in MeOH (5 mL) was added 4- (trifluoromethyl)bicyclo[2.2.2]octane-1-carbaldehyde (67.43 mg, 196.19 µmol, 60% purity, 1 eq), followed by 1 drop of AcOH. The mixture was stirred at 25 °C for 2 h. NaBH3CN (36.99 mg, 588.58 µmol, 3 eq) was added and the mixture was stirred at 25 °C for 16 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN];B%: 50%-80%,10min), followed by lyophilization to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)-1-bicyclo[2.2.2]octanyl]methylamino]benzenesulfonamide (8.74 mg, 19.14 µmol, 9.8% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.75 (br s, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 2.2, 8.8 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J = 1.2 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.11 (q, J = 5.4 Hz, 1H), 3.76 (s, 3H), 3.00 (d, J = 5.4 Hz, 2H), 2.61 (d, J = 5.4 Hz, 3H), 1.77-1.67 (m, 6H), 1.64-1.56 (m, 6H); ES-LCMS m/z 457.3 [M+H]+. T-C-103
Figure imgf000434_0002
Step 1: N-Ethyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000435_0001
[001017] To a solution of ethanamine (102.70 mg, 2.28 mmol, 149.05 µL, 9 eq) in DMF (5 mL) was added 3-(1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (100 mg, 253.10 µmol, 95% purity, 1 eq), Et3N (76.83 mg, 759.30 µmol, 105.69 µL, 3 eq) and HATU (173.23 mg, 455.58 µmol, 1.8 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 40%-70%, 10 min) and lyophilized to yield N-ethyl-3-(1-methylimidazol- 4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide (40 mg, 98.77 µmol, 39.0 % yield, 99.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.95 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.59-7.55 (m, 2H), 7.49 (d, J = 9.5 Hz, 3H), 7.36 (dd, J = 2.2, 8.6 Hz, 1H), 7.32 (d, J = 1.2 Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 5.94 (s, 1H), 4.60 (d, J = 5.4 Hz, 2H), 3.77 (s, 3H), 3.51- 3.44 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 403.3 [M+H]+. T-C-104
Figure imgf000435_0002
Step 1: N-Cyclopropyl-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000436_0001
[001018] To a solution of cyclopropanamine (57.80 mg, 1.01 mmol, 70.15 µL, 4 eq) in THF (3 mL) was added DIEA (65.42 mg, 506.20 µmol, 88.17 µL, 2 eq) and 3-(1-methylimidazol-4-yl)- 4-[[4-(trifluoromethyl)phenyl]methylamino]benzoic acid (100 mg, 253.10 µmol, 95%, 1 eq) and HATU (192.47 mg, 506.20 µmol, 2 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05% NH3·H2O + 10 mM NH4HCO3)-ACN]; B%: 40%-70%, 10 min), followed by lyophilization to yield N-cyclopropyl-3- (1-methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide (73.29 mg, 176.85 µmol, 69.8% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz,CDCl3) δ ppm 8.98 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.60-7.54 (m, 2H), 7.48 (d, J = 8.2 Hz, 3H), 7.34-7.29 (m, 2H), 6.45 (d, J = 8.6 Hz, 1H), 6.07 (s, 1H), 4.59 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 2.87 (m, 1H), 0.87-0.81 (m, 2H), 0.61-0.54 (m, 2H); ES-LCMS m/z 415.2 [M+H]+. T-C-105
Figure imgf000436_0002
Figure imgf000436_0003
Step 1: 3-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[(2S)-2- phenylpropyl]amino]benzenesulfonamide
Figure imgf000437_0001
[001019] To a solution of 3-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl- benzenesulfonamide (300 mg, 734.06 µmol, 95% purity, 1 eq) in DMSO (5 mL) was added (2S)- 2-phenylpropan-1-amine (198.50 mg, 1.47 mmol, 210.05 µL, 2 eq). The mixture was stirred at 140 °C for 2 h. The mixture was added water (20 mL) and extracted with EtOAc (20 mL x 3).The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 5/1, Rf = 0.55) to yield 3-bromo- N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[(2S)-2-phenylpropyl]amino]benzenesulfonamide (336 mg, 634.02 µmol, 86.3% yield, 95.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.83 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 2.0, 8.6 Hz, 1H), 7.39-7.34 (m, 2H), 7.30-7.26 (m, 2H), 7.25 (s, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 1H), 4.79 (t, J = 5.3 Hz, 1H), 4.03 (s, 2H), 3.80 (s, 3H), 3.47-3.41 (m, 1H), 3.36-3.29 (m, 1H), 3.15-3.07 (m, 1H), 2.53 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H); ES-LCMS m/z 505.1 [M+H]+. Step 2: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[(2S)-2- phenylpropyl]amino]benzenesulfonamide
Figure imgf000437_0002
[001020] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[(2S)-2- phenylpropyl]amino]benzenesulfonamide (330 mg, 622.70 µmol, 95% purity, 1 eq) in DMF (4 mL) was added tributyl-(1-methylimidazol-4-yl)stannane (486.56 mg, 1.25 mmol, 95% purity, 2 eq) and Pd(dppf)Cl2 (45.56 mg, 62.27 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 3 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 3/1, Rf = 0.2) to yield N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[(2S)-2- phenylpropyl]amino]benzenesulfonamide (310 mg, 583.58 µmol, 93.7% yield, 95.0% purity) as blue oil.1H NMR (400 MHz, CDCl3) δ ppm 8.61 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 2.2, 8.8 Hz, 1H), 7.39 (s, 1H), 7.36-7.26 (m, 5H), 7.26-7.15 (m, 5H), 6.84 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 9.0 Hz, 1H), 4.01 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.47-3.36 (m, 2H), 3.21-3.12 (m, 1H), 2.51 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H); ES-LCMS m/z 505.3 [M+H]+. Step 3: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[(2S)-2- phenylpropyl]amino]benzenesulfonamide
Figure imgf000438_0001
[001021] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4- yl)-4-[[(2S)-2-phenylpropyl]amino]benzenesulfonamide (150 mg, 297.24 µmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 45.44 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150 * 25 mm * 5 µm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 40%-70%,10 min), followed by lyophilization to yield N- methyl-3-(1-methylimidazol-4-yl)-4-[[(2S)-2-phenylpropyl]amino]benzenesulfonamide (48.27 mg, 125.54 µmol, 42.2% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 2.2, 8.8 Hz, 1H), 7.37 (s, 1H), 7.34-7.31 (m, 1H), 7.31-7.27 (m, 3H), 7.26-7.20 (m, 1H), 7.18 (d, J = 0.8 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 4.20-4.10 (m, 1H), 3.72 (s, 3H), 3.45-3.35 (m, 2H), 3.20-3.09 (m, 1H), 2.60 (d, J = 5.5 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H); ES-LCMS m/z 385.3 [M+H]+. T-C-106
Figure imgf000439_0002
Step 1: 3-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[(2R)-2- phenylpropyl]amino]benzenesulfonamide
Figure imgf000439_0001
[001022] To a solution of 3-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl- benzenesulfonamide (100 mg, 244.69 µmol, 95% purity, 1 eq) in DMSO (2 mL) was added (2R)- 2-phenylpropan-1-amine (66.17 mg, 489.37 µmol, 70.02 µL, 2 eq). The mixture was stirred at 140 °C for 2 h. The mixture was added water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl- 4-[[(2R)-2-phenylpropyl]amino]benzenesulfonamide (120 mg, 166.85 µmol, 68.1% yield, 70.0% purity) as a yellow oil.1H NMR (500 MHz, CDCl3) δ ppm 7.82 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 2.1, 8.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.7 Hz, 3H), 6.86 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.7 Hz, 1H), 4.79 (t, J = 5.3 Hz, 1H), 4.03 (s, 2H), 3.80 (s, 3H), 3.44 (td, J = 6.4, 12.5 Hz, 1H), 3.36-3.31 (m, 1H), 3.14-3.07 (m, 1H), 2.61 (s, 3H), 1.41 (d, J = 6.9 Hz, 3H); ES-LCMS m/z 505.1 [M+H]+. Step 2: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[(2R)-2- phenylpropyl]amino]benzenesulfonamide
Figure imgf000440_0001
[001023] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[(2R)-2- phenylpropyl]amino]benzenesulfonamide (120 mg, 166.85 µmol, 70% purity, 1 eq) in DMF (3 mL) was added tributyl-(1-methylimidazol-4-yl)stannane (130.37 mg, 333.70 µmol, 95% purity, 2 eq) and Pd(dppf)Cl2 (12.21 mg, 16.69 µmol, 0.1 eq). The mixture was stirred at 130 °C for 3 h under N2 atmosphere. To the mixture was added water (10 mL) was added and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 3/1, Rf = 0.2) to yield N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[(2R)-2- phenylpropyl]amino]benzenesulfonamide (80 mg, 150.60 µmol, 90.2% yield, 95.0% purity) as blue oil.1H NMR (400 MHz, CDCl3) δ ppm 8.59 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 2.2, 8.8 Hz, 1H), 7.39 (s, 1H), 7.35-7.28 (m, 5H), 7.25-7.16 (m, 5H), 6.84 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 9.0 Hz, 1H), 4.01 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.46-3.37 (m, 2H), 3.18-3.12 (m, 1H), 2.51 (s, 3H), 1.42 (d, J = 7.0 Hz, 3H); ES-LCMS m/z 505.3 [M+H]+. Step 3: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[(2R)-2- phenylpropyl]amino]benzenesulfonamide
Figure imgf000440_0002
[001024] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4- yl)-4-[[(2R)-2-phenylpropyl]amino]benzenesulfonamide (80 mg, 150.60 µmol, 95% purity, 1 eq) in DCM (3 mL) was added TFA (1.46 g, 12.83 mmol, 950.00 µL, 85.20 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150 * 25 mm * 5 µm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 40%-70%, 10 min), followed by lyophilization to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[(2R)-2- phenylpropyl]amino]benzenesulfonamide (21.87 mg, 56.88 µmol, 37.7% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.62 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 2.3, 8.6 Hz, 1H), 7.37 (d, J = 0.8 Hz, 1H), 7.34-7.31 (m, 1H), 7.30 (d, J = 2.3 Hz, 3H), 7.25- 7.20 (m, 1H), 7.18 (d, J = 1.2 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 4.17 (q, J = 5.3 Hz, 1H), 3.72 (s, 3H), 3.40 (t, J = 11.0 Hz, 2H), 3.17-3.11 (m, 1H), 2.60 (d, J = 5.5 Hz, 3H), 1.41 (d, J = 6.7 Hz, 3H); ES-LCMS m/z 385.2 [M+H]+. T-C-121
Figure imgf000441_0002
Step 1: 2-(1-Methylimidazol-4-yl)-4-methylsulfonyl-N-[[4- (trifluoromethyl)phenyl]methyl]aniline
Figure imgf000441_0001
[001025] A mixture of 4-bromo-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline (100 mg, 236.45 µmol, 97%, 1 eq), methylsulfinyloxysodium (163.80 mg, 1.18 mmol, 5 eq, HCl), CuI (45.03 mg, 236.45 µmol, 1 eq), D-glucosamine (42.37 mg, 236.45 µmol, 1 eq) and KOAc (69.62 mg, 709.36 µmol, 3 eq) in DMSO (2.5 mL) and H2O (2.5 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 24 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 43%- 73%, 10 min) and lyophilized to yield 2-(1-methylimidazol-4-yl)-4-methylsulfonyl-N-[[4- (trifluoromethyl)phenyl]methyl]aniline (11.7 mg, 28.58 µmol, 12.1% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.37 (s, 1H), 7.93 (s, 1H), 7.63-7.45 (m, 6H), 6.57 (d, J = 8.1 Hz, 1H), 4.62 (s, 2H), 3.79 (s, 3H), 3.02 (s, 3H); ES-LCMS m/z 410.2 [M+H]+. T-C-122
Figure imgf000442_0001
Step 1: 3-(1-Methylimidazol-4-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000442_0002
[001026] To a solution of 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (50.00 mg, 133.21 μmol, 1 eq) in DMF (3 mL) was added NH4Cl (50 mg, 934.75 μmol, 7.02 eq) and HATU (100 mg, 263.00 μmol, 1.97 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25mm x 5 μm; mobile phase: [water(10 mM NH4HCO3)- ACN]; B%: 35%-65%, 10 min), followed by lyophilization to yield 3-(1-methylimidazol-4-yl)-4- [[4-(trifluoromethyl)phenyl]methylamino]benzamide (27.25 mg, 72.79 µmol, 54.6% yield, 100.0%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.20 (t, J = 6.1 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.72-7.67 (m, 3H), 7.62 (s, 1H), 7.57-7.53 (m, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 1.7, 8.6 Hz, 1H), 6.93 (s, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 3.75 (s, 3H); ES-LCMS m/z 375.3 [M+H]+. T-C-126
Figure imgf000443_0001
Figure imgf000443_0003
Step 1: N-Methyl-4-[[4-(trifluoromethyl)phenyl]methylamino]-3-(2- trimethylsilylethynyl)benzenesulfonamide
Figure imgf000443_0002
[001027] To a solution of 3-bromo-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (3.5 g, 7.09 mmol, 84% purity, 1 eq) and ethynyl(trimethyl)silane (2.09 g, 21.26 mmol, 2.95 mL, 3 eq) in TEA (30 mL)was added Pd(PPh3)2Cl2 (248.75 mg, 354.40 µmol, 0.05 eq) and CuI (67.50 mg, 354.40 µmol, 0.05 eq).The mixture was stirred at 70 °C for 5 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.53) to yield N-methyl-4-[[4-(trifluoromethyl)phenyl]methylamino]-3-(2- trimethylsilylethynyl)benzenesulfonamide (3.0 g, 6.36 mmol, 89.7% yield, 93.3% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.83 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 2.1, 8.7 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H), 5.58 (t, J = 5.5 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.18 (q, J = 5.5 Hz, 1H), 2.63 (d, J = 5.4 Hz, 3H), 0.25 (s, 9H); ES-LCMS m/z 441.3 [M+H]+. Step 2: tert-Butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-(2- trimethylsilylethynyl)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000444_0001
[001028] To a solution of N-methyl-4-[[4-(trifluoromethyl)phenyl]methylamino]-3-(2- trimethylsilylethynyl)benzenesulfonamide (3 g, 6.36 mmol, 93.3% purity, 1 eq) in DCM (20 mL) was added DMAP (3.88 g, 31.78 mmol, 5 eq) and (Boc)2O (13.87 g, 63.56 mmol, 14.60 mL, 10 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 3/1, Rf = 0.49) to yield tert-butyl N-[4-[tert- butoxycarbonyl(methyl)sulfamoyl]-2-(2-trimethylsilylethynyl)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (1.9 g, 2.56 mmol, 40.3% yield, 86.5% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (br s, 1H), 7.72 (d, J = 6.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.07 (br s, 1H), 4.88 (s, 2H), 3.36 (s, 3H), 1.40 (s, 9H), 1.34 (s, 9H), 0.25 (s, 9H); ES-LCMS m/z 658.3 [M+NH4]+. Step 3: 1-[4-[5-[tert-Butoxycarbonyl(methyl)sulfamoyl]-2-[tert-butoxycarbonyl-[[4- (trifluoromethyl)phenyl]methyl]amino]phenyl]triazol-1-yl]cyclopropanecarboxylic acid
Figure imgf000445_0001
[001029] To a solution of tert-butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-(2- trimethylsilylethynyl)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (1 g, 1.56 mmol, 1 eq) and 1-azidocyclopropanecarboxylic acid (595.06 mg, 4.68 mmol, 3 eq) in t-BuOH (15 mL) and H2O (15 mL) was added sodium ascorbate (309.17 mg, 1.56 mmol, 1 eq) and CuSO4 (249.09 mg, 1.56 mmol, 239.51 µL, 1 eq) .The mixture was stirred at 25 °C for 12 h. The mixture was diluted with EtOAc (200 mL), washed with brine (20 mL x 2), dried over Na2SO4, concentrated under reduced pressure to yield 1-[4-[5-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[tert- butoxycarbonyl-[[4-(trifluoromethyl)phenyl]methyl]amino]phenyl]triazol-1- yl]cyclopropanecarboxylic acid (1.44 g, 1.55 mmol, 99.4% yield, 75.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (br s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 3H), 7.39-7.29 (m, 2H), 7.03 (br s, 1H), 5.53 (s, 2H), 3.39 (s, 3H), 2.03 (s, 2H), 1.79 (d, J = 8.8 Hz, 2H), 1.35 (s, 9H), 1.20 (s, 9H); ES-LCMS m/z 696.2 [M+H]+. Step 4: tert-Butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[1-(1- carbamoylcyclopropyl)triazol-4-yl]phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000446_0001
[001030] To a solution of 1-[4-[5-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[tert- butoxycarbonyl-[[4-(trifluoromethyl)phenyl]methyl]amino]phenyl]triazol-1- yl]cyclopropanecarboxylic acid (1.2 g, 1.38 mmol, 80% purity, 1 eq) in DMF (15 mL) was added HATU (787.02 mg, 2.07 mmol, 1.5 eq), DIEA (356.68 mg, 2.76 mmol, 480.71 µL, 2 eq) and NH4Cl (147.62 mg, 2.76 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.59) to yield tert- butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[1-(1-carbamoylcyclopropyl)triazol-4- yl]phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (1.1 g, 1.14 mmol, 83.0% yield, 72.3% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.57 (br s, 1H), 8.02 (s, 3H), 7.85 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.11 (br s, 1H), 5.50 (s, 2H), 3.40 (s, 3H), 1.99 (s, 2H), 1.61 (s, 9H), 1.51 (s, 2H), 1.37 (s, 9H); ES-LCMS m/z 695.2 [M+H]+. Step 5: tert-Butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[1-(1- cyanocyclopropyl)triazol-4-yl]phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000447_0001
[001031] To a solution of tert-butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[1-(1- carbamoylcyclopropyl)triazol-4-yl]phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (400 mg, 416.23 µmol, 72.3% purity, 1 eq) in EtOAc (5 mL) was added TFAA (437.10 mg, 2.08 mmol, 289.47 µL, 5 eq) and pyridine (329.23 mg, 4.16 mmol, 335.95 µL, 10 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl N-[4-[tert- butoxycarbonyl(methyl)sulfamoyl]-2-[1-(1-cyanocyclopropyl)triazol-4-yl]phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (300 mg, 324.82 µmol, 78.0% yield, 73.3% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.63 (br s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 6.6, 11.0 Hz, 3H), 7.15 (br s, 1H), 5.07 (s, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.40 (s, 3H), 3.05 (s, 4H), 1.37 (s, 9H), 1.15 (s, 9H); ES-LCMS m/z 696.2 [M+H]+. Step 6: N-Cyclopropyl-5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]benzamide
Figure imgf000447_0002
[001032] To a solution of tert-butyl N-[4-[tert-butoxycarbonyl(methyl)sulfamoyl]-2-[1-(1- cyanocyclopropyl)triazol-4-yl]phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (300 mg, 324.82 µmol, 73.3% purity, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 41.58 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05%NH3·H2O+10mM NH4HCO3)-ACN]; B%: 45%- 75%, 10min), followed by lyophilization to yield 3-[1-(1-cyanocyclopropyl)triazol-4-yl]-N- methyl-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (91.24 mg, 191.49 µmol, 59.0% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, 1H), 8.19 (t, J = 6.0 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.47 (dd, J = 2.0, 8.8 Hz, 1H), 7.05 (q, J = 4.7 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 2.36 (d, J = 5.1 Hz, 3H), 2.11 (d, J = 10.0 Hz, 4H); ES-LCMS m/z 477.2 [M+H]+. T-C-127
Figure imgf000448_0001
Step 1: 4-Cyclopropylsulfonyl-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline
Figure imgf000448_0002
[001033] To a solution of 4-bromo-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline (100 mg, 236.45 µmol, 97%, 1 eq) and cyclopropylsulfinyloxysodium (302.96 mg, 2.36 mmol, 10 eq) in DMSO (2.5 mL) and H2O (2.5 mL) was added CuI (45.03 mg, 236.45 µmol, 1 eq) and D-glucosamine (42.37 mg, 236.45 µmol, 1 eq) and KOAc (92.82 mg, 945.81 µmol, 4 eq). The mixture was stirred at 110 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 42%-72%, 10 min), followed by lyophilization to yield 4-cyclopropylsulfonyl-2-(1- methylimidazol-4-yl)-N-[[4-(trifluoromethyl)phenyl]methyl]aniline (15.99 mg, 35.69 µmol, 15.0% yield, 97.2% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.31 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.54-7.47 (m, 4H), 7.33 (s, 1H), 6.56 (d, J = 8.8 Hz, 1H), 4.61 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H), 2.47-2.39 (m, 1H), 1.32-1.26 (m, 2H), 1.00-0.94 (m, 2H); ES-LCMS m/z 436.0 [M+H]+. T-C-136
Figure imgf000449_0002
Step 1: 3-Fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-4-nitro-benzenesulfonamide
Figure imgf000449_0001
[001034] To a solution of 3-fluoro-4-nitro-benzenesulfonyl chloride (950 mg, 3.96 mmol, 1 eq) in THF (14 mL) was added 1-(4-methoxyphenyl)-N-methyl-methanamine (608.00 mg, 4.02 mmol, 1.01 eq) and DIEA (1.54 g, 11.89 mmol, 2.07 mL, 3 eq) at -20 °C. The mixture was stirred at -20 °C for 1 h under N2 atmosphere. TLC (PE/EtOAc = 3/1, Rf = 0.40) indicated starting material was consumed completely and one new spot formed. The reaction mixture was quenched by 2 M HCl at -10 °C until pH = 2, diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with 1 M HCl (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-fluoro-N-[(4-methoxyphenyl)methyl]-N- methyl-4-nitro-benzenesulfonamide (1.33 g, 3.57 mmol, 89.9% yield, 95.0% purity) as a yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.21 (dd, J = 7.0, 8.7 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.74-7.72 (m, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.18 (s, 2H), 3.82 (s, 3H), 2.69 (s, 3H). Step 2: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)-4-nitro- benzenesulfonamide
Figure imgf000450_0001
[001035] To a solution of 4-methyl-1H-pyrazole (292.75 mg, 3.57 mmol, 287.01 μL, 1 eq) in THF (15 mL) was added NaH (855.68 mg, 21.39 mmol, 60% purity, 6 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. 3-Fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-4-nitro- benzenesulfonamide (1.33 g, 3.57 mmol, 95% purity, 1 eq) was added and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative TLC (PE/EtOAc = 2/1, Rf = 0.40) to yield N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)-4-nitro- benzenesulfonamide (360 mg, 821.23 μmol, 23.0% yield, 95.0% purity) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 1.7 Hz, 1H), 7.95-7.89 (m, 1H), 7.87-7.82 (m, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.19 (s, 2H), 3.81 (s, 3H), 2.70 (s, 3H), 2.18 (s, 3H); ES-LCMS m/z 417.4 [M+H]+. Step 3: 4-Amino-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1- yl)benzenesulfonamide
Figure imgf000451_0001
[001036] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1- yl)-4-nitro-benzenesulfonamide (310 mg, 707.17 μmol, 95% purity, 1 eq) in MeOH (80 mL) was added Pd/C (294.50 mg, 277.83 μmol, 10% purity, 3.93e-1 eq). The mixture was stirred at 25 °C for 2 h. TLC (PE/EtOAc = 2/1, Rf = 0.50) indicated starting material was consumed completely and one new spot formed. The mixture was filtered and concentrated under reduced pressure to yield 4-amino-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1- yl)benzenesulfonamide (300 mg, 698.64 μmol, 98.8% yield, 90.0% purity) as a brown solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.62 (s, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 2.0, 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.50 (s, 2H), 4.00 (s, 2H), 3.74 (s, 3H), 2.46 (s, 3H), 2.15-2.07 (m, 3H); ES-LCMS m/z 387.2 [M+H]+. Step 4: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000451_0002
[001037] To a solution of 4-amino-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4- methylpyrazol-1-yl)benzenesulfonamide (200 mg, 465.76 μmol, 90% purity, 1 eq) and 2-fluoro- 5-(trifluoromethyl)pyridine (76.89 mg, 465.76 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (193.11 mg, 1.40 mmol, 3 eq). The mixture was stirred at 130 °C for 3 h. TLC (PE/EtOAc = 3/1, Rf = 0.60) indicated 40% of starting material remained and one major new spot with lower polarity was detected. The reaction mixture was quenched by water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 4/1, TLC: PE/EtOAc = 3/1, Rf = 0.60) to yield N-[(4- methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (110 mg, 186.25 μmol, 40.0% yield, 90.0% purity) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.53 (s, 1H), 8.87 (d, J = 9.5 Hz, 1H), 8.55 (s, 1H), 7.78-7.74 (m, 3H), 7.71-7.67 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.90-6.85 (m, 3H), 4.13 (s, 2H), 3.82-3.80 (m, 3H), 2.67-2.57 (m, 3H), 2.21 (s, 3H); ES-LCMS m/z 532.6 [M+H]+. Step 5: N-Methyl-3-(4-methylpyrazol-1-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000452_0001
[001038] A solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)- 4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (110 mg, 186.25 μmol, 90% purity, 1 eq) in DCM (1 mL) and TFA (0.2 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)- ACN]; B%: 48%-78%, 10 min), followed by lyophilization to yield N-methyl-3-(4-methylpyrazol- 1-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (15.09 mg, 36.68 μmol, 19.7% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 10.51 (s, 1H), 8.84 (d, J = 8.9 Hz, 1H), 8.54 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 2.0, 8.9 Hz, 1H), 7.75 (dd, J = 2.4, 8.6 Hz, 1H), 7.70 (d, J = 13.9 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.44-4.21 (m, 1H), 2.71 (d, J = 5.5 Hz, 3H), 2.21 (s, 3H); ES-LCMS m/z 412.2 [M+H]+. T-C-138
Figure imgf000453_0001
Step 1: N-Methyl-3-[1-(4-pyridyl)imidazol-4-yl]-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000453_0002
[001039] To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (150 mg, 347.21 µmol, 95.0% purity, 1 eq) and 4-iodopyridine (92.53 mg, 451.37 µmol, 1.3 eq) in DMF (4 mL) was added KI (57.64 mg, 347.21 µmol, 1 eq) and K2CO3 (110.37 mg, 798.59 µmol, 2.3 eq). The mixture was bubbled with N2 for 3 min and stirred under microwave (0 Bar) at 130 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18 150*30mm*4µm; mobile phase: [water(0.05%HCl)-ACN]; B%: 27%-57%, 10 min) to yield N-methyl-3-[1-(4-pyridyl)imidazol-4- yl]-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (12.92 mg, 23.81 µmol, 6.9% yield, 96.6% purity, HCl) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01- 8.89 (m, 3H), 8.74 (s, 1H), 8.29 (s, 2H), 8.03 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.8 Hz, 2H), 7.44 (dd, J = 2.2, 8.8 Hz, 1H), 7.08 (s, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.68 (s, 2H), 2.38 (s, 3H); ES-LCMS m/z 488.1 [M+H]+. T-C-139 & T-C-140 (isomers of T-C-175)
Figure imgf000454_0001
Step 1: N-Methyl-3-(1-methyl-1H-imidazol-4-yl)-4-(((1r,4r)-4- (trifluoromethyl)cyclohexyl)amino)benzenesulfonamide and N-methyl-3-(1-methyl-1H- imidazol-4-yl)-4-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)amino)benzenesulfonamide
Figure imgf000454_0002
[001040] To a solution of 4-amino-N-methyl-3-(1-methylimidazol-4-yl)benzenesulfonamide (100 mg, 337.94 µmol, 90% purity, 1 eq) in MeOH (5 mL) was added 4- (trifluoromethyl)cyclohexanone (168.44 mg, 1.01 mmol, 3 eq), followed by 1 drop of AcOH. The mixture was stirred at 50 °C for 2 h. NaBH3CN (63.71 mg, 1.01 mmol, 3 eq) was added and the mixture was stirred at 50 °C for 16 h. The solvent was removed to yield a residue which was purified by preparative TLC (PE/EtOAc = 1/1, P1 (Rf = 0.36); P2 (Rf = 0.52)) to yield a product which was dissolved in ACN (5 mL) and H2O (20 mL) and lyophilized to yield N-methyl-3-(1- methyl-1H-imidazol-4-yl)-4-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)amino)benzenesulfonamide (33.97 mg, 79.94 µmol, 23.7% yield, 98.0% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (d, J = 7.6 Hz, 1H), 7.82-7.70 (m, 2H), 7.62 (s, 1H), 7.38 (dd, J = 2.0, 8.8 Hz, 1H), 6.98 (q, J = 5.1 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H), 3.51-3.39 (m, 1H), 2.35 (d, J = 5.1 Hz, 4H), 2.13 (d, J = 11.5 Hz, 2H), 1.92 (d, J = 11.5 Hz, 2H), 1.55-1.40 (m, 2H), 1.34- 1.20 (m, 2H); ES-LCMS m/z 417.2 [M+H]+ and N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4- (((1s,4s)-4-(trifluoromethyl)cyclohexyl)amino)benzenesulfonamide (19.83 mg, 47.62 µmol, 14.1% yield, 100.0% purity) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (d, J = 7.8 Hz, 1H), 7.84-7.74 (m, 2H), 7.67 (d, J = 1.0 Hz, 1H), 7.39 (dd, J = 2.0, 8.8 Hz, 1H), 6.99 (q, J = 5.1 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 3.91 (s, 1H), 3.73 (s, 3H), 2.36 (d, J = 5.1 Hz, 4H), 1.87 (d, J = 12.5 Hz, 2H), 1.78-1.51 (m, 6H); ES-LCMS m/z 417.2 [M+H]+. T-C-141
Figure imgf000455_0001
Step 1: 3-Bromo-N-(cyclopropylmethyl)-4-fluoro-benzenesulfonamide
Figure imgf000455_0002
[001041] To a solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (0.5 g, 1.83 mmol, 1 eq) in THF (10 mL) was added cyclopropylmethanamine (260.03 mg, 3.66 mmol, 2 eq) and DIEA (708.79 mg, 5.48 mmol, 955.25 µL, 3 eq). The mixture was stirred at 25 °C for 2 h. TLC (PE/EtOAc = 5/1, Rf = 0.40) showed the starting materials was consumed completely and one new spot was detected. The mixture was adjusted pH = 7-8 by HCl (1 N), added water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by silica gel column chromatography (from pure PE to PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.40) to yield 3-bromo-N-(cyclopropylmethyl)-4-fluoro-benzenesulfonamide (230 mg, 716.50 µmol, 39.2% yield, 96.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.10 (dd, J = 2.3, 6.3 Hz, 1H), 7.81 (m, 1H), 7.24 (t, J = 8.5 Hz, 1H), 4.89-4.40 (m, 1H), 2.86 (t, J = 6.5 Hz, 2H), 0.91-0.87 (m, 1H), 0.52-0.49 (m, 2H), 0.15-0.12 (m, 2H); ES-LCMS m/z 308.1, 310.1 [M+H]+. Step 2: 3-Bromo-N-(cyclopropylmethyl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide
Figure imgf000456_0001
[001042] To a solution of 3-bromo-N-(cyclopropylmethyl)-4-fluoro-benzenesulfonamide (160 mg, 498.43 µmol, 96%, 1 eq) in DMSO (5 mL) was added [4- (trifluoromethyl)phenyl]methanamine (174.60 mg, 996.86 µmol, 141.95 µL, 2 eq). The mixture was stirred at 130 °C for 12 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (100 mL x 3). The organic phase was separated, washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified on silica gel column chromatography (from pure PE to PE/EtOAc = 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.55) to yield 3-bromo-N-(cyclopropylmethyl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (50 mg, 52.88 µmol, 10.6% yield, 49.0% purity) as white oil.1H NMR (500 MHz, CDCl3) δ ppm 7.97 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.60 (dd, J = 2.0, 8.7 Hz, 1H), 7.46 (d, J = 7.9 Hz, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.33 (s, 1H), 4.56 (d, J = 5.0 Hz, 2H), 4.42 (t, J = 5.9 Hz, 1H), 2.81 (t, J = 6.5 Hz, 2H), 0.91-0.87 (m, 1H), 0.51-0.46 (m, 2H), 0.11 (q, J = 5.0 Hz, 2H); ES-LCMS m/z 463.1 [M+H]+. Step 3: N-(Cyclopropylmethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide
Figure imgf000456_0002
[001043] To a solution of 3-bromo-N-(cyclopropylmethyl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (50 mg, 52.88 µmol, 49%, 1 eq) and tributyl- (1-methylimidazol-4-yl)stannane (43.61 mg, 105.76 µmol, 90%, 2 eq) in DMF (5 mL) was added Pd(PPh3)4 (3.06 mg, 2.64 µmol, 0.05 eq) under N2 atmosphere. The mixture was stirred under N2 atmosphere at 130 °C for 12 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10 mM NH4HCO3)-ACN]; B%: 50%-80%, 10 min) to yield N-(cyclopropylmethyl)-3-(1-methyl-1H- imidazol-4-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (8.75 mg, 18.84 µmol, 35.6% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.22 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 5.9 Hz, 4H), 7.31 (d, J = 1.2 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 4.60 (d, J = 5.5 Hz, 2H), 4.32-4.24 (m, 1H), 3.79 (s, 3H), 2.82-2.74 (m, 2H), 0.88 (s, 1H), 0.49-0.40 (m, 2H), 0.11-0.02 (m, 2H); ES-LCMS m/z 465.2 [M+H]+. T-C-143
Figure imgf000457_0001
Step 1: 3-Bromo-4-fluoro-N-(2,2,2-trifluoroethyl)benzenesulfonamide
Figure imgf000457_0002
[001044] To a solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (300 mg, 1.04 mmol, 95% purity, 1 eq) in THF (5 mL) was added a solution of 2,2,2-trifluoroethanamine (206.43 mg, 2.08 mmol, 163.84 µL, 2 eq) in THF (3 mL). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.3) to yield 3-bromo-4-fluoro-N-(2,2,2- trifluoroethyl)benzenesulfonamide (300 mg, 847.96 µmol, 81.3% yield, 95.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.09 (dd, J = 2.3, 6.3 Hz, 1H), 7.81 (ddd, J = 2.3, 4.3, 8.6 Hz, 1H), 7.28-7.24 (m, 1H), 5.18 (s, 1H), 3.75-3.66 (m, 2H). Step 2: 3-Bromo-N-(2,2,2-trifluoroethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000458_0001
[001045] To a solution of 3-bromo-4-fluoro-N-(2,2,2-trifluoroethyl)benzenesulfonamide (200 mg, 595.06 µmol, 1 eq) in DMSO (3 mL) was added [4- (trifluoromethyl)phenyl]methanamine (208.45 mg, 1.19 mmol, 169.47 µL, 2 eq). The mixture was stirred at 140 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 3/1, Rf = 0.2) to yield 3-bromo-N-(2,2,2-trifluoroethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 458.02 µmol, 76.9% yield, 90.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.96 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.60 (dd, J = 2.0, 8.6 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 6.53 (d, J = 8.6 Hz, 1H), 5.39 (s, 1H), 4.80 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 8.6 Hz, 2H); ES-LCMS m/z 493.0 [M+H]+. Step 3: 3-(1-Methylimidazol-4-yl)-N-(2,2,2-trifluoroethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000458_0002
[001046] To a solution of 3-bromo-N-(2,2,2-trifluoroethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 458.02 µmol, 90% purity, 1 eq) in DMF (3 mL) was added tributyl-(1-methylimidazol-4-yl)stannane (357.88 mg, 916.04 µmol, 95% purity, 2 eq) and Pd(dppf)Cl2 (33.51 mg, 45.80 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 3 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150 * 25 mm * 5 µm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 49%-79%, 10 min), followed by lyophilization to yield 3-(1-methylimidazol-4-yl)-N-(2,2,2-trifluoroethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (66.05 mg, 131.70 µmol, 28.7% yield, 98.1% purity) as a gray solid.1H NMR (400 MHz, CDCl3) δ ppm 9.39-9.28 (m, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.53-7.45 (m, 4H), 7.30 (d, J = 1.2 Hz, 1H), 6.53 (d, J = 9.0 Hz, 1H), 4.75 (s, 1H), 4.60 (d, J = 5.9 Hz, 2H), 3.78 (s, 3H), 3.59 (d, J = 5.5 Hz, 2H); ES-LCMS m/z 493.1 [M+H]+. T-C-144
Figure imgf000459_0001
Step 1: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000459_0002
[001047] To a solution of 4-amino-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4- methylpyrazol-1-yl)benzenesulfonamide (50 mg, 116.44 μmol, 90% purity, 1 eq) in MeOH (1 mL) was added 4-(trifluoromethyl)benzaldehyde (22.30 mg, 128.08 μmol, 17.16 μL, 1.1 eq). The mixture was stirred at 25 °C for 2 h. NaBH3CN (36.59 mg, 582.20 μmol, 5 eq) was added and the mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative TLC (PE/EtOAc = 2/1, Rf = 0.60) to yield N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4- methylpyrazol-1-yl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (12 mg, 19.83 μmol, 17.0% yield, 90.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.65- 7.54 (m, 6H), 7.48 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.05 (s, 2H), 3.80 (s, 3H), 2.55 (s, 3H), 2.24-2.15 (m, 3H); ES-LCMS m/z 545.2 [M+H]+. Step 2: N-Methyl-3-(4-methylpyrazol-1-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000460_0001
[001048] A solution of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(4-methylpyrazol-1-yl)- 4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (12 mg, 19.83 μmol, 90% purity, 1 eq) in DCM (1 mL) and TFA (0.2 mL) was stirred at 25 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 45%-75%, 10 min), followed by lyophilization to yield N-methyl-3-(4-methylpyrazol-1-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (3.38 mg, 7.95 μmol, 40.1% yield, 99.8% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 7.68 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.62-7.56 (m, 5H), 7.46 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 8.9 Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 4.22 (d, J = 4.9 Hz, 1H), 2.64 (d, J = 5.0 Hz, 3H), 2.19 (s, 3H); ES-LCMS m/z 425.2 [M+H]+. T-C-145
Figure imgf000461_0001
Step 1: 2-[(3-Bromo-4-fluoro-phenyl)sulfonylamino]acetamide
Figure imgf000461_0002
[001049] To a solution of 3-bromo-4-fluoro-benzenesulfonyl chloride (300 mg, 1.10 mmol, 1 eq) in THF (8 mL) was added DIEA (296.80 mg, 2.30 mmol, 400 μL, 2.09 eq) and 2- aminoacetamide (160 mg, 2.16 mmol, 1.97 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h and at 20 °C for 1 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to yield 2-[(3-bromo-4-fluoro-phenyl)sulfonylamino]acetamide (330 mg, 1.03 mmol, 93.8% yield, 97.0%) as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (dd, J = 2.2, 6.4 Hz, 1H), 7.97 (s, 1H), 7.84 (ddd, J = 2.2, 4.6, 8.6 Hz, 1H), 7.59 (t, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.09 (s, 1H), 3.45 (s, 2H); ES-LCMS m/z 311.0, 313.0 [M+H]+. Step 2: 2-[[3-Bromo-4-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]sulfonylamino]acetamide
Figure imgf000462_0001
[001050] To a solution of 2-[(3-bromo-4-fluoro-phenyl)sulfonylamino]acetamide (200 mg, 623.54 μmol, 97%, 1 eq) in DMSO (2 mL) was added [4-(trifluoromethyl)phenyl]methanamine (210 mg, 1.20 mmol, 170.73 μL, 1.92 eq). The mixture was stirred under microwave at 140 °C for 1 h. TLC (PE/EtOAc = 1/1, Rf = 0.20) showed the starting material was consumed completely. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.20) to yield 2-[[3-bromo-4-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]sulfonylamino]acetamide (200 mg, 386.04 μmol, 61.9% yield, 90.0%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.42 (dd, J = 2.0, 8.6 Hz, 1H), 7.21 (s, 1H), 7.05 (s, 1H), 6.87 (t, J = 6.1 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 3.24 (s, 2H); ES-LCMS m/z 466.0, 468.0 [M+H]+. Step 3: 2-[[3-(1-Methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]sulfonylamino]acetamide
Figure imgf000462_0002
[001051] To a solution of 2-[[3-bromo-4-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]sulfonylamino]acetamide (200 mg, 386.04 μmol, 90%, 1 eq) in DMF (2 mL) was added Pd(dppf)Cl2 (30 mg, 41.00 μmol, 0.1 eq) and tributyl-(1- methylimidazol-4-yl)stannane (210 mg, 565.81 μmol, 1.47 eq).The mixture was stirred under N2 atmosphere at 130 °C for 2 h. The reaction mixture was quenched with H2O (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm;mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 34%-64%, 10 min) to yield 2-[[3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]sulfonylamino]acetamide (60 mg, 126.30 μmol, 32.7% yield, 98.4%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (t, J = 5.5 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 7.73-7.67 (m, 3H), 7.56 (d, J = 8.1 Hz, 2H), 7.39-7.29 (m, 2H), 7.26-7.20 (m, 1H), 7.11 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.64 (d, J = 5.6 Hz, 2H), 3.75 (s, 3H), 3.27 (s, 2H); ES-LCMS m/z 468.1 [M+H]+. T-C-146
Figure imgf000463_0002
Step 1: N-Methyl-3-(1-methyltriazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000463_0001
[001052] To a solution of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (300 mg, 510.30 µmol, 80% purity, 1 eq) and 4-bromo-1-methyl-triazole (123.99 mg, 765.45 µmol, 1.5 eq) in 1,4-dioxane (5 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (37.34 mg, 51.03 µmol, 0.1 eq) and Cs2CO3 (332.53 mg, 1.02 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water(0.05%NH3·H2O+10mM NH4HCO3)-ACN]; B%: 42%- 72%, 10min), followed by lyophilization to yield N-methyl-3-(1-methyltriazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (80.15 mg, 188.40 µmol, 36.9% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.92 (t, J = 5.6 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 2.0, 8.8 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 6.62 (d, J = 8.8 Hz, 1H), 4.65 (d, J = 5.9 Hz, 2H), 4.27 (d, J = 5.4 Hz, 1H), 4.21 (s, 3H), 2.63 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 426.2 [M+H]+. T-C-147
Figure imgf000464_0002
Step 1: N-Methyl-3-[1-(trideuteriomethyl)imidazol-4-yl]-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000464_0001
[001053] To a stirred solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (500 mg, 1.13 mmol, 93.0% purity, 1 eq) in DMF (20 mL) was added trideuterio(iodo)methane (361.32 mg, 2.49 mmol, 155.07 µL, 2.2 eq) and K2CO3 (187.91 mg, 1.36 mmol, 1.2 eq). The reaction mixture was stirred under N2 atmosphere at 25 °C for 3 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 50%-80%, 10 min) to yield N-methyl-3- [1-(trideuteriomethyl)imidazol-4-yl]-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (240 mg, 551.77 µmol, 48.7% yield, 98.3% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.24 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 6.8 Hz, 4H), 7.32 (d, J = 1.0 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 5.4 Hz, 1H), 2.62 (d, J = 5.6 Hz, 3H); ES-LCMS m/z 428.2 [M+H]+. T-C-148
Figure imgf000465_0001
Step 1: N-[(4-Methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3- vinyl-benzenesulfonamide
Figure imgf000465_0002
[001054] To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (50 mg, 103.55 µmol, 85%, 1 eq) in DMF (5 mL) was added K2CO3 (28.62 mg, 207.11 µmol, 2 eq) and 1-(2-bromoethoxy)-2-methoxy- ethane (37.91 mg, 207.11 µmol, 2 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; B%: 42%-72%, 10min), followed by lyophilization to yield 3-[1-[2-(2- methoxyethoxy)ethyl]imidazol-4-yl]-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (24.95 mg, 48.34 µmol, 46.6% yield, 99.3% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 9.30 (t, J = 5.6 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 7.3 Hz, 3H), 7.52-7.47 (m, 3H), 7.43 (d, J = 1.0 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.22-4.16 (m, 3H), 3.82 (t, J = 5.0 Hz, 2H), 3.66-3.61 (m, 2H), 3.57-3.52 (m, 2H), 3.40 (s, 3H), 2.62 (d, J = 5.6 Hz, 3H); ES-LCMS m/z 513.2 [M+H]+. T-C-149
Figure imgf000466_0001
Step 1: N-(2-Methoxyethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzamide
Figure imgf000466_0002
[001055] To a solution of 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (51.02 mg, 133.21 µmol, 98%, 1 eq) in DMF (2 mL) was added HATU (60.78 mg, 159.85 µmol, 1.2 eq), 2-methoxyethanamine (16.01 mg, 213.14 µmol, 18.53 µL, 1.6 eq) and TEA (40.44 mg, 399.63 µmol, 55.62 µL, 3 eq). The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (basic) to yield N-(2-methoxyethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzamide (26.85 mg, 62.09 µmol, 46.6% yield, 100.0% purity) as a green solid.1H NMR (400 MHz, CDCl3) δ ppm 8.98 (br s, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.60- 7.55 (m, 2H), 7.49 (d, J = 9.4 Hz, 3H), 7.40 (dd, J = 2.3, 8.6 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 6.39 (br s, 1H), 4.60 (d, J = 5.9 Hz, 2H), 3.78 (s, 3H), 3.63 (q, J = 5.2 Hz, 2H), 3.58-3.50 (m, 2H), 3.38 (s, 3H); ES-LCMS m/z 433.2 [M+H]+. T-C-150
Figure imgf000467_0001
Step 1: 3-[1-(Cyanomethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000467_0002
[001056] A mixture of 2-(4-bromoimidazol-1-yl)acetonitrile (150 mg, 806.41 μmol, 100% purity, 1 eq), tert-butyl N-[4-[(4-methoxyphenyl)methyl-methyl-sulfamoyl]-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[5-(trifluoromethyl)-2-pyridyl]carbamate (500 mg, 652.36 μmol, 88.4% purity, 8.09e-1 eq), Pd(PPh3)4 (100 mg, 86.54 umol, 1.07e-1 eq) and Cs2CO3 (800 mg, 2.46 mmol, 3.04 eq) in 1,4-dioxane (3 mL) and H2O (1 mL) was stirred under N2 atmosphere at 100 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 0/1, TLC: PE/EtOAc = 1/1, Rf = 0.16, 0.05) to yield 3-[1- (cyanomethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (30 mg, 35.41 μmol, 4.4% yield, 65.7% purity) as a colorless gum. ES-LCMS m/z 557.2 [M+H]+. Step 2: 3-[1-(Cyanomethyl)imidazol-4-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000468_0001
[001057] To a solution of 3-[1-(cyanomethyl)imidazol-4-yl]-N-[(4-methoxyphenyl)methyl]- N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (30 mg, 53.90 μmol, 1 eq) in DCM (2 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 125.28 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 41%-71%, 10 min) and lyophilized to yield 3-[1-(cyanomethyl)imidazol-4-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide (1.76 mg, 4.03 μmol, 7.5% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CD3OD) δ ppm 8.81 (d, J = 8.9 Hz, 1H), 8.53 (s, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.99 (s, 1H), 7.87 (dd, J = 2.4, 8.9 Hz, 1H), 7.83 (s, 1H), 7.72 (dd, J = 2.2, 8.8 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 5.37 (s, 2H), 2.58 (s, 3H); ES-LCMS m/z 437.2 [M+H]+. Step 3: 2-(4-Bromoimidazol-1-yl)acetonitrile
Figure imgf000468_0002
[001058] To a solution of 2-bromoacetonitrile (2.45 g, 20.41 mmol, 1.36 mL, 1.2 eq) and 4- bromo-1H-imidazole (2.5 g, 17.01 mmol, 1 eq) in DMF (12 mL) was added K2CO3 (4.70 g, 34.02 mmol, 2 eq). The mixture was stirred at 50 °C for 3 h. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18150 x 25mm x 5 μm; mobile phase: [water(10 mM NH4HCO3)-ACN]; B%: 0%-40%, 10 min) and lyophilized to yield 2-(4-bromoimidazol-1-yl)acetonitrile (1.5 g, 8.06 mmol, 47.4% yield, 90.0%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H), 5.33 (s, 2H); ES-LCMS m/z 186.1, 188.1 [M+H]+. T-C-154
Figure imgf000469_0001
Step 1: 3-Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N- (trideuteriomethyl)benzenesulfonamide
Figure imgf000469_0002
[001059] To a solution of 3-bromo-4-fluoro-N-[(4- methoxyphenyl)methyl]benzenesulfonamide (3.2 g, 8.12 mmol, 95%, 1 eq) in THF (50 mL) was added NaH (649.88 mg, 16.25 mmol, 60%, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. Trideuterio(iodo)methane (2.31 g, 16.25 mmol, 989.74 µL, 2 eq) was added to the mixture dropwise with stirring at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N- (trideuteriomethyl)benzenesulfonamide (3 g, 7.67 mmol, 94.3% yield, 100.0% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.04 (dd, J = 2.1, 6.2 Hz, 1H), 7.78 (m, 1H), 7.32-7.27 (m, 1H), 7.22 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.12 (s, 2H), 3.82 (s, 3H); ES-LCMS: no desired m/z was found. Step 2: 3-Bromo-N-[(4-methoxyphenyl)methyl]-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000470_0001
[001060] To a solution of [4-(trifluoromethyl)phenyl]methanamine (2.69 g, 15.33 mmol, 2.18 mL, 2 eq) in DMSO (30 mL) was added 3-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N- (trideuteriomethyl)benzenesulfonamide (3 g, 7.67 mmol, 1 eq). The mixture was stirred at 140 °C for 12 h. The reaction mixture was quenched by addition of water (80 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.58) to yield 3-bromo- N-[(4-methoxyphenyl)methyl]-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (3.2 g, 5.27 mmol, 68.7% yield, 90.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 9.8 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 8.6 Hz, 1H), 5.36 (t, J = 5.5 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.05 (s, 2H), 3.81 (s, 3H); ES-LCMS m/z 546.1, 548.1 [M+H]+. Step 3: 3-Bromo-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000471_0001
[001061] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-N-(trideuteriomethyl)-4- [[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (3.1 g, 5.11 mmol, 90%, 1 eq) in DCM (40 mL) was added TFA (11.09 g, 97.24 mmol, 7.20 mL, 19.04 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-bromo-N- (trideuteriomethyl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (2.2 g, 4.64 mmol, 90.9% yield, 90.0% purity) as a yellow solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.60 (dd, J = 2.1, 8.7 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 8.8 Hz, 1H), 5.35 (s, 1H), 4.57 (d, J = 4.6 Hz, 2H), 4.21-4.15 (m, 1H); ES-LCMS m/z 426.1, 428.1 [M+H]+. Step 4: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000471_0002
[001062] To a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3,2-dioxaborolane (3.22 g, 12.67 mmol, 3 eq) and 3-bromo-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (2 g, 4.22 mmol, 90%, 1 eq) in 1,4- dioxane (10 mL) was added Pd(dppf)Cl2 (308.98 mg, 422.27 µmol, 0.1 eq) and KOAc (828.83 mg, 8.45 mmol, 2 eq). The mixture was stirred under microwave (1 bar) at 75 °C for 1 h. The reaction mixture was quenched by addition of water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.64) to yield 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (1.5 g, 2.85 mmol, 67.5% yield, 90.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.14 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 2.4, 8.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.91 (t, J = 5.5 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 1.36 (s, 12H); ES-LCMS m/z 474.1[M+H]+. Step 5: 3-(1H-Imidazol-4-yl)-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000472_0001
[001063] To a solution of 4-iodo-1H-imidazole (553.24 mg, 2.85 mmol, 1 eq), 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(trideuteriomethyl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (1.5 g, 2.85 mmol, 90%, 1 eq) in 1,4- dioxane (20 mL) and H2O (4 mL) was added Pd(dppf)Cl2 (208.69 mg, 285.21 µmol, 0.1 eq) and Cs2CO3 (1.86 g, 5.70 mmol, 2 eq). The mixture was stirred under N2 atmosphere at 80 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.36) and by preparative HPLC ( column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water(0.05% NH3·H2O + 10 mM NH4HCO3)-ACN]; B%: 40%-70%, 10 min), followed by lyophilization to yield 3-(1H-imidazol- 4-yl)-N-(trideuteriomethyl)-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (500 mg, 1.21 mmol, 42.4% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.39 (s, 1H), 9.25 (s, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.54-7.48 (m, 3H), 7.47 (s, 1H), 6.57 (d, J = 8.6 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 4.13 (s, 1H); ES-LCMS m/z 413.9 [M+H]+. T-C-155
Figure imgf000473_0001
Step 1: tert-Butyl N-[2-[2-(2-bromoethoxy)ethoxy]ethyl]carbamate
Figure imgf000473_0002
[001064] To a solution of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (300 mg, 1.20 mmol, 1 eq) and PPh3 (631.24 mg, 2.41 mmol, 2 eq) in THF (5 mL) was added CBr4 (798.13 mg, 2.41 mmol, 2 eq) slowly. The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.37) to yield tert-butyl N-[2-[2-(2- bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 µmol, 54.4% yield, 73.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 5.03 (s, 1H), 3.81 (t, J = 6.3 Hz, 2H), 3.69-3.60 (m, 4H), 3.55 (t, J = 5.1 Hz, 2H), 3.48 (t, J = 6.3 Hz, 2H), 3.36-3.27 (m, 2H), 1.43 (s, 9H). Step 2: tert-Butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate
Figure imgf000474_0001
[001065] To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 527.52 µmol, 86.6% purity, 1 eq) in DMF (3 mL) was added K2CO3 (145.81 mg, 1.06 mmol, 2 eq) and tert-butyl N-[2-[2-(2- bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 µmol, 73% purity, 1.24 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.15) to yield tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 µmol, 68.5% yield, 80.0% purity) as a yellow gum.1H NMR (500 MHz, CDCl3) δ ppm 9.31 (t, J = 5.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.58 (d, J = 6.4 Hz, 3H), 7.47 (d, J = 10.7 Hz, 2H), 6.52 (d, J = 8.9 Hz, 1H), 5.08 (s, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 4.11- 4.07 (m, 1H), 3.79 (t, J = 5.0 Hz, 2H), 3.60 (s, 4H), 3.56-3.52 (m, 2H), 3.32 (d, J = 4.6 Hz, 2H), 2.60 (d, J = 5.3 Hz, 3H), 1.39 (s, 9H); ES-LCMS m/z 642.2 [M+H]+. Step 3: 3-[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]imidazol-4-yl]-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000475_0001
[001066] To a solution of tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 µmol, 80% purity, 1 eq) in DCM (6 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h. The solvent was removed to yield 3-[1-[2-[2-(2- aminoethoxy)ethoxy]ethyl]imidazol-4-yl]-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (170 mg, 142.62 µmol, 39.5% yield, 55.0% purity, TFA) as a green gum.1H NMR (500 MHz, CDCl3) δ ppm 9.25 (t, J = 5.8 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.81-7.75 (m, 1H), 7.59 (s, 2H), 7.56-7.53 (m, 2H), 7.49-7.45 (m, 3H), 6.50 (d, J = 8.9 Hz, 1H), 4.58 (d, J = 5.5 Hz, 2H), 4.14-4.11 (m, 2H), 4.10-4.08 (m, 2H), 3.81-3.78 (m, 2H), 3.61-3.55 (m, 4H), 3.01 (s, 2H), 2.55-2.52 (m, 3H); ES-LCMS m/z 542.2 [M+H]+. Step 4: N-[2-[2-[2-[4-[5-(Methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]acetamide
Figure imgf000475_0002
[001067] To a solution of 3-[1-[2-[2-(2-aminoethoxy)ethoxy]ethyl]imidazol-4-yl]-N-methyl- 4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (100 mg, 147.71 µmol, 80% purity, 1 eq) in DCM (3 mL) was added acetyl chloride (10.44 mg, 132.94 µmol, 9.49 µL, 0.9 eq). The mixture was stirred at 25 °C for 1 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Phenomenex Synergi C18150*30mm*4um; mobile phase: [water(0.05%HCl)-ACN]; B%: 30%-50%, 10 min), followed by lyophilization to yield N-[2-[2- [2-[4-[5-(methylsulfamoyl)-2-[[4-(trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1- yl]ethoxy]ethoxy]ethyl]acetamide (12.96 mg, 20.90 µmol, 14.2% yield, 100.0% purity, HCl) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1H), 8.02-7.85 (m, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.64 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.3 Hz, 1H), 7.17-7.02 (m, 1H), 6.65 (d, J = 8.8 Hz, 1H), 4.56 (s, 2H), 4.36 (s, 2H), 3.84 (t, J = 4.9 Hz, 2H), 3.62-3.58 (m, 2H), 3.52 (dd, J = 2.7, 5.4 Hz, 4H), 3.16 (q, J = 5.8 Hz, 2H), 2.35 (d, J = 4.2 Hz, 3H), 1.78 (s, 3H); ES- LCMS m/z 584.2 [M+H]+. T-C-156
Figure imgf000476_0001
Step 1: N-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzamide
Figure imgf000476_0002
[001068] To a solution of 3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzoic acid (140 mg, 331.96 μmol, 89.0% purity, 1 eq) in DMF (25 mL) was added 2,2'-(ethane-1,2-diylbis(oxy))diethanamine (344.38 mg, 2.32 mmol, 7 eq), HATU (151.47 mg, 398.35 μmol, 1.2 eq) and N,N-diethylethanamine (100.77 mg, 995.89 μmol, 138.61 μL, 3 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-3-(1-methylimidazol-4-yl)-4- [[4-(trifluoromethyl)phenyl]methylamino]benzamide (250 mg, crude) as a black brown solid, which was used in the next step without further purification. ES-LCMS m/z 506.2 [M+H]+. Step 2: N-(2-(2-(2-Acetamidoethoxy)ethoxy)ethyl)-3-(1-methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzamide
Figure imgf000477_0001
[001069] To a solution of N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-3-(1-methylimidazol-4-yl)- 4-[[4-(trifluoromethyl)phenyl]methylamino]benzamide (133.40 mg, 263.88 μmol, N/A purity, 1 eq) in DCM (30 mL) was added acetyl chloride (20.71 mg, 263.88 μmol, 18.83 μL, 1 eq) and TEA (80.11 mg, 791.64 μmol, 110.19 μL, 3 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um;mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 35%-65%, 10 min), followed by lyophilization to yield N-[2-[2-(2- acetamidoethoxy)ethoxy]ethyl]-3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzamide (45.54 mg, 82.25 μmol, 31.1% yield, 98.9% purity) as a brown solid.1H NMR (400 MHz, CDCl3) δ ppm 8.97 (s, 1H), 7.99 (s, 1H), 7.61-7.55 (m, 2H), 7.49 (d, J = 8.1 Hz, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.32 (s, 1H), 6.58-6.45 (m, 2H), 6.08 (s, 1H), 4.60 (s, 2H), 3.78 (s, 3H), 3.67-3.62 (m, 6H), 3.55-3.48 (m, 4H), 3.40 (d, J = 5.4 Hz, 2H), 1.94 (s, 3H); ES-LCMS m/z 548.3 [M+H]+. T-C-158
Figure imgf000478_0001
Step 1: 4-Bromo-1-cyclopropyl-triazole
Figure imgf000478_0002
[001070] To a solution of 4-bromo-1H-triazole (250 mg, 1.69 mmol, 1 eq) in 1,2- dichloroethane (10 mL) was added 2-(2-pyridyl)pyridine (263.89 mg, 1.69 mmol, 1 eq) ,Cu(OAc)2 (306.89 mg, 1.69 mmol, 1 eq), K2CO3 (467.05 mg, 3.38 mmol, 2 eq) and cyclopropylboronic acid (217.70 mg, 2.53 mmol, 1.5 eq). The mixture was stirred under N2 atmosphere at 50 °C for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to yield a residue which was purified by preparative TLC (PE/DCM = 3/1, TLC: PE/DCM = 3/1, Rf = 0.60) to yield 4-bromo-1-cyclopropyl-triazole (150 mg, 398.88 μmol, 23.6% yield, 50.0% purity) as colorless oil. ES-LCMS m/z 188.1, 190.1 [M+H]+. Step 2: 3-(1-Cyclopropyltriazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide
Figure imgf000478_0003
[001071] A mixture of 4-bromo-1-cyclopropyl-triazole (120 mg, 319.11 µmol, 50% purity, 1 eq), N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (187.60 mg, 319.11 µmol, 80% purity, 1 eq), Pd(dppf)Cl2 (23.35 mg, 31.91 µmol, 0.1 eq), Cs2CO3 (103.97 mg, 319.11 µmol, 1 eq) in 1,4- dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10mM NH4HCO3)-ACN]; B%: 51%-81%, 10min), followed by lyophilization to yield 3-(1-cyclopropyltriazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (24.08 mg, 53.34 µmol, 16.7% yield, 100.0% purity) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ ppm 8.80 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 1.9, 8.8 Hz, 1H), 7.02 (q, J = 5.2 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 4.69 (d, J = 6.0 Hz, 2H), 4.09 (tt, J = 3.8, 7.5 Hz, 1H), 2.36 (d, J = 5.2 Hz, 3H), 1.31-1.27 (m, 2H), 1.20-1.15 (m, 2H); ES- LCMS m/z 452.1 [M+H]+. T-C-162
Figure imgf000479_0001
[001072] Step 1: Methyl 3-bromo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzoate
Figure imgf000479_0002
[001073] To a solution of methyl 4-amino-3-bromo-benzoate (5 g, 21.73 mmol, 1 eq) in DMF (30 mL) was added dropwise NaH (1.74 g, 43.47 mmol, 60% purity, 2 eq) at 0°C under N2 atmosphere. After addition, the mixture was stirred at 25 °C for 30 min. 2-Fluoro-5- (trifluoromethyl)pyridine (4.31 g, 26.11 mmol, 1.2 eq) was added. The resulting mixture was stirred at 100 °C for 12 h. The mixture was added to sat. aq. NH4Cl at 0°C, diluted with water (300 mL) and extracted with EtOAc (300 mL x 3). The organlic layer was washed with brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yeild a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.72) to yield methyl 3-bromo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzoate (1.7 g, 4.34 mmol, 19.9% yield, 95.7% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.57 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 1.8, 8.8 Hz, 1H), 7.80 (dd, J = 2.2, 8.8 Hz, 1H), 7.37 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H); LCMS m/z 376.7 [M+H]+. Step 2: Methyl 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzoate
Figure imgf000480_0001
[001074] To a solution of methyl 3-bromo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzoate (1.7 g, 4.53 mmol, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (2.02 g, 5.44 mmol, 1.2 eq) in DMF (20 mL) was added Pd(dppf)Cl2 (331.58 mg, 453.00 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 12 h. TLC (PE/EtOAc = 3/1, Rf1 = 0.60, Rf2=0.42) showed the start materials were remained and one new spot was detected. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.19) to yield methyl 3-(1-methylimidazol-4-yl)-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzoate (1.2 g, 3.01 mmol, 66.5% yield, 94.5% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.70 (d, J = 8.6 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J = 2.0, 8.6 Hz, 1H), 7.68 (dd, J = 2.2, 8.8 Hz, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.36 (d, J = 1.2 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H); LCMS m/z 377.2 [M+H]+. Step 3: 3-(1-Methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzoic acid
Figure imgf000481_0001
[001075] To a solution of methyl 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzoate (1.2 g, 3.19 mmol, 1 eq) in H2O (10 mL), MeOH (10 mL) and THF (10 mL) was added LiOH·H2O (669.04 mg, 15.94 mmol, 5 eq). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzoic acid (700 mg, 1.93 mmol, 60.6% yield, 100.0% purity) as a yellow solid..1H NMR (500 MHz, DMSO-d6) δ ppm 12.42 (s, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.62 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 2.5, 8.8 Hz, 1H), 7.94 (s, 1H), 7.89 (d, J = 1.1 Hz, 1H), 7.81 (dd, J = 2.0, 8.7 Hz, 1H), 7.09 (d, J =8.7 Hz, 1H), 3.78 (s, 3H); LCMS m/z 363.2 [M+H]+. Step 4: N-(2-Methoxyethyl)-3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzamide
Figure imgf000481_0002
[001076] To a solution of 3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzoic acid (100 mg, 276.01 µmol, 100% purity, 1 eq) in DMF (3 mL) was added HATU (125.94 mg, 331.21 µmol, 1.2 eq) and DIEA (107.02 mg, 828.03 µmol, 144.23 µL, 3 eq). The mixture was stirred at 25 °C for 0.5 h.2-methoxyethanamine (103.65 mg, 1.38 mmol, 119.97 µL, 5 eq) was added and the resulting mixture was stirred 25 °C for 5 h. The reaction mixture was diluted with EtOAc (15 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HCO3)- ACN]; B%: 43%-73%, 10 min), followed by lyophilization to yield N-(2-methoxyethyl)-3-(1- methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzamide (61.73 mg, 131.86 µmol, 53.3% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.25 (s, 1H), 8.60-8.55 (m, 2H), 8.48-8.44 (m, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.95-7.89 (m, 2H), 7.81 (s, 1H), 7.72 (dd, J = 2.0, 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.51-3.42 (m, 4H), 3.28 (s, 3H); LCMS m/z 420.2 [M+H]+. T-C-170
Figure imgf000482_0001
Step 1: 3-Methyl-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000482_0002
[001077] To a solution of 3-chloro-5-(trifluoromethyl)pyridin-2-amine (1 g, 5.09 mmol, 1 eq) in 1,2-dimethoxyethane (10 mL) was added K2CO3 (2.11 g, 15.26 mmol, 3 eq), trimethylboroxine (2.30 g, 9.16 mmol, 2.56 mL, 50%, 1.8 eq) and Pd(dppf)Cl2·CH2Cl2 (415.47 mg, 508.76 µmol, 0.1 eq). The mixture was bubbled with N2 for 3 min and stirred under microwave at 130 °C for 0.5 h. TLC (PE/EtOAc = 3/1, Rf = 0.64) indicated the starting material was consumed completely and two new spots formed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.42) to yield 3-methyl-5-(trifluoromethyl)pyridin-2-amine (500 mg, 2.70 mmol, 53.0% yield, 95.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.22 (s, 1H), 7.47 (s, 1H), 4.90-4.70 (m, 2H), 2.18 (s, 3H); ES-LCMS m/z 176.8 [M+H]+. Step 2: 3-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[3-methyl-5-(trifluoromethyl)- 2-pyridyl]amino]benzenesulfonamide
Figure imgf000483_0001
[001078] To a solution of 3-methyl-5-(trifluoromethyl)pyridin-2-amine (272.20 mg, 1.47 mmol, 95%, 1.2 eq) in DMF (10 mL) was added NaH (146.81 mg, 3.67 mmol, 60%, 3 eq) at 0 °C. After being stirred for 0.5 h, 3-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl- benzenesulfonamide (500 mg, 1.22 mmol, 95%, 1 eq) was added. The mixture was stirred at 25 °C for 12 h. TLC (PE/EtOAc = 3/1, Rf = 0.55) indicated the starting material was consumed completely and two new spots formed. The residue was diluted with H2O (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with sat. aq. NaCl (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.50) to yield 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[3-methyl-5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (420 mg, 694.36 µmol, 56.8% yield, 90.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 9.00 (d, J = 8.8 Hz, 1H), 8.47 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 1.5, 8.8 Hz, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.23 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.11 (s, 2H), 3.81 (s, 3H), 2.61 (s, 3H), 2.45 (s, 3H); ES- LCMS m/z 544.0, 546.0 [M+H]+. [001079] Step 3: N-[(4-Methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4- [[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000484_0001
[001080] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[3-methyl-5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (350 mg, 578.64 µmol, 90%, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (438.28 mg, 1.16 mmol, 98%, 2 eq) in DMF (10 mL) was added Pd(PPh3)4 (33.43 mg, 28.93 µmol, 0.05 eq). The mixture was stirred under N2 atmosphere at 130 °C for 12 h. TLC (PE/EtOAc = 1/1, Rf = 0.57) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.35) to yield N-[(4- methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)-4-[[3-methyl-5-(trifluoromethyl)- 2-pyridyl]amino]benzenesulfonamide (280 mg, 502.96 µmol, 86.9% yield, 98.0% purity) as a yellow solid.1H NMR (500 MHz, CDCl3) δ ppm 11.88 (s, 1H), 9.10 (d, J = 9.0 Hz, 1H), 8.43 (s, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 2.2, 8.9 Hz, 1H), 7.58 (d, J = 5.2 Hz, 2H), 7.37 (s, 1H), 7.24 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.10 (s, 2H), 3.81 (d, J = 4.6 Hz, 6H), 2.59 (s, 3H), 2.50 (s, 3H); ES-LCMS m/z 546.2 [M+H]+. Step 4: N-Methyl-3-(1-methylimidazol-4-yl)-4-[[3-methyl-5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000484_0002
[001081] A mixture of N-[(4-methoxyphenyl)methyl]-N-methyl-3-(1-methylimidazol-4-yl)- 4-[[3-methyl-5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (230 mg, 413.14 µmol, 98%, 1 eq) in DCM (3 mL) and TFA (1.54 g, 13.51 mmol, 1 mL, 32.69 eq) was stirred under N2 atmosphere at 25 °C for 3 h. TLC (PE/EtOAc = 1/1, Rf = 0.51) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to yield a residue. To the residue was added sat. aq. NaHCO3 (80 mL) and the mixture was extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.32) to yield N-methyl-3-(1-methylimidazol-4-yl)-4-[[3-methyl-5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (120.57 mg, 277.17 µmol, 67.1% yield, 97.8% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 11.88 (s, 1H), 9.05 (d, J = 8.8 Hz, 1H), 8.41 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 2.2, 8.8 Hz, 1H), 7.57 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 1.0 Hz, 1H), 4.33 (q, J = 5.2 Hz, 1H), 3.81 (s, 3H), 2.68 (d, J = 5.6 Hz, 3H), 2.49 (s, 3H); ES-LCMS m/z 426.2 [M+H]+. T-C-58 to T-C-99, T-C-108, T-C-110, T-C-113 to T-C-117
Figure imgf000485_0001
[001082] A001 (80.0 mg, 0.30 mmol, 1.0 equiv.) and B001 (0.30 mmol, 1.0 equiv.) was dissolved in DCM (3 mL) and TFA (1 mL). The mixture was added NaBH(OAc)3 (189.9 mg, 0.90 mmol, 3.0 equiv.). The mixture was stirred at 30 °C for 16 hours. Check the reactions by LCMS. The reaction mixture was filtered and concentrated under reduced pressure to give residues. The resulting mixture was adjusted to pH 10 by the dropwise addition of saturated aqueous NH3•H2O. Some products were precipitated out from ACN (2 mL) and H2O (4 mL). Or the crude product was purified by prep-HPLC to give product. T-C-107, T-C-109, T-C-111, T-C-112, T-C-118
Figure imgf000486_0003
[001083] A001 (80.0 mg, 0.30 mmol, 1.0 equiv.) and B001 (0.30 mmol, 1.0 equiv.) dissolved in MeOH (3 mL), was added TEA (130.0 ul, 0.90 mmol, 3.0 equiv.) and acetic acid (300 ul). The mixture was added picoline borane (96.3 mg, 0.90 mmol, 3.0 equiv.). The mixture was stirred at 50 °C for 16 hours. Check the reactions by LCMS. The reaction mixture was filtered and concentrated under reduced pressure to give residues. The resulting mixture was adjusted to pH 10 by the dropwise addition of saturated aqueous NH3•H2O. Some products were precipitated out from ACN (2 mL) and H2O (4 mL). Or the crude product was purified by prep-HPLC to give product. T-D-1
Figure imgf000486_0001
Step 1: 5-Bromo-6-chloro-N-methyl-pyridine-3-sulfonamide
Figure imgf000486_0002
[001084] To a solution of 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (2.5 g, 8.59 mmol, 1 eq) in THF (50 mL) was added MeNH2 (1.62 g, 17.19 mmol, 33% purity, 2 eq) dropwise at -50 °C and the mixture was stirred for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.59) indicated the starting material was consumed completely and one new spot formed. The reaction was treated with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 5- bromo-6-chloro-N-methyl-pyridine-3-sulfonamide (2.4 g, 7.73 mmol, 90% yield, 92% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.77 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 4.64 (d, J = 4.4 Hz, 1H), 2.76 (d, J = 5.1 Hz, 4H); ES-LCMS m/z 285.0, 287.0, 289.0 [M+H]+. Step 2: 5-Bromo-N-methyl-6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3- sulfonamide
Figure imgf000487_0001
[001085] A solution of 5-bromo-6-chloro-N-methyl-pyridine-3-sulfonamide (2.4 g, 7.73 mmol, 92% purity, 1 eq) and [4-(trifluoromethyl)phenyl]methanamine (2.71 g, 15.47 mmol, 2.20 mL, 2 eq) in DMSO (50 mL) was stirred at 140 °C for 16 h. TLC (PE/EtOAc = 3/1, Rf = 0.35) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was poured into water (80 mL), extracted with EtOAc (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.35) to yield 5-bromo-N-methyl-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (3.45 g, 7.40 mmol, 95.7% yield, 91.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.51 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 5.92 (br s, 1H), 4.82 (d, J = 5.9 Hz, 2H), 4.41 (q, J = 5.1 Hz, 1H), 2.69 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 424.1, 426.1 [M+H]+. Step 3: N-Methyl-5-(1-methylimidazol-4-yl)-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide
Figure imgf000487_0002
[001086] To a solution of 5-bromo-N-methyl-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (4.2 g, 9.01 mmol, 91% purity, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (4.83 g, 11.71 mmol, 90% purity, 1.3 eq) in DMF (80 mL) was added Pd(dppf)Cl2 (659.20 mg, 0.90 mmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 16 h. TLC (PE/EtOAc = 1/1, Rf = 0.24) indicated the starting material was consumed completely and one new spot formed. The solvent was removed and the residue was treated with sat. aq. KF (200 mL) and stirred for 1 h. The mixture was filtered and the filter cake was washed with EtOAc (400 mL x 2). The organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/1 to 1/2, TLC: PE/EtOAc = 3/1, Rf = 0.32) to yield 3.5 g of crude product which was trituration with MeOH (30 mL) to yield N-methyl-5-(1- methylimidazol-4-yl)-6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (2.71 g, 6.37 mmol, 70.7% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (t, J = 5.9 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 5.4 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.18 (q, J = 4.8 Hz, 1H), 4.87 (d, J = 5.9 Hz, 2H), 3.75 (s, 3H), 2.41 (d, J = 5.1 Hz, 3H); ES-LCMS m/z 426.2 [M+H]+. T-D-3
Figure imgf000488_0001
Step 1: 5-Bromo-N-methyl-6-[[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]amino]pyridine-3- sulfonamide
Figure imgf000488_0002
[001087] To a solution of 5-bromo-6-chloro-N-methyl-pyridine-3-sulfonamide (60 mg, 189.11 µmol, 90% purity, 1 eq) in DMSO (2 mL) was added (1R)-1-[4- (trifluoromethyl)phenyl]ethanamine (71.55 mg, 378.22 µmol, 2 eq). The mixture was stirred at 140 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 3/1, Rf = 0.4) to yield 5-bromo- N-methyl-6-[[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]amino]pyridine-3-sulfonamide (83 mg, 179.92 µmol, 95.1% yield, 95.0% purity) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.44 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 5.76 (d, J = 6.3 Hz, 1H), 5.41-5.35 (m, 1H), 4.23 (s, 1H), 2.67 (d, J = 5.5 Hz, 3H), 1.63 (d, J = 7.0 Hz, 3H); ES-LCMS m/z 440.1 [M+H]+. Step 2: N-Methyl-5-(1-methylimidazol-4-yl)-6-[[(1S)-1-[4- (trifluoromethyl)phenyl]ethyl]amino]pyridine-3-sulfonamide
Figure imgf000489_0001
[001088] To a solution of 5-bromo-N-methyl-6-[[(1S)-1-[4- (trifluoromethyl)phenyl]ethyl]amino]pyridine-3-sulfonamide (83 mg, 179.92 µmol, 95% purity, 1 eq) in DMF (2 mL) was added tributyl-(1-methylimidazol-4-yl)stannane (140.58 mg, 359.83 µmol, 95% purity, 2 eq) and Pd(dppf)Cl2 (13.16 mg, 17.99 µmol, 0.1 eq). The mixture was stirred at 130 °C for 3 h. The reaction mixture was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150 * 25 mm * 5 µm; mobile phase: [water(0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 46%-76%, 10 min), followed by lyophilization to yield N-methyl-5-(1-methylimidazol-4-yl)-6-[[(1S)-1-[4- (trifluoromethyl)phenyl]ethyl]amino]pyridine-3-sulfonamide (17.54 mg, 39.91 µmol, 22.1% yield, 100.0% purity) as a black brown solid.1H NMR (500 MHz, CDCl3) δ ppm 9.80 (d, J = 7.3 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.57-7.54 (m, 2H), 7.52 (d, J = 7.5 Hz, 3H), 7.32 (d, J = 1.1 Hz, 1H), 5.50 (m, J = 7.0 Hz, 1H), 4.26 (q, J = 5.3 Hz, 1H), 3.77 (s, 3H), 2.64 (d, J = 5.5 Hz, 3H), 1.63 (d, J = 6.9 Hz, 3H); ES-LCMS m/z 440.2 [M+H]+. T-D-5
Figure imgf000490_0001
Step 1: 5-[1-(2-Methoxyethyl)imidazol-4-yl]-N-methyl-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide
Figure imgf000490_0002
[001089] To a solution of 5-(1H-imidazol-4-yl)-N-methyl-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (100 mg, 243.07µmol, 1 eq) in DMF (2 mL) were added K2CO3 (67.19 mg, 486.14 µmol, 2 eq) and 1-bromo-2-methoxyethane (33.78 mg, 243.07 µmol, 22.83 µL, 1 eq). The mixture was stirred at 25 °C for 16 h. The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5um; mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN]; B%: 46%-76%, 10 min), followed by lyophilization to yield 5-[1-(2- methoxyethyl)imidazol-4-yl]-N-methyl-6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3- sulfonamide (36.58 mg, 76.36 µmol, 31.4% yield, 98.3% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (t, J = 5.9 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.93-7.85 (m, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 4.9 Hz, 1H), 4.87 (d, J = 5.9 Hz, 2H), 4.22 (t, J = 5.1 Hz, 2H), 3.67 (t, J = 5.1 Hz, 2H), 3.27 (s, 3H), 2.41 (d, J = 4.9 Hz, 3H); ES-LCMS m/z 470.0 [M+H]+. T-D-6
Figure imgf000491_0001
Step 1: N-Methyl-5-[1-[[(2R)-oxiran-2-yl]methyl]imidazol-4-yl]-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide
Figure imgf000491_0002
[001090] To a solution of (2S)-2-(chloromethyl)oxirane (44.98 mg, 486.14 µmol, 38.12 µL, 2 eq) and KI (80.70 mg, 486.14 µmol, 2 eq) in DMF (2 mL) was added 5-(1H-imidazol-4-yl)-N- methyl-6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (100 mg, 243.07 µmol, 100%, 1 eq) and K2CO3 (67.19 mg, 486.14 µmol, 2 eq). The mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered to yield the liquid which was purified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10 mM NH4HCO3)-ACN]; B%: 43%-73%, 10 min), followed by lyophilization to yield N-methyl-5-[1-[[(2R)-oxiran-2-yl]methyl]imidazol-4-yl]-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (20.51 mg, 43.88 µmol, 18.1% yield, 100.0% purity, [ α]31.7D = +1.111 (MeOH, c = 0.18 g/100 mL)) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.77 (t, J = 5.4 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.60-7.56 (m, 3H), 7.51 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 1.1 Hz, 1H), 4.92 (d, J = 5.6 Hz, 2H), 4.45-4.35 (m, 2H), 3.97 (dd, J = 6.3, 14.8 Hz, 1H), 3.30 (qd, J = 3.0, 6.2 Hz, 1H), 2.93 (t, J = 4.2 Hz, 1H), 2.68 (d, J = 5.5 Hz, 3H), 2.57 (dd, J = 2.4, 4.4 Hz, 1H); ES-LCMS m/z 468.1 [M+H]+. T-D-10
Figure imgf000492_0001
Step 1: 5-[1-(2-Chloroethyl)imidazol-4-yl]-N-methyl-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide
Figure imgf000492_0002
[001091] To a solution of 5-(1H-imidazol-4-yl)-N-methyl-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (100 mg, 243.07 μmol, 100% purity, 1 eq) in DMF (2 mL) was added K2CO3 (100.78 mg, 729.22 μmol, 3 eq) and 1-bromo-2- chloro-ethane (52.29 mg, 364.61 μmol, 30.22 μL, 1.5 eq). The mixture was stirred at 25 °C for 8 h. The reaction mixture was quenched by addition H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45%-75%, 10 min) to yield 5-[1-(2-chloroethyl)imidazol-4-yl]-N-methyl- 6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (43.57 mg, 91.94 μmol, 37.8% yield, 100.0% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 2.0, 4.4 Hz, 2H), 7.96 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 5.2 Hz, 1H), 4.88 (d, J = 6.0 Hz, 2H), 4.42 (t, J = 5.6 Hz, 2H), 4.05 (t, J = 5.6 Hz, 2H), 2.41 (d, J = 4.8 Hz, 3H); ES-LCMS m/z 474.1 [M+H]+. T-D-11
Figure imgf000493_0001
Step 1: N-Methyl-5-(1-methylimidazol-2-yl)-6-[[4- (trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide
Figure imgf000493_0002
[001092] To a solution of 1-methylimidazole (500 mg, 6.09 mmol, 485.44 μL, 18.13 eq) in THF (10 mL) was added n-BuLi (2.5 M, 2.38 mL, 17.68 eq) dropwise under N2 atmosphere at -30 °C. The mixture was stirred at 0 °C for 0.5 h. Tributyl(chloro)stannane (2.27 g, 6.97 mmol, 1.88 mL, 20.76 eq) was added. The mixture was stirred under N2 atmosphere at 0 °C for 0.5 h and at 25 °C for 1 h. 5-Bromo-N-methyl-6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3- sulfonamide (150 mg, 335.90 μmol, 95% purity, 1 eq) and Pd(dppf)Cl2 (95.00 mg, 129.83 umol, 3.87e-1 eq) were added. The mixture was stirred under N2 atmosphere at 100 °C for 12 h. The mixture was diluted with water (50 mL) and KF (5 g) was added. The mixture was stirred at 25 °C for 1 h and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.20) and by preparative HPLC (column: Boston Prime C18 150*30mm*5um;mobile phase: [water (0.05%NH3H2O+10mM NH4HCO3)-ACN]; B%: 47%-77%, 10 min) and lyophilized to yield N- methyl-5-(1-methylimidazol-2-yl)-6-[[4-(trifluoromethyl)phenyl]methylamino]pyridine-3- sulfonamide (25.36 mg, 58.85 μmol, 17.5% yield, 98.7% purity) as a white solid.1H NMR (500 MHz, CD3OD) δ ppm 8.52 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.18 (s, 1H), 4.82 (s, 2H), 3.74 (s, 3H), 2.58 (s, 3H); ES-LCMS m/z 426.2 [M+H]+. T-E-1
Figure imgf000494_0001
Step 1: [3-(Trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methanol
Figure imgf000494_0002
[001093] To a solution of LiAlH4 (84.28 mg, 2.22 mmol, 2 eq) in THF (5 mL) was added 3- (trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (200 mg, 1.11 mmol, 1 eq) at 0°C and stirred at 25°C for 2 h. TLC (PE/EtOAc = 1/1, Rf = 0.60) indicated the starting material was consumed completely and one new spot formed. The mixture was quenched by 10% aq. NaOH (0.5 mL) and the precipitated solid was filtered and the filtrate was concentrated to yield [3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methanol (180 mg, 975.08 µmol, 87.8% yield, 90% purity) as colorless oil, which was used in the next step without further purification.1H NMR (500 MHz, CDCl3) δ ppm 3.67 (s, 2H), 1.92 (s, 6H). Step 2: [3-(Trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methyl methanesulfonate
Figure imgf000494_0003
[001094] To a solution of [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methanol (180 mg, 975.08 µmol, 90% purity, 1 eq) and Et3N (197.33 mg, 1.95 mmol, 271.44 µL, 2 eq) in DCM (3 mL) was added MsCl (170 mg, 1.48 mmol, 114.86 µL, 1.52 eq) dropwise at 0 °C and the mixture stirred at 25°C for 2 h. TLC (PE/EtOAc = 1/1, Rf = 0.67) indicated the starting material was consumed completely and one new spot formed. The mixture was quenched with sat. aq.NaHCO3 (10 mL) and extracted with DCM (15 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to yield [3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]methyl methanesulfonate (230 mg, 894.65 µmol, 91.8% yield, 95.0% purity) as a colorless gum, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 4.25 (s, 2H), 3.02 (s, 3H), 2.02 (s, 6H). Step 3: N-[(1S,5R)-3-[[3-(Trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methyl]-3- azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide
Figure imgf000495_0001
[001095] To a solution of N-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (120 mg, 360.61 µmol, 80% purity, 1 eq, TFA) and [3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]methyl methanesulfonate (92.71 mg, 360.61 µmol, 95% purity, 1 eq) in ACN (3 mL) were added K2CO3 (149.52 mg, 1.08 mmol, 3 eq) and KI (5.99 mg, 36.06 µmol, 0.1 eq). The mixture was stirred at 60 °C for 16 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 48%-78%, 10min), followed by lyophilization to yield N- [(1S,5R)-3-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methyl]-3-azabicyclo[3.1.0]hexan-6- yl]prop-2-enamide (18.28 mg, 60.87 µmol, 16.9% yield, 100.0% purity) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 6.26 (d, J = 16.9 Hz, 1H), 6.01 (dd, J = 10.4, 16.9 Hz, 1H), 5.61 (d, J = 10.2 Hz, 1H), 5.54 (br s, 1H), 3.17 (d, J = 8.9 Hz, 2H), 3.02 (d, J = 2.0 Hz, 1H), 2.51 (s, 2H), 2.37 (d, J = 8.4 Hz, 2H), 1.86 (s, 6H), 1.61 (s, 2H); ES-LCMS m/z 301.2 [M+H]+. T-E-8
Figure imgf000495_0002
Step 1: [4-(Trifluoromethyl)-1-bicyclo[2.2.2]octanyl]methanol
Figure imgf000495_0003
[001096] To a solution of 4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carboxylic acid (300 mg, 1.35 mmol, 1 eq) in THF (5 mL) was added LiAlH4 (102.49 mg, 2.70 mmol, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.59) indicated the starting material was consumed completely and one new spot formed. The mixture was quenched by 10% aq. NaOH (0.5 mL) and the precipitated solid was filtered and the filtrate was concentrated to yield [4-(trifluoromethyl)-1-bicyclo[2.2.2]octanyl]methanol (280 mg, 1.28 mmol, 94.6% yield, 95.0% purity) as colorless gum, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 3.30 (s, 2H), 1.76-1.65 (m, 6H), 1.51-1.41 (m, 6H). Step 2: 4-(Trifluoromethyl)bicyclo[2.2.2]octane-1-carbaldehyde
Figure imgf000496_0001
[001097] To a solution of [4-(trifluoromethyl)-1-bicyclo[2.2.2]octanyl]methanol (50 mg, 228.12 µmol, 95% purity, 1 eq) in DCM (3 mL) was added PCC (98.35 mg, 456.25 µmol, 2 eq). The mixture was stirred at 25 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.75) indicated the starting material was consumed completely and one new spot formed. The solvent was removed to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 2/1, TLC: PE/EtOAc = 3/1, Rf = 0.75) to yield 4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbaldehyde (50 mg, 223.08 µmol, 97.8% yield, 92.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 9.47 (s, 1H), 1.76-1.69 (m, 12H). Step 3: N-[(1R,5S)-3-[[4-(Trifluoromethyl)-1-bicyclo[2.2.2]octanyl]methyl]-3- azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide
Figure imgf000496_0002
[001098] To a solution of N-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (120 mg, 360.61 µmol, 80% purity, 1 eq, TFA) and TEA (36.49 mg, 360.61 µmol, 50.19 µL, 1 eq) in MeOH (10 mL) was added 4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbaldehyde (47.43 mg, 211.62 µmol, 92% purity). The mixture was stirred at 25 °C for 2 h. NaBH3CN (67.98 mg, 1.08 mmol, 3 eq) was added and the mixture was stirred at 25 °C for 16 h. The solvent was removed to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um;mobile phase: [water(0.05% NH3H2O+10 mM NH4HCO3)-ACN];B%: 51%- 81%,10min), followed by lyophilization to yield N-[(1R,5S)-3-[[4-(trifluoromethyl)-1- bicyclo[2.2.2]octanyl]methyl]-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (24.64 mg, 71.96 µmol, 20.0% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 6.31-6.22 (m, 1H), 6.01 (dd, J = 10.3, 17.1 Hz, 1H), 5.61 (dd, J = 1.1, 10.1 Hz, 1H), 5.49 (br s, 1H), 3.13 (d, J = 8.8 Hz, 2H), 3.02 (d, J = 1.7 Hz, 1H), 2.48 (d, J = 8.3 Hz, 2H), 2.13 (s, 2H), 1.68-1.59 (m, 6H), 1.49 (s, 2H), 1.43-1.32 (m, 6H); ES-LCMS m/z 343.2 [M+H]+. T-E-9
Figure imgf000497_0001
Step 1: tert-Butyl (2-bromo-4-nitrophenyl)(4-(trifluoromethyl)benzyl)carbamate
Figure imgf000497_0002
[001099] To a solution of 2-bromo-4-nitro-N-[[4-(trifluoromethyl)phenyl]methyl]aniline (1.10 g, 2.67 mmol, 91.1% purity, 1 eq) in DCM (10 mL) was added (Boc)2O (1.75 g, 8.00 mmol, 1.84 mL, 3 eq) and DMAP (325.66 mg, 2.67 mmol, 1 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to10/1, TLC: PE/EtOAc =10/1, Rf = 0.51) to yield tert- butyl N-(2-bromo-4-nitro-phenyl)-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (1.15 g, 2.40 mmol, 89.9% yield, 98.7% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.49 (br s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 5.20 (d, J = 14.1 Hz, 1H), 4.39 (d, J = 15.7 Hz, 1H), 1.57-1.40 (m, 9H); ES-LCMS m/z 375.3[M-Boc+H]+. Step 2: tert-Butyl (4-amino-2-bromophenyl)(4-(trifluoromethyl)benzyl)carbamate
Figure imgf000497_0003
[001100] To a solution of tert-butyl N-(2-bromo-4-nitro-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (1.11 g, 2.31 mmol, 98.7%, 1 eq) in EtOH (5 mL) and H2O (5 mL) was added Fe (646.28 mg, 11.57 mmol, 5 eq) and NH4Cl (1.24 g, 23.15 mmol, 10 eq). The mixture was stirred at 80 °C for 1 h. The reaction mixture was quenched by addition of water (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert- butyl N-(4-amino-2-bromo-phenyl)-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (1.01 g, 2.06 mmol, 89.1% yield, 91.0% purity) as a yellow solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J = 7.8 Hz, 2H), 7.39 (s, 2H), 6.95-6.88 (m, 1H), 6.58 (d, J = 8.6 Hz, 1H), 6.50-6.39 (m, 1H), 5.20 (d, J = 14.9 Hz, 1H), 4.27- 4.20 (m, 1H), 3.72 (s, 2H), 1.38 (s, 9H); ES-LCMS m/z 391.0 [M-Boc+H]+. Step 3: tert-Butyl (4-acrylamido-2-bromophenyl)(4-(trifluoromethyl)benzyl)carbamate
Figure imgf000498_0001
[001101] To a solution of tert-butyl N-(4-amino-2-bromo-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (250 mg, 539.00 µmol, 96% purity, 1 eq) in DCM (10 mL) was added acryloyl chloride (73.18 mg, 808.49 µmol, 65.92 µL, 1.5 eq) and DIEA (139.32 mg, 1.08 mmol, 187.77 µL, 2 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.43) to yield tert-butyl N-[2-bromo-4-(prop- 2-enoylamino)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (243 mg, 486.66 µmol, 90.2% yield, 100% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 7.60-7.53 (m, 2H), 7.40-7.29 (m, 3H), 7.26-7.18 (m, 1H), 6.92-6.75 (m, 1H), 6.46 (d, J = 16.8 Hz, 1H), 6.21 (dd, J = 10.6, 16.8 Hz, 1H), 5.84-5.74 (m, 1H), 5.21 (d, J = 15.3 Hz, 1H), 4.30 (s, 1H), 4.26 (s, 1H), 4.13 (q, J = 7.2 Hz, 1H), 2.06 (s, 1H), 1.63-1.52 (m, 9H), 1.33-1.25 (m, 2H); ES-LCMS m/z 521.1 [M+H]+. Step 4: tert-Butyl (4-acrylamido-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4- (trifluoromethyl)benzyl)carbamate
Figure imgf000499_0001
[001102] To a solution of tert-butyl N-[2-bromo-4-(prop-2-enoylamino)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (200 mg, 400.54 µmol, 100%, 1 eq) and tributyl-(1- methylimidazol-4-yl)stannane (234.73 mg, 600.82 µmol, 95%, 1.5 eq) in DMF (7 mL) was added Pd(dppf)Cl2 (29.31 mg, 40.05 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 1 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 4/5, TLC: PE/EtOAc = 3/1, Rf = 0.20) to yield tert-butyl N-[2-(1-methylimidazol-4-yl)-4-(prop-2-enoylamino)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (100 mg, 199.80 µmol, 49.8% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 7.86 (s, 1H), 7.55-7.43 (m, 4H), 7.34 (d, J = 7.8 Hz, 3H), 6.88 (br s, 1H), 6.73 (d, J = 7.0 Hz, 1H), 6.45-6.35 (m, 1H), 6.25-6.14 (m, 1H), 5.76 (d, J = 10.6 Hz, 1H), 5.18 (d, J = 14.5 Hz, 1H), 4.18-4.07 (m, 1H), 4.11 (d, J = 13.7 Hz, 1H), 3.67 (s, 3H), 1.26 (s, 9H); ES-LCMS m/z 501.2 [M+H]+. Step 5: N-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)phenyl)acrylamide
Figure imgf000499_0002
[001103] To a solution of tert-butyl N-[2-(1-methylimidazol-4-yl)-4-(prop-2- enoylamino)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (100 mg, 199.80 µmol, 100%, 1 eq) in DCM (3 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 135.20 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 40%-70%, 10min), followed by lyophilization to yield N-[3-(1-methylimidazol-4-yl)-4-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]prop-2-enamide (10.48 mg, 26.17 µmol, 13.1% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.35 (br s, 1H), 7.92 (s, 1H), 7.57-7.45 (m, 5H), 7.24 (br s, 1H), 7.08-6.94 (m, 2H), 6.47-6.36 (m, 2H), 6.26-6.14 (m, 1H), 5.71 (d, J = 11.3 Hz, 1H), 4.53 (s, 2H), 3.74 (s, 3H); ES-LCMS m/z 401.2 [M+H]+. T-E-10 and T-E-11 (isomers of T-E-25)
Figure imgf000500_0002
Step 1: N-[(4-Methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3- vinyl-benzenesulfonamide
Figure imgf000500_0001
[001104] To a solution of 3-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (600 mg, 1.13 mmol, 1 eq) and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (348.48 mg, 2.26 mmol, 383.79 µL, 2 eq) in 1,4-dioxane (10 mL) and H2O (2 mL) was added Cs2CO3 (737.21 mg, 2.26 mmol, 2 eq) and Pd(dppf)Cl2 (82.78 mg, 113.13 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.59) to yield N-[(4- methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-vinyl- benzenesulfonamide (500 mg, 1.04 mmol, 91.6% yield, 98.9% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 7.98-7.90 (m, 2H), 7.76 (dt, J = 2.2, 8.9 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 6.93-6.82 (m, 5H), 5.83 (d, J = 17.6 Hz, 1H), 5.58 (d, J = 11.0 Hz, 1H), 4.13 (s, 2H), 3.81 (s, 3H), 2.63 (s, 3H); ES-LCMS m/z 478.6 [M+H]+. Step 2: N-Methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-vinyl-benzenesulfonamide
Figure imgf000501_0001
[001105] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)- 2-pyridyl]amino]-3-vinyl-benzenesulfonamide (500 mg, 1.04 mmol, 98.9% purity, 1 eq) in DCM (2 mL) was added TFA (1.52 g, 13.37 mmol, 989.70 µL, 12.90 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 2/1, Rf = 0.49) to yield N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-vinyl-benzenesulfonamide (300 mg, 805.09 µmol, 77.7% yield, 95.9% purity) as colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 8.50 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.77 (dt, J = 2.1, 8.5 Hz, 2H), 6.94 (s, 1H), 6.90-6.80 (m, 2H), 5.83 (d, J = 17.4 Hz, 1H), 5.56 (d, J = 11.2 Hz, 1H), 4.51 (q, J = 5.1 Hz, 1H), 2.72 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 358.1 [M+H]+. Step 3: 3-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide and 3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N- methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide
Figure imgf000502_0001
[001106] To a stirred solution of N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3- vinyl-benzenesulfonamide (270 mg, 724.58 µmol, 95.9%, 1 eq) and dibromomethanone oxime (293.94 mg, 1.45 mmol, 2 eq) in EtOAc (10 mL) was added NaHCO3 (608.70 mg, 7.25 mmol, 281.80 µL, 10 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05% NH3·H2O+10mM NH4HCO3)- ACN]; B%: 40%-70%, 10min), followed by lyophilization to yield the mixture which was separated by chiral SFC column: DAICEL CHIRALPAK IG (250mm*30mm, 10µm); mobile phase: [0.1% NH3·H2O MEOH]; B%: 40%-40%) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) and lyophilized to yield 3-[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (44.51 mg, 92.87 µmol, 12.8% yield, 100.0% purity, SFC: Rt = 1.658, ee = 100%, [α]31.4D = -44.4 (CH3OH, c = 0.054 g/100 mL)) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.51 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 2.1, 8.7 Hz, 1H), 7.84-7.76 (m, 2H), 7.40 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.81 (t, J = 11.1 Hz, 1H), 4.41 (s, 1H), 3.62-3.52 (m, 1H), 3.49-3.38 (m, 1H), 2.71 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 479.0481.0 [M+H]+. Peak 2 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) and lyophilizedto yield 3-[(5R)-3-bromo-4,5- dihydroisoxazol-5-yl]-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (48.81 mg, 101.84 µmol, 14.1% yield, 100.0% purity, SFC: Rt = 1.982, ee = 100%, [α]31.4D = + 40.0 (CH3OH, c = 0.050 g/100 mL)) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.51 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 2.2, 8.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.39 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.81 (t, J = 11.1 Hz, 1H), 4.35 (d, J = 4.9 Hz, 1H), 3.62-3.51 (m, 1H), 3.49-3.39 (m, 1H), 2.71 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 479.1, 481.1 [M+H]+. T-E-12 and T-E-13 (isomers of T-E-26)
Figure imgf000503_0001
Step 1: 5-Bromo-2-iodo-N-[[4-(trifluoromethyl)phenyl]methyl]aniline
Figure imgf000503_0002
[001107] To a solution of 5-bromo-2-iodo-aniline (2.5 g, 8.39 mmol, 1 eq) and 4- (trifluoromethyl)benzaldehyde (4.38 g, 25.17 mmol, 3.37 mL, 3 eq) in MeOH (25 mL) was added AcOH (50.39 mg, 839.16 µmol, 47.99 µL, 0.1 eq). The mixture was stirred at 60 °C for 4 h. NaBH3CN (2.64 g, 41.96 mmol, 5 eq) was added at 25 °C. The mixture was stirred at 60 °C for 12 h. The solvent was removed and the residue was quenched by addition of water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.70) to yield 5-bromo-2-iodo-N-[[4-(trifluoromethyl)phenyl]methyl]aniline (1.88 g, 3.67 mmol, 43.7% yield, 89.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.64 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 7.8 Hz, 2H), 6.64-6.58 (m, 2H), 4.72 (s, 1H), 4.47 (d, J = 5.6 Hz, 2H); ES-LCMS m/z 455.9, 457.9 [M+H]+. Step 2: tert-Butyl N-(5-bromo-2-iodo-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000504_0001
[001108] To a solution of 5-bromo-2-iodo-N-[[4-(trifluoromethyl)phenyl]methyl]aniline (1.88 g, 3.67 mmol, 89%, 1 eq) in THF (20 mL) was added DMAP (448.24 mg, 3.67 mmol, 1 eq) and Boc2O (2.40 g, 11.01 mmol, 2.53 mL, 3 eq). The mixture was stirred at 20 °C for 12 h. The solvent was removed to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 10/1, TLC: PE/EtOAc = 10/1, Rf = 0.8) to yield tert-butyl N-(5-bromo- 2-iodo-phenyl)-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (2.23 g, crude) as a green solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 7.3 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 5.16 (d, J = 15.2 Hz, 1H), 4.27 (d, J = 14.9 Hz, 1H), 1.57 (s, 9H); ES-LCMS m/z 499.9, 421.9 [M-t-Bu+H]+. Step 3: tert-Butyl N-[5-bromo-2-(1-methylimidazol-4-yl)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000504_0002
[001109] A mixture of tert-butyl N-(5-bromo-2-iodo-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (1 g, 1.73 mmol, 96.3% purity, 1 eq), tributyl-(1- methylimidazol-4-yl)stannane (662.53 mg, 1.73 mmol, 97% purity, 1 eq) and Pd(dppf)Cl2 (126.70 mg, 173.15 µmol, 0.1 eq) in DMF (10 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 120 °C for 4 h. The reaction mixture was quenched by addition of water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.40) to yield tert-butyl N-[5-bromo-2-(1-methylimidazol- 4-yl)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (530 mg, 934.66 µmol, 54.0% yield, 90.0% purity) as black brown oil.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.46 (s, 2H), 7.35 (d, J = 6.8 Hz, 2H), 6.94 (s, 1H), 6.82 (s, 1H), 5.15 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.9 Hz, 1H), 3.66 (s, 3H), 1.26 (s, 9H); ES-LCMS m/z 510.1, 512.1 [M+H]+. Step 4: tert-Butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000505_0001
[001110] A mixture of tert-butyl N-[5-bromo-2-(1-methylimidazol-4-yl)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (530 mg, 934.66 µmol, 90%, 1 eq), 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (287.90 mg, 1.87 mmol, 317.07 µL, 2 eq), Pd(dppf)Cl2 (68.39 mg, 93.47 µmol, 0.1 eq), Cs2CO3 (761.33 mg, 2.34 mmol, 2.5 eq) in 1,4-dioxane (4.5 mL) and H2O (1.5 mL) was degassed and purged with N2 for 3 times and the mixture was stirred under N2 atmosphere at 100 °C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc =3/1, Rf = 0.40) to yield tert-butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N- [[4-(trifluoromethyl)phenyl]methyl]carbamate (219 mg, 464.34 µmol, 49.7% yield, 97.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 8.05 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.8 Hz, 3H), 7.47 (s, 1H), 7.38 (d, J = 7.3 Hz, 3H), 6.85 (s, 1H), 6.74 (s, 1H), 6.57 (dd, J = 10.9, 17.5 Hz, 1H), 5.55 (d, J = 17.4 Hz, 1H), 5.18 (d, J = 10.8 Hz, 1H), 5.22-5.15 (m, 1H), 3.67 (s, 3H), 1.25 (s, 9H); ES-LCMS m/z 458.1 [M+H]+. Step 5: tert-Butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
Figure imgf000506_0001
[001111] To a solution of tert-butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (169 mg, 358.33 µmol, 97%, 1 eq) and dibromomethanone oxime (109.02 mg, 537.49 µmol, 1.5 eq) in EtOAc (3 mL) was added NaHCO3 (301.02 mg, 3.58 mmol, 10 eq). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl N-[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1- methylimidazol-4-yl)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (248 mg, crude) as a yellow solid which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 1H), 7.64 (s, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.51-7.47 (m, 1H), 6.95-6.82 (m, 2H), 6.68 (s, 1H), 5.54 (d, J = 8.8 Hz, 1H), 5.30-5.08 (m, 2H), 3.71 (s, 3H), 3.59-3.45 (m, 2H), 1.54 (s, 9H). Step 6: (S)-5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methyl-1H-imidazol-4-yl)-N-(4- (trifluoromethyl)benzyl)aniline and (R)-5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methyl- 1H-imidazol-4-yl)-N-(4-(trifluoromethyl)benzyl)aniline
Figure imgf000507_0001
[001112] To a solution of tert-butyl N-[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1- methylimidazol-4-yl)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate (248 mg, 428.02 µmol, 1 eq) in DCM (3 mL) was added TFA (184.80 mg, 1.62 mmol, 120 µL, 3.79 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.05)to yield the compound which was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10µm); mobile phase: [0.1% NH3H2O ETOH]; B%: 50%- 50%) to yield Peak 1 and Peak 2. Peak 1 was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)- ACN]; B%: 52%-82%, 10min) and lyophilized to yield (S)-5-(3-bromo-4,5-dihydroisoxazol-5-yl)- 2-(1-methyl-1H-imidazol-4-yl)-N-(4-(trifluoromethyl)benzyl)aniline (10.44 mg, 21.35 µmol, 5.0% yield, 98.5% purity, SFC : Rt = 2.143, ee = 98.2%, [α]32.0 D= + 180.0 (MeOH, c = 0.02 g/100 mL)) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 7.60-7.56 (m, 2H), 7.54- 7.50 (m, 2H), 7.47 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.47 (s, 1H), 5.57-5.47 (m, 1H), 4.55 (s, 2H), 3.77 (s, 3H), 3.50 (dd, J = 10.9, 17.2 Hz, 1H), 3.07 (dd, J = 8.9, 17.2 Hz, 1H); ES-LCMS m/z 478.8, 480.8 [M+H]+. Peak 2 was purified by preparative HPLC (column: Agela DuraShell C18150*25mm*5µm; mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 51%-81%, 10 min) and lyophilized to yield (R)-5-(3-bromo-4,5- dihydroisoxazol-5-yl)-2-(1-methyl-1H-imidazol-4-yl)-N-(4-(trifluoromethyl)benzyl)aniline (9.5 mg, 18.99 µmol, 4.4% yield, 95.9% purity, SFC : Rt = 2.482, ee = 98.8%, ee = 98.8%, [α]32.0D= - 187.5(MeOH, c = 0.016 g/100 mL)) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 7.60-7.56 (m, 2H), 7.53-7.50 (m, 2H), 7.47 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 6.47 (s, 1H), 5.52 (dd, J = 8.9, 10.9 Hz, 1H), 4.55 (s, 2H), 3.77 (s, 3H), 3.50 (dd, J = 10.9, 17.2 Hz, 1H), 3.07 (dd, J = 8.8, 17.1 Hz, 1H); ES-LCMS m/z 479.0, 481.0 [M+H]+. T-E-14
Figure imgf000508_0001
Step 1: N-(2-Bromo-4-nitrophenyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000508_0002
[001113] To a solution of 5-(trifluoromethyl) pyridin-2-amine (1.84 g, 11.36 mmol, 1 eq) in THF (30 mL) was added NaH (1.36 g, 34.09 mmol, 60%, 3 eq) at 0 °C. The mixture was stirred for 30 min. 2-Bromo-1-fluoro-4-nitro-benzene (2.5 g, 11.36 mmol, 1 eq) was added at 0 °C and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 10/1, TLC: PE/EtOAc = 5/1, Rf = 0.65) to yield N-(2-bromo-4-nitro-phenyl)-5-(trifluoromethyl)pyridin-2-amine (850 mg, 2.00 mmol, 17.6% yield, 85.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.76 (d, J = 9.3 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 2.4, 9.3 Hz, 1H), 7.87 (dd, J = 2.2, 8.8 Hz, 1H), 7.54 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H); ES-LCMS m/z 363.9 [M+H]+. Step 2: 2-(1-Methyl-1H-imidazol-4-yl)-N1-(5-(trifluoromethyl)pyridin-2-yl)benzene-1,4- diamine
Figure imgf000508_0003
[001114] To a solution of N-(2-bromo-4-nitro-phenyl)-5-(trifluoromethyl)pyridin-2-amine (700 mg, 1.93 mmol, 1 eq) and tributyl-(1-methylimidazol-4-yl)stannane (1.58 g, 3.87 mmol, 91%, 2 eq) in DMF (15 mL) was added Pd(dppf)Cl2 (70.73 mg, 96.66 µmol, 0.05 eq) under N2 atmosphere. The mixture was stirred under N2 atmosphere at 130 °C for 12 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (100 mL x 3). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by silica gel column chromatography (from pure PE to PE/EtOAc = 0/1, TLC: PE/EtOAc = 0/1, Rf = 0.34) to yield 2-(1-methylimidazol-4-yl)-N1-[5- (trifluoromethyl)-2-pyridyl]benzene-1,4-diamine (300 mg, 648.04 µmol, 33.5% yield, 72.1% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.40 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.59-7.43 (m, 2H), 7.27 (s, 1H), 7.18-7.01 (m, 2H), 6.74-6.57 (m, 2H), 3.71 (s, 3H); ES-LCMS m/z 334.3 [M+H]+. Step 3: N-(3-(1-Methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2- yl)amino)phenyl)acrylamide
Figure imgf000509_0001
[001115] To a solution of 2-(1-methylimidazol-4-yl)-N1-[5-(trifluoromethyl)-2- pyridyl]benzene-1,4-diamine (230 mg, 496.83 µmol, 72%, 1 eq) and Et3N (150.82 mg, 1.49 mmol, 207.46 µL, 3 eq) in DCM (3 mL) was added prop-2-enoyl chloride (58.46 mg, 645.88 µmol, 52.66 µL, 1.3 eq) under N2 atmosphere at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 mL x 3). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18150*25 mm*5 µm; mobile phase: [water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN]; B%: 38%-68%, 10 min) to yield N-[3-(1-methylimidazol-4-yl)-4-[[5-(trifluoromethyl)-2- pyridyl]amino]phenyl]prop-2-enamide (85.15 mg, 215.43 µmol, 43.4% yield, 98.2% purity) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.30 (s, 1H), 8.44 (s, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.60 (dd, J = 2.0, 8.9 Hz, 1H), 7.47 (s, 1H), 7.18 (s, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.49-6.40 (m, 1H), 6.35-6.24 (m, 1H), 5.75 (d, J = 10.4 Hz, 1H), 3.68 (s, 3H); ES-LCMS m/z 388.2 [M+H]+. T-E-15 and T-E-16 (isomers of T-E-27)
Figure imgf000510_0001
Step 1: 3-[(5S)-3-Chloro-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide
Figure imgf000510_0002
[001116] To a solution of 3-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-4-[[5- (trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (900 mg, 723.35 µmol, 38.5% purity, 1 eq) in 1,4-dioxane (10 mL) was added aq. HCl (2 mL). The mixture was stirred at 40 °C for 12 h. The reaction mixture was quenched by addition of saturated NaHCO3 (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5µm; mobile phase: [water (0.05%NH3·H2O+10mM NH4HCO3)-ACN]; B%: 40%-70%, 10 min), followed by lyophilization to yield the mixture which was separated by chiral SFC (column: column: DAICEL CHIRALPAK AS(250mm*30mm,10µm); mobile phase: [0.1% NH3·H2O EtOH]; B%: 25%-20%) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) then lyophilized to yield 3-[(5S)-3-chloro-4,5- dihydroisoxazol-5-yl]-N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide (48.36 mg, 111.22 µmol, 15.4% yield, 100.0% purity, SFC: Rt = 1.382, ee = 99.84%, [α]31.4 D = - 46.15 (CH3OH, c = 0.052 g/100 mL)) as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.51 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 2.1, 8.7 Hz, 1H), 7.82-7.77 (m, 2H), 7.42 (s, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.88 (t, J = 11.1 Hz, 1H), 4.46-4.33 (m, 1H), 3.56-3.37 (m, 2H), 2.71 (d, J = 5.1 Hz, 3H); ES-LCMS m/z 435.1, 437.1 [M+H]+. T-E-17 and T-E-18 (isomers of T-E-28)
Figure imgf000511_0001
Step 1: 5-Bromo-6-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-pyridine-3-sulfonamide
Figure imgf000511_0002
[001117] To a solution of 5-bromo-6-chloro-pyridine-3-sulfonyl chloride (1.0 g, 3.44 mmol, 1 eq) and Et3N (695.58 mg, 6.87 mmol, 956.78 µL, 2 eq) in THF (10 mL) was added 1-(4- methoxyphenyl)-N-methyl-methanamine (571.67 mg, 3.78 mmol, 1.1 eq). The mixture was stirred at -30 °C for 1 h. TLC (PE/EtOAc = 3/1, Rf = 0.56) indicated the starting material was consumed completely and one new spot formed. The mixture was poured into water (50 mL) and the precipitated solid was filtered and dried to yield 5-bromo-6-chloro-N-[(4-methoxyphenyl)methyl]- N-methyl-pyridine-3-sulfonamide (1.1 g, 2.49 mmol, 72.6% yield, 92.0% purity) as a light yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, CDCl3) δ ppm 8.71 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.90-6.85 (m, 2H), 4.18 (s, 2H), 3.81 (s, 3H), 2.70 (s, 3H); ES-LCMS m/z 405.0, 407.0 [M+H]+. Step 2: 6-Amino-5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-pyridine-3-sulfonamide
Figure imgf000512_0001
[001118] To a solution of 5-bromo-6-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl- pyridine-3-sulfonamide (950 mg, 2.15 mmol, 92% purity, 1 eq) in THF (5 mL) was added NH3.H2O (1.48 mL, 28% purity, 5 eq). The mixture was stirred under microwave at 100 °C for 12 h. TLC (PE/EtOAc = 1/1, Rf = 0.31) indicated the starting material was consumed completely and one new spot formed. The solvent was removed to yield 6-amino-5-bromo-N-[(4- methoxyphenyl)methyl]-N-methyl-pyridine-3-sulfonamide (860 mg, 2.12 mmol, 98.2% yield, 95.0% purity) as a yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ ppm 8.33 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.31 (br s, 2H), 7.23 (d, J = 8.4 Hz, 3H), 6.92 (d, J = 8.5 Hz, 2H), 3.75 (s, 3H). Step 3: 5-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide
Figure imgf000512_0002
[001119] To a solution of 6-amino-5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl- pyridine-3-sulfonamide (510 mg, 1.25 mmol, 95% purity, 1 eq) and 1-iodo-4- (trifluoromethyl)benzene (409.42 mg, 1.51 mmol, 221.31 µL, 1.2 eq) in anisole (20 mL) were added Pd(OAc)2 (42.24 mg, 188.15 µmol, 0.15 eq), xantphos (72.58 mg, 125.43 µmol, 0.1 eq) and Cs2CO3 (613.02 mg, 1.88 mmol, 1.5 eq). The mixture was stirred under N2 atmosphere at 130 °C for 16 h. The solvent was removed and the residue was treated with EtOAc (30 mL). The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.57) to yield 5- bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4-(trifluoromethyl)anilino]pyridine-3- sulfonamide (587 mg, 1.05 mmol, 83.8% yield, 95.0% purity) as a yellow solid.1H NMR (500 MHz, CDCl3) δ ppm 8.61 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.51 (s, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.14 (s, 2H), 3.81 (s, 3H), 2.65 (s, 3H); ES-LCMS m/z 530.0, 532.0 [M+H]+. Step 4: N-[(4-Methoxyphenyl)methyl]-N-methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl- pyridine-3-sulfonamide
Figure imgf000513_0001
[001120] To a solution of 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide (587 mg, 1.05 mmol, 95% purity, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (323.88 mg, 2.10 mmol, 356.70 µL, 2 eq) in 1,4- dioxane (18 mL) and H2O (3 mL) were added Pd(dppf)Cl2 (76.94 mg, 105.15 µmol, 0.1 eq) and Cs2CO3 (685.17 mg, 2.10 mmol, 2 eq). The mixture was stirred under N2 atmosphere at 90 °C for 16 h. The solvent was removed and the residue was treated with EtOAc (20 mL). The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 3/1, TLC: PE/EtOAc = 3/1, Rf = 0.49) to yield N-[(4- methoxyphenyl)methyl]-N-methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl-pyridine-3-sulfonamide (350 mg, 732.99 µmol, 69.7% yield, 100.0% purity) as a yellow solid.1H NMR (500 MHz, CDCl3) δ ppm 8.62 (d, J = 2.3 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 3H), 6.75 (dd, J = 11.1, 17.3 Hz, 1H), 5.84 (d, J = 17.2 Hz, 1H), 5.71 (d, J = 11.1 Hz, 1H), 4.13 (s, 2H), 3.80 (s, 3H), 2.63 (s, 3H); ES-LCMS m/z 478.2 [M+H]+. Step 5: N-Methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl-pyridine-3-sulfonamide
Figure imgf000513_0002
[001121] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4- (trifluoromethyl)anilino]-5-vinyl-pyridine-3-sulfonamide (300 mg, 628.27 µmol, 100% purity, 1 eq) in DCM (5 mL) was added TFA (1.5 mL). The mixture was stirred at 25 °C for 16 h. TLC (PE/EtOAc = 1/1, Rf = 0.58) indicated the starting material was consumed completely and one new spot formed. The mixture was concentrated to yield N-methyl-6-[4-(trifluoromethyl)anilino]- 5-vinyl-pyridine-3-sulfonamide (330 mg, 616.07 µmol, 98.1% yield, 88.0% purity, TFA) as an off- white solid, which was used in the next step without further purification.1H NMR (500 MHz, CD3OD) δ ppm 8.50 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.05 (dd, J = 10.9, 17.2 Hz, 1H), 5.91 (d, J = 17.1 Hz, 1H), 5.62 (d, J = 11.0 Hz, 1H), 2.59 (s, 3H). Step 6: 5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide
Figure imgf000514_0001
[001122] To a solution of N-methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl-pyridine-3- sulfonamide (330 mg, 616.07 µmol, 88% purity, 1 eq, TFA) and dibromomethanone oxime (249.92 mg, 1.23 mmol, 2 eq) in EtOAc (20 mL) was added NaHCO3 (517.54 mg, 6.16 mmol, 10 eq). The mixture was stirred at 25 °C for 3 h. TLC (PE/EtOAc = 1/1, Rf = 0.78) indicated the starting material was consumed completely and one new spot formed. The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 2/1, TLC: PE/EtOAc = 1/1, Rf = 0.78) to yield 5-(3-bromo-4,5- dihydroisoxazol-5-yl)-N-methyl-6-[4-(trifluoromethyl)anilino]pyridine-3-sulfonamide (290 mg, 574.83 µmol, 93.3% yield, 95.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.71 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.74-7.66 (m, 2H), 7.64-7.57 (m, 2H), 5.77 (t, J = 11.2 Hz, 1H), 4.39 (q, J = 5.4 Hz, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.56 (dd, J = 1.8, 11.4 Hz, 2H), 2.71 (d, J = 5.4 Hz, 3H); ES-LCMS m/z 479.0, 481.0 [M+H]+. Step 7: (S)-5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide
Figure imgf000515_0001
[001123] The compound 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide (100 mg, 198.22 µmol, 95% purity, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O EtOH]; B%: 30%-30%) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) and lyophilized to yield (S)-5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide (32.79 mg, 68.42 µmol, 34.5% yield, 100.0% purity, SFC: Rt = 1.372, ee = 100%, [ α]28.6 D = -5.00 (MeOH, c = 0.08 g/100 mL) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.71 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.72- 7.65 (m, 3H), 7.64-7.58 (m, 2H), 5.77 (t, J = 11.2 Hz, 1H), 4.44 (q, J = 5.2 Hz, 1H), 3.62-3.51 (m, 2H), 2.71 (d, J = 5.3 Hz, 3H); ES-LCMS m/z 478.9, 480.9 [M+H]+ and Peak 2 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) and lyophilized to yield (R)-5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide (31.64 mg, 66.02 µmol, 33.3% yield, 100.0% purity, SFC: Rt = 1.596, ee = 100%, [ α]28.8D = +6.67 (MeOH, c = 0.09 g/100 mL) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.70 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.72-7.65 (m, 3H), 7.63-7.59 (m, 2H), 5.77 (t, J = 11.1 Hz, 1H), 4.48 (q, J = 5.3 Hz, 1H), 3.62- 3.51 (m, 2H), 2.70 (d, J = 5.3 Hz, 3H); ES-LCMS m/z 479.0, 481.0 [M+H]+. T-E-19 and T-E-20 (isomers of T-E-29)
Figure imgf000516_0001
Step 1: 4-Bromo-2-(1-methylimidazol-4-yl)aniline
Figure imgf000516_0002
[001124] To a mixture of 4-bromo-2-iodo-aniline (2 g, 6.71 mmol, 1 eq) and tributyl-(1- methylimidazol-4-yl)stannane (2.72 g, 6.71 mmol, 91.5%, 1 eq) in DMF (20 mL) was added Pd(dppf)Cl2 (491.22 mg, 671.32 µmol, 0.1 eq). The mixture was stirred under N2 atmosphere at 130 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 0/1, TLC: PE/EtOAc = 0/1, Rf = 0.30) to yield 4- bromo-2-(1-methylimidazol-4-yl)aniline (1 g, 3.25 mmol, 48.5% yield, 82.0% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.42 (m, 2H), 7.13-7.06 (m, 2H), 6.58 (d, J = 8.6 Hz, 1H), 5.72-5.34 (m, 2H), 3.72 (s, 3H); ES-LCMS m/z 252.0, 254.0 [M+H]+. Step 2: 2-(1-Methylimidazol-4-yl)-4-vinyl-aniline
Figure imgf000516_0003
[001125] To a solution of 4-bromo-2-(1-methylimidazol-4-yl)aniline (1 g, 3.25 mmol, 82.0%, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.00 g, 6.51 mmol, 1.10 mL, 2 eq) in 1,4-dioxane (30 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (237.99 mg, 325.25 µmol, 0.1 eq) and Cs2CO3 (3.18 g, 9.76 mmol, 3 eq). The mixture was stirred under N2 atmosphere at 100 °C for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 0/1, TLC: PE/EtOAc = 0/1, Rf = 0.35) to yield 2-(1- methylimidazol-4-yl)-4-vinyl-aniline (500 mg, 2.16 mmol, 66.4% yield, 86.0% purity) as brown oil.1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 2.0, 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.55 (dd, J = 11.0, 17.6 Hz, 1H), 6.43 (s, 2H), 5.53 (dd, J = 1.2, 17.6 Hz, 1H), 4.94 (dd, J = 1.0, 10.8 Hz, 1H), 3.70 (s, 3H); ES- LCMS m/z 200.3 [M+H]+. Step 3: 4-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methylimidazol-4-yl)aniline
Figure imgf000517_0001
[001126] To a solution of 2-(1-methylimidazol-4-yl)-4-vinyl-aniline (500 mg, 2.16 mmol, 86.0%, 1 eq) in EtOAc (10 mL) was added NaHCO3 (1.81 g, 21.58 mmol, 839.35 µL, 10 eq) and dibromomethanone oxime (656.59 mg, 3.24 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to yield a residue which was purified by preparative TLC (PE/EtOAc = 0/1, TLC: PE/EtOAc = 0/1, Rf = 0.20) to yield 4-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methylimidazol-4-yl)aniline (150 mg, 434.35 µmol, 20.1% yield, 93.0% purity) as yellow oil.1H NMR (500 MHz, CDCl3) δ ppm 7.47 (s, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.17 (s, 1H), 7.01-6.99 (m, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.57 (t, J = 10.2 Hz, 2H), 3.80-3.71 (m, 3H), 3.51 (dd, J = 10.8, 17.3 Hz, 1H), 3.23 (dd, J = 9.8, 17.3 Hz, 1H), 2.98- 1.99 (m, 1H); ES-LCMS m/z 321.1, 323.1 [M+H]+. Step 4: 4-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline and 4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1- methylimidazol-4-yl)-N-[[4-(trifluoromethyl)phenyl]methyl]aniline
Figure imgf000518_0001
[001127] To a solution of 4-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methylimidazol-4- yl)aniline (120 mg, 347.48 µmol, 93.0%, 1 eq) in THF (5 mL) was added DIEA (134.73 mg, 1.04 mmol, 181.57 µL, 3 eq) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (166.12 mg, 694.95 µmol, 107.17 µL, 2 eq). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30 mm*5 µm; mobile phase: [water (0.05% NH3·H2O+10 mM NH4HCO3)-ACN]; B%: 60%-90%, 10 min), followed by lyophilization to yield a product. The product was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 µm); mobile phase: [0.1% NH3·H2O EtOH]; B%: 60%-60%) to yield peak 1 and peak 2. Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (20 mL) and H2O (40 mL) and lyophilized to yield 4-[(5S)- 3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline (24.61 mg, 50.72 µmol, 14.6% yield, 98.8% purity, SFC: Rt = 2.248, ee = 100%, [α]26.8D = +140.000 (MeOH, c = 0.180 g/100 mL)) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.52 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 10.2 Hz, 3H), 7.39 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 7.00 (dd, J = 2.1, 8.5 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.57 (t, J = 10.2 Hz, 1H), 4.56 (s, 2H), 3.77 (s, 3H), 3.50 (dd, J = 10.7, 17.4 Hz, 1H), 3.23 (dd, J = 9.8, 17.3 Hz, 1H); ES-LCMS m/z 478.9, 480.9 [M+H]+. Peak 2 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (20 mL) and H2O (40 mL) and lyophilized to yield 4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline (24.58 mg, 50.61 µmol, 14.6% yield, 98.7% purity, SFC: Rt = 3.301, ee = 100%, [α]26.8 D = -198.71 (MeOH, c = 0.155 g/100 mL)) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.54 (s, 1H), 7.58-7.55 (m, 2H), 7.49 (d, J = 9.2 Hz, 3H), 7.39 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 7.00 (dd, J = 2.0, 8.4 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.57 (t, J = 10.3 Hz, 1H), 4.56 (s, 2H), 3.77 (s, 3H), 3.50 (dd, J = 10.8, 17.3 Hz, 1H), 3.23 (dd, J = 9.8, 17.3 Hz, 1H); ES-LCMS m/z 478.9, 480.9 [M+H]+. T-E-21 and T-E-22 (isomers of T-E-30)
Figure imgf000519_0001
Step 1: (S)-5-(3-Chloro-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide
Figure imgf000519_0002
[001128] To a solution of 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide (185 mg, 366.70 µmol, 95% purity, 1 eq) in 1,4- dioxane (10 mL) was added HCl (4 M, 0.5 mL). The mixture was stirred at 40 °C for 16 h. The solvent was removed and the residue was treated with water (10 mL), adjusted to pH 8 with sat. aq. NaHCO3 and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by preparative TLC (PE/EtOAc = 1/1, Rf = 0.71) to yield a product which was separated by chiral SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1%NH3H2O EtOH];B%: 35%-35%) to yield Peak 1 and Peak 2. Peak 1 was concentrated under reduced pressure to yield a residue which was dissolved in MeCN (10 mL) and H2O (20 mL) and lyophilized to yield (S)-5-(3-chloro-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide (43.65 mg, 97.09 µmol, 26.5% yield, 96.7% purity, SFC: Rt = 1.279, ee = 99.4%, [α]24.4D = -24.24 (MeOH, c = 0.0825 g/100 mL) as a white solid.1H NMR (500 MHz, CDCl3) δ ppm 8.71 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.70-7.68 (m, 3H), 7.64-7.58 (m, 2H), 5.84 (t, J = 11.2 Hz, 1H), 4.41 (br s, 1H), 3.62-3.41 (m, 2H), 2.71 (d, J = 5.3 Hz, 3H); ES-LCMS m/z 435.0 [M+H]+. T-E-23 and T-E-24 (isomers of T-E-31)
Figure imgf000520_0001
Step 1: 5-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2- pyridyl]amino]pyridine-3-sulfonamide
Figure imgf000520_0002
[001129] To a solution of 5-(trifluoromethyl)pyridin-2-amine (91.11 mg, 562.00 µmol, 1.5 eq) in DMF (3 mL) was added NaH (59.94 mg, 1.50 mmol, 60% purity, 4 eq) and the mixture was stirred at 0 °C for 0.5 h. 5-Bromo-6-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-pyridine-3- sulfonamide (160 mg, 374.67 µmol, 95% purity, 1 eq) was added and the mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue. To the residue was added MeOH (5 mL) and the mixture was stirred at 25 °C for 2 h. The slurry was filtered and the cake was rinsed with MeOH (3 mL x 2). The solid was collected and dried in vacuo to yield 5-bromo- N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]pyridine-3- sulfonamide (160 mg, 301.12 µmol, 80.8% yield, 100.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (s, 1H), 8.72 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.28-8.19 (m, 2H), 7.24 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.16 (s, 2H), 3.74 (s, 3H), 2.60 (s, 3H); ES-LCMS m/z 533.0 [M+H]+. Step 2: N-[(4-Methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5- vinyl-pyridine-3-sulfonamide
Figure imgf000521_0001
[001130] To a solution of 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[5- (trifluoromethyl)-2-pyridyl]amino]pyridine-3-sulfonamide (260 mg, 489.32 µmol, 100% purity, 1 eq) in 1,4-dioxane (6 mL) and H2O (1 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (301.45 mg, 1.96 mmol, 331.99 µL, 4 eq), Pd(dppf)Cl2 (35.80 mg, 48.93 µmol, 0.1 eq) and Cs2CO3 (318.86 mg, 978.64 µmol, 2 eq). The mixture was stirred under N2 atmosphere at 90 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 5/1, TLC: PE/EtOAc = 5/1, Rf = 0.35) to yield N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5- vinyl-pyridine-3-sulfonamide (200 mg, 409.62 µmol, 83.7% yield, 98.0% purity) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.69 (d, J = 2.3 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.55 (s, 1H), 8.01-7.91 (m, 2H), 7.79 (s, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.95-6.86 (m, 2H), 6.82 (dd, J = 11.0, 17.3 Hz, 1H), 5.86 (d, J = 17.3 Hz, 1H), 5.74 (d, J = 11.0 Hz, 1H), 4.16 (s, 2H), 3.81 (s, 3H), 2.66 (s, 3H); ES-LCMS m/z 479.6 [M+H]+. Step 3: N-Methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5-vinyl-pyridine-3-sulfonamide
Figure imgf000521_0002
[001131] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)- 2-pyridyl]amino]-5-vinyl-pyridine-3-sulfonamide (200 mg, 409.62 µmol, 98% purity, 1 eq) in DCM (3 mL) was added TFA (1.51 g, 13.24 mmol, 980.00 µL, 32.31 eq). The mixture was stirred at 25 °C for 3 h. The solvent was removed to yield N-methyl-6-[[5-(trifluoromethyl)-2- pyridyl]amino]-5-vinyl-pyridine-3-sulfonamide (140 mg, crude) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.71 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 5.94 (d, J = 16.9 Hz, 1H), 5.78 (d, J = 11.0 Hz, 1H), 3.99 (s, 3H); ES-LCMS m/z 359.2 [M+H]+. Step 4: 5-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-6-[[5-(trifluoromethyl)-2- pyridyl]amino]pyridine-3-sulfonamide and 5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N- methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]pyridine-3-sulfonamide
Figure imgf000522_0001
[001132] To a solution of N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5-vinyl- pyridine-3-sulfonamide (140 mg, 390.69 µmol, 1 eq) in EtOAc (10 mL) was added NaHCO3 (328.22 mg, 3.91 mmol, 151.95 µL, 10 eq) and dibromomethanone oxime (158.49 mg, 781.38 µmol, 2 eq). The mixture was stirred at 25 °C for 6 h. The mixture was filtered and the filtrate was concentrated to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.32) to yield a product which was separated by chiral SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O MeOH]; B%: 55%-55%) to yield Peak 1 and Peak 2. Peak 2 was concentrated under reduced pressure to yield 5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-6-[[5- (trifluoromethyl)-2-pyridyl]amino]pyridine-3-sulfonamide (39.4 mg, 81.48 µmol, 20.9% yield, 99.3% purity, SFC: Rt = 4.427, ee = 99.9%, [α]24.5 D = +39.22 (MeOH, c = 0.051 g/100 mL) as a white solid.1H NMR (500 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 8.68-8.55 (m, 2H), 8.14-8.07 (m, 1H), 8.06-7.98 (m, 2H), 7.63 (q, J = 4.8 Hz, 1H), 6.19 (dd, J = 7.9, 11.0 Hz, 1H), 3.92 (dd, J = 11.0, 17.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.45 (d, J = 4.9 Hz, 3H); ES-LCMS m/z 480.1 [M+H]+. Example 2. TEAD inhibition Assay [001133] TEAD inhibition can be assayed using Hippo Pathway TEAD Reporter – MCF7 Cell Line (BPS Bioscience, Catalog #: 60618). Background [001134] The Hippo pathway regulates cell proliferation and cell death. It is activated by high cell density and cell stress to stop cell proliferation and induce apoptosis. The mammalian Hippo pathway comprises MST kinases and LATS kinases. When the Hippo pathway is activated, MST kinases phosphorylate LATS kinases, which phosphorylate transcriptional co-activators YAP and TAZ. Unphosphorylated YAP and TAZ can translocate to the nucleus and interact with TEAD/TEF transcriptional factors to turn on cell cycle-promoting gene transcription. However, when phosphorylated, YAP and TAZ are recruited from the nucleus to the cytosol, so that the YAP and TAZ-dependent gene transcription is turned off. Dysfunction of the Hippo pathway is frequently detected in human cancer and its down-regulation correlates with the aggressive properties of cancer cells and poor prognosis. Description [001135] The TEAD Reporter – MCF7 cell line contains the firefly luciferase gene under the control of TEAD responsive elements stably integrated into the human breast cancer cell line, MCF7. Inside the cells, basal unphosphorylated YAP/TAZ remains in the nucleus and induces the constitutive expression of luciferase reporter. The cell line is validated for the inhibition of the expression of luciferase reporter by the activators of the Hippo pathway. Application • Monitor Hippo pathway activity. • Screen for activators or inhibitors of the Hippo pathway. Format [001136] Each vial contains ~1.5 X 106cells in 1 ml of 10% DMSO. Storage [001137] Immediately upon receipt, store in liquid nitrogen. General Culture Conditions [001138] Thaw Medium 1 (BPS Bioscience #60187) + 10 µg/ml of Insulin (Sigma- Aldrich # I0516): MEM medium (Hyclone #SH30024.01) supplemented with 10% FBS (Invitrogen #26140-079), 1% non-essential amino acids (Hyclone #SH30238.01), 1 mM Na pyruvate (Hyclone #SH30239.01), 1% Penicillin/Streptomycin (Hyclone SV30010.01), plus 10 µg/ml of insulin (Sigma-Aldrich # I0516) [001139] Growth Medium 1B (BPS Bioscience #79531) + 10 µg/ml of Insulin (Sigma- Aldrich # I0516): Thaw Medium 1 (BPS Cat. #60187) + 10 µg/ml of insulin (Sigma-Aldrich # I0516), and 400 µg/ml of Geneticin (Invitrogen #11811031). [001140] Cells should be grown at 37oC with 5% CO2 using Growth Medium 1B with 10 µg/ml of Insulin. It may be necessary to adjust the percentage of CO2 in the incubator depending on the NaHCO3 level in the basal medium. [001141] To thaw the cells, it is recommended to quickly thaw the frozen cells from liquid nitrogen in a 37oC water-bath, transfer to a tube containing 10 ml of Thaw Medium 1 + Insulin (no Geneticin), spin down cells, resuspend cells in pre-warmed Thaw Medium 1 + Insulin (no Geneticin), transfer resuspended cells to a T25 flask and culture in a CO2 incubator at 37oC overnight. The next day, replace the medium with fresh Thaw Medium 1 + Insulin (no Geneticin), and continue growing culture in a CO2 incubator at 37°C until the cells are ready to be split. At first passage, switch to Growth Medium 1B + 10 µg/ml of Insulin (includes Thaw Medium 1, Insulin, and Geneticin). Cells should be split before they reach complete confluence. [001142] To passage the cells, rinse cells with phosphate buffered saline (PBS), and detach cells from the culture vessel with 0.25% Trypsin/EDTA. Add Growth Medium 1B + 10 µg/ml of Insulin (Includes Thaw Medium 1, Insulin, and Geneticin) and transfer to a tube, spin down the cells, then, resuspend cells and seed appropriate aliquots of cell suspension into new culture vessels. Subcultivation ration: 1:5 to 1:10 weekly. [001143] To freeze down the cells, rinse cells with phosphate buffered saline (PBS), and detach cells from culture vessel with Trypsin/EDTA. Add Growth Medium 1B + 10 µg/ml of Insulin (Includes Thaw Medium 1, Insulin, and Geneticin) and transfer to a tube, spin down cells, and resuspend in freezing medium (10% DMSO + 90% FBS). Place at -80°C overnight and place in liquid nitrogen the next day. Alternatively, vials may be placed directly in liquid nitrogen. Functional Validation and Assay Performance [001144] The following assays are designed for 96-well format. To perform the assay in different tissue culture formats, the cell number and reagent volume should be scaled appropriately. Materials Required but Not Supplied for Cell Culture • Thaw Medium 1 (BPS Bioscience #60187) + 10 µg/ml of insulin • Growth Medium 1B (BPS Bioscience #79531) + 10 µg/ml of insulin • Insulin Solution from Bovine Pancreas (Sigma-Aldrich #: I0516) Materials Required but Not Supplied for Cellular Assay • H2O2: activator of Hippo pathway (activate MST kinases) • Insulin • Assay Medium: Thaw Medium 1 (BPS Cat. #60187) + 10 µg/ml of insulin • Insulin Solution from Bovine Pancreas (Sigma-Aldrich Cat#: I0516) • Okadaic acid (BPS bioscience #27047): activator of Hippo pathway (activate MST kinases). Prepare 10 mM stock in DMSO. • 96-well tissue culture plate or 96-well tissue culture-treated white clear-bottom assay plate • ONE-Step™ Luciferase Assay System (BPS, Cat. #60690) • Luminometer Mycoplasma testing [001145] The cell line has been screened using the PCR-based VenorGeM Mycoplasma Detection kit (Sigma-Aldrich) to confirm the absence of Mycoplasma species. Inhibition of TEAD reporter activity by activator of Hippo pathway in TEAD Reporter – MCF7 cells 1) Harvest TEAD Reporter – MCF7 cells from culture in growth medium and seed cells at a density of 35,000 cells per well into white clear-bottom 96-well microplate in 45 µl of assay medium. 2) Incubate cells at 37oC in a CO2 incubator for overnight. 3) Dilute the activators (H2O2 or okadaic acid) stock in assay medium. Add 5 µl of diluted activators to the wells. The final concentration of DMSO in assay medium is 0.1%. 4) Add 5 µl of assay medium with same concentration of DMSO without activator to control wells. 5) Add 50 µl of assay medium with DMSO to cell-free control wells (for determining background luminescence). 6) Set up each treatment in at least triplicate. 7) Incubate cells at 37oC in a CO2 incubator for 5-6 hours. 8) Perform luciferase assay using the ONE-Step™ Luciferase Assay System following the protocol provided: Add 100 µl of ONE-Step™ Luciferase reagent per well and rock at room temperature for ~15 minutes. Measure luminescence using a luminometer. 9) Data Analysis: Obtain the background-subtracted luminescence by subtracting the average background luminescence (cell-free control wells) from the luminescence reading of all wells. [001146] Certain compounds were tested in TEAD reporter assay, and in H226 and H28. The data are listed in Table 2 below. A: EC50 < 0.1 uM; B: 0.1 uM ≤ EC50 ≤ 0.5 uM; C: EC50 > 0.5 uM. Table 2. In vitro Data of Certain Exemplary Compounds.
Figure imgf000526_0001
Example 3: Mouse Pharmacokinetics Study [001147] Formulated compounds are administered intravenously or orally via gavage to BALB/c mice. Typically, at 0.167, 0.5, 1, 2, 4, 6, 12, and 24 hours post-dose, blood is collected and processed to plasma by centrifugation and stored at -80 °C until analysis. Internal standard is added to each sample prior to protein precipitation with acetonitrile or TCA. The precipitates are filtered through a filter plate and the samples are analyzed by LC/MS/MS. A standard curve is prepared in plasma from typically from 1.0 ng/mL to 3000 ng/mL and processed in the same manner as the samples. Sample analysis is typically performed on a suitable LC/MS/MS system fitted with an analytical UPLC column and compounds eluted from the analytical column with a gradient from 30-95% 0.1 % formic acid (v/v) in ACN: 0.1 % formic acid (v/v) in water. Mass spectrometric detection of test compound and the internal standard is performed by MRM in positive mode. The pharmacokinetics of each compound are analyzed by Phoenix WinNonlin software (Pharsight, St. Louis, MO) via noncompartmental analysis. Example 4. CTGF Data Analysis [001148] NU/NU nude female mice are obtained from Charles River Laboratories and subcutaneously injected with NCI-H226 (ATCC) human mesothelioma cells. Once tumors grow to an average size of 350-400 mm3, mice are randomized into each treatment group. NCI-H226 tumor bearing mice are treated by oral gavage with Vehicle (5%DMSO/95% PEG 400) or a TEAD inhibitor for a total of 3 administrations. 4 hours post-third administration, mice are euthanized and tumors collected for isolation of RNA for pharmacodynamic (PD) analysis. [001149] RNA is extracted from the tumors utilizing the QIAZOL (Qiagen) lysis reagent, tissues are then homogenized for 10 minutes using TissueLyser II (Qiagen). Once sample disruption and digestion is complete, chloroform is added to each sample, the homogenate is separated into aqueous and organic phases by centrifugation. [001150] RNA is then isolated from samples using the KingFisher Flex automated extraction system and MagMAX mirvana total RNA isolation kit. Manufacturer’s recommended protocol for high-throughput isolation of RNA from tissue samples is followed for RNA extraction. [001151] Expression of the YAP/TEAD-regulated gene, CCN2 that encodes CTFG (Connective Tissue Growth Factor), and the housekeeping gene, human glyceraldehyde 3- phosphate dehydrogenase (GAPDH), are quantified by qRT-PCR analysis using the TaqMan Gene Expression Master Mix and TaqMan probes. CTGF and GAPDH cycle threshold (Ct) values for tumor cDNA samples are determined, and CTGF expression is normalized to GAPDH as an internal control. [001152] The relative CTGF mRNA expression levels for each treatment group from tumor tissues are normalized to the vehicle control group. For comparisons between vehicle control and TEAD inhibitor treatment groups, an independent sample t-test is used for statistical analysis. Example 5. Anti-Proliferation Assay [001153] Individual cell lines are grown in medium according to supplier instructions and seeded into 96-well plates at a density that ensures logarithmic growth over 72-96 hours. TEAD inhibitor compounds are administered to cells at a top concentration of 10 µm and subsequently a 10 point 3-fold serial dilution is conducted. After 72-96 hours, proliferation is quantified using Cell TITERGLOTM (Promega, Inc.) and compared to vehicle control. IC50 and EC50 values are generated using Prism or XLFit curve fitting software. Example 6. In vivo Inhibition of Tumor Growth NCI-H226 in vivo Efficacy Studies [001154] 6-8 week old nu/nu nude mice (CRL) are inoculated subcutaneously with 5 x106 NCI-H226 human mesothelioma tumor cells in the right flank. Tumor growth is monitored twice per week using vernier calipers and mean tumor volume (MTV) calculated using the formula V= W2 x L/2. [001155] When the MTV reaches approximately 150-200 mm3, animals are randomized into treatment groups (n=8-10/group) and dosed per os (PO) on a once everyday (QD) schedule for 27- 40 days with either Vehicle (5% DMSO + 95% PEG 400) or TEAD inhibitors. [001156] Randomization and treatments start on Day 0 and % Tumor Growth Inhibition is calculated on the last day of the study (when the control MTV reaches maximum allowable tumor volume), and the following calculation is performed. [001157] %TGI= 100 – [MTV treated / MTV control] x 100 [001158] Tumor growth and body weight change are measured twice per week. [001159] For comparisons between vehicle control and TEAD inhibitor treatment groups, an independent sample t-test is used for statistical analysis. MSTO-211H in vivo efficacy studies [001160] 6-8 week old SCID mice (CRL) are inoculated subcutaneously with 5 x106 MSTO- 211H human mesothelioma tumor cells in the right flank. Tumor growth is monitored twice per week using vernier calipers and mean tumor volume (MTV) is calculated using the formula V= W2 x L/2. [001161] When the MTV reached approximately 150-200 mm3, animals are randomized into treatment groups (n=6-8/group) and dosed per os (PO) on a once everyday (QD) schedule for 22- 25 days with either Vehicle (5% DMSO + 95% PEG 400) or TEAD inhibitors. [001162] Randomization and treatments started on Day 0 and % Tumor Growth Inhibition is calculated on the last day of the study (when the control MTV reaches maximum allowable tumor volume), the following calculation is performed. [001163] %TGI= 100 – [MTV treated / MTV control] x 100 [001164] Tumor growth and body weight change are measured twice per week. [001165] For comparisons between vehicle control and TEAD inhibitor treatment groups, an independent sample t-test is used for statistical analysis. Example 7. TEAD Selectivity Assays [001166] The TEAD targeting selectivity profiles of the TEAD inhibitor compounds described herein can be determined by any of the exemplary assays provided herein designed to monitor the interaction of TEAD isoforms or variants, e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4), and YAP1 or TAZ. While co-immunoprecipitation techniques can be used to monitor protein-protein interactions, it is difficult to increase the throughput based on the basic methodology required. Accordingly, alternative but complementary assays are employed to monitor the interaction of the different TEAD isoforms or variants, e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4), and YAP1 (or TAZ). [001167] The first exemplary assay is an in vitro biochemical fluorescent polarization assay using recombinantly expressed and purified YAP-binding domains of individual TEAD isoforms and a fluorescently labeled peptide derived from the primary sequence of YAP1. (Bum-Erdene et al., Cell Chem Biol. 2019 Mar 21;26(3):378-389.e13, the contents of which are herein incorporated by reference in their entireties). Compounds are incubated with individual TEAD isoform proteins and the fluorescent peptide and potency is determined by quantifying the displacement of the peptide. [001168] The second exemplary assay is a cell-based assay employing the split luciferase reporter system (Hall et al., ACS Chem. Biol.2012, 7, 11, 1848-1857, the contents of which are herein incorporated by reference in their entireties). Briefly, the YAP-binding domain of each TEAD isoform is transiently co-expressed with the TEAD-binding domain or either YAP1 or TAZ in HEK293 cells and the proximity of the two chimeric gene fusion products is monitored by luciferase activity (Nouri et al. Cancers (Basel). 2019 Oct 19;11(10), the contents of which are herein incorporated by reference in their entireties). Compounds that interfere with the interaction of a TEAD isoform and YAP1 (or TAZ) decrease the resulting luciferase activity relative to vehicle treated controls. Similar in process to the fluorescent polarization assay, these chimeric gene fusions are recombinantly expressed in bacteria or insect cells and employed as an in vitro biochemical assay with a similar luciferase readout as the cell-based assay. [001169] Another exemplary assay is a thiol conjugation assay that monitors prevention of covalent binding of a fluorescence turn-on probe to a cysteine in the central pocket of TEAD isoforms by small molecules, as described in Karatas et al., “Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain (TEAD) Central Pocket,” J. Med. Chem.2020, the contents of which are herein incorporated by reference in their entireties. Briefly, the thiol reactive pro-fluorescent probe, N-(4-(7-diethylamino-4-methylcoumarin-3-yl) phenyl) maleimide (CPM) is used. The fluorescence in CPM is quenched due to the maleimide substitution on the phenyl group that modulates the resonance between the coumarin carbonyl and 7-amino groups. However, upon reaction with a thiol, CPM fluorescence increases strongly. CPM can be used to investigate TEAD inhibition because reaction of a free cysteine residue in the TEAD central pocket yields a fluorescence signal, such that small molecules that bind to the TEAD central pocket with appreciable potency prevents covalent labeling of the cysteine by CPM. Thus, in thiol conjugation assays, freshly prepared TEAD protein solutions are added and incubated at room temperature with test compounds in assay buffer, followed by the addition of a CPM solution and fluorescence is measured (Ex/Em: 380/470 nm). Any test compounds that bind the TEAD central pocket with appreciable potency show less fluorescence or inhibition of fluorescence relative to compounds that do not bind the TEAD central pocket. Example 8. Inhibition of malignant mesothelioma tumor cell growth [001170] The tumor cell growth inhibitory activity of the TEAD inhibitors described herein is evaluated in NCI-H2052 mesothelioma cell line harboring a NF2 mutation. This cell line is selected, in part, based on its mutational status and the ability of a siRNA directed against YAP, TAZ or TEAD1-TEAD4 to inhibit cell proliferation. The nuclear localization of YAP at confluence is also taken into account. 10,000 cells/well are plated in a 96-well black plate with clear flat bottom TC-Treated Imaging plate in regular medium with serum, which is replaced the day after with starvation medium containing 1% serum. After one day growth in the starvation medium, cells are incubated with TEAD inhibitor compounds. The starting concentration is 30 µM and serial dilutions in DMSO and medium are performed until 0.1 µM to achieve a final DMSO concentration of 0.5%. The cells are then allowed to grow for 3 days, and then, EdU (Invitrogen, Molecular Probe) is added in each well at a final concentration of 10 mM and the cells are returned to the incubator for an additional 24h. The starvation medium is removed and 100 µl of PFA 4% containing Hoechst dye is added in each well to fix the cells. Plates are then incubated at room temperature for 15 min, washed twice with PBS, and the cells permeabilized by adding 100 µl per well of triton-100 containing 0.3% BSA. After 20 min, cells are washed with PBS and EdU detection is performed according to the instructions of the manufacturer. Image acquisition is performed, for example, using the ImageXpress Micro and analyzed using the MetaXpress software (Molecular Device). [001171] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS 1. A compound of formula I:
Figure imgf000532_0001
or a pharmaceutically acceptable salt thereof, wherein: TBM is a TEAD binding moiety capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4; L is a bivalent moiety that connects TBM to LBM; and LBM is a ligase binding moiety. 2. The compound of claim 1, wherein LBM is a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquine ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety. 3. The compound of claim 1 or 2, wherein LBM is
Figure imgf000532_0004
or
Figure imgf000532_0002
. 4. The compound of any one of claims 1-3, wherein LBM is
Figure imgf000532_0005
Figure imgf000532_0003
, , ,
Figure imgf000533_0001
. 5. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula A:
Figure imgf000533_0002
, thereby forming a compound of formula I-A :
Figure imgf000533_0003
or a pharmaceutically acceptable salt thereof, wherein L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Rw is an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R is independently -H or optionally substituted -C1-6 aliphatic. 6. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula A-1:
Figure imgf000534_0001
thereby forming a compound of formula I-A-1:
Figure imgf000534_0002
or a pharmaceutically acceptable salt thereof, wherein L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by -halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0-6 times by -halogen, -CN, or –NO2; R2 is -H, or an optionally substituted 4-, 5-, or 6- membered ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is -H; R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, or -C(O)N(R)2; R6 is -H or -C1-6 aliphatic substituted 0-6 times by -halogen, -CN, or –NO2; and each R is independently -H or optionally substituted -C1-6 aliphatic.
7. The compound of any one of claims 1-4, wherein TBM is a moiety selected from the following: i. Formula (A-20) or (A-21):
Figure imgf000535_0001
wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R4, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; ii. Formula (A-22) or (A-23):
Figure imgf000535_0002
wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; iii. Formula (A-24) or (A-25):
Figure imgf000535_0003
wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, each of R2 and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; iv. Formula (A-26) or (A-27):
Figure imgf000536_0001
A-26 A-27 wherein L1 is a C2-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; v. Formula (A-28) or (A-29):
Figure imgf000536_0002
A-28 A-29 wherein L1 is a C2-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is optionally substituted -C1-6 aliphatic, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; vi. Formula (A-30) or (A-31):
Figure imgf000536_0003
A-30 A-31 wherein L1 is a C2-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; vii. Formula (A-32) or (A-33):
Figure imgf000537_0001
wherein R2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen; viii. Formula (A-34) or (A-35):
Figure imgf000537_0002
wherein R is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; ix. Formula (A-36) or (A-37):
Figure imgf000537_0003
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R4, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; x. Formula (A-38) or (A-39):
Figure imgf000537_0004
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -N(R)-, and each of R2, R6, and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xi. Formula (A-40) or (A-41):
Figure imgf000538_0003
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, each of R2 and R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xii. Formula (A-42) or (A-43):
Figure imgf000538_0004
wherein L1 is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is -C1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xiii. Formula (A-44) or (A-45):
Figure imgf000538_0001
wherein L1 is a C1-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, R is optionally substituted -C1-6 aliphatic, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xiv. Formula (A-46) or (A-47):
Figure imgf000538_0002
A-46 A-47 wherein L1 is a C1-6 bivalent straight hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -NH-, and R2 is as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50; xv. Formula (A-48) or (A-49):
Figure imgf000539_0001
wherein R2 is an optionally substituted 5-membered ring having 1, 2, 3, or 4 nitrogen; or xvi. Formula (A-50) or (A-51):
Figure imgf000539_0002
wherein R is independently as defined and described in embodiments in the section of TBM of Formulas A, and A-1 to A-50. 8. The compound of any one of claims 1-4, wherein TBM is a moiety set forth in Table A, or a pharmaceutically acceptable salt thereof. 9. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula B:
Figure imgf000539_0004
thereby forming a compound of formula I-B:
Figure imgf000539_0003
or a pharmaceutically acceptable salt thereof, wherein L1 is a covalent bond, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, –CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, - C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, or a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring B is an optionally substituted ring selected from phenyl, a 4-, 5-, or 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8- 10 membered bicyclic aromatic ring, a 8-10 membered bicyclic heteroaromatic ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Rw is a warhead group; wherein when Rw is a saturated or partially unsaturated monocyclic carbocyclic or heterocyclic ring, it optionally forms a spiro bicyclic ring with Ring B; and each R is independently -H or optionally substituted -C1-6 aliphatic. 10. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula B-1: thereby forming a compound of formula I-B-1:
Figure imgf000540_0001
Figure imgf000540_0002
or a pharmaceutically acceptable salt thereof, wherein L1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -CH(OR)-, -CH(SR)-, – CH(N(R)2)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, - (R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, - OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; Ring A is a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-, 5-, or 6- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ring A is optionally substituted 1-2 times by halogen, -CN, –NO2, or -C1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO2; R2 is -H, or a warhead group; R3 is -H or a warhead group; R4 is -H, halogen, -S(O)2N(R)2, -S(O)N(R)2, -C(O)N(R)2, or a warhead group; R6 is -H or -C1-6 aliphatic substituted 0-6 times by halogen, -CN, or –NO2; and each R is independently -H or optionally substituted -C1-6 aliphatic. 11. The compound of any one of claims 1-4, wherein TBM is a moiety selected from the following: i. Formula (B-19):
Figure imgf000541_0001
wherein each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ii. Formula (B-20) or (B-21):
Figure imgf000541_0002
wherein each of Ring A, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; iii. Formula (B-22):
Figure imgf000542_0004
wherein each of Ring B, Rw, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; optionally, L1 is not –NH-C(O)- or -O-CH2- ; iv. Formula (B-23):
Figure imgf000542_0005
wherein each of Ring B and Rw is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; v. Formula (B-24):
Figure imgf000542_0006
wherein each of Ring A, Ring B, and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; optionally, Ring B is not
Figure imgf000542_0003
Figure imgf000542_0001
, , ; optionally, Ring B is an optionally substituted 6-, 7-, 8-, 9-, or 10- membered bicyclic heterocyclic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; further optionally, Ring B is an optionally substituted 6- membered bicyclic heterocyclic ring having 1 nitrogen; vi. Formula (B-25):
Figure imgf000542_0002
B-25 wherein each of Rw and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; vii. Formula (B-26) or (B-27):
Figure imgf000543_0001
wherein each of Rw and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; viii. Formula (B-28):
Figure imgf000543_0002
wherein each of Ring A and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; ix. Formula (B-29) or (B-30):
Figure imgf000543_0003
wherein each of Ring A and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; x. Formula (B-31):
Figure imgf000543_0004
wherein each of Ring B and L1 is independently as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; optionally, L1 is –CH2–; xi. Formula (B-32):
Figure imgf000544_0001
wherein L1 is as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34; or xii. Formula (B-33) or (B-34):
Figure imgf000544_0005
wherein L1 is as defined and described in embodiments in the section of TBM of Formulas B, and B-1 to B-34. 12. The compound of any one of claims 1-4, wherein TBM is a moiety set forth in Table B, or a pharmaceutically acceptable salt thereof. 13. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula C:
Figure imgf000544_0002
, thereby forming a compound of formula I-C:
Figure imgf000544_0003
or a pharmaceutically acceptable salt thereof, and wherein L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from
Figure imgf000544_0004
,
Figure imgf000545_0003
and
Figure imgf000545_0004
, each of which is optionally substituted; Ring B is selected from
Figure imgf000545_0001
; each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000545_0002
; each Y is independently N or CR5; R3 is H, -C(O)R, or optionally substituted -C1-6 aliphatic; each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 14. The compound of any one of claims 1-4, wherein TBM is a moiety selected from the following:
,
Figure imgf000546_0001
Figure imgf000547_0001
, or a pharmaceutically acceptable salt thereof, wherein each of R, R1, L1, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas C, and C-1 to C-85. 15. The compound of any one of claims 1-4, wherein TBM is a moiety set forth in Table C, or a pharmaceutically acceptable salt thereof. 16. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula D:
Figure imgf000547_0002
, thereby forming a compound of formula I-D:
Figure imgf000547_0003
or a pharmaceutically acceptable salt thereof, wherein each of L, LBM, and DIM is independently as defined above and described in embodiments herein, and wherein L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from
Figure imgf000547_0004
Figure imgf000547_0005
and
Figure imgf000548_0001
each of which is optionally substituted;; Ring B is
Figure imgf000548_0002
each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000548_0003
each Y is independently N or CR5; each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 17. The compound of any one of claims 1-4, wherein TBM is a moiety selected from the following:
Figure imgf000548_0004
Figure imgf000549_0001
, or a pharmaceutically acceptable salt thereof, wherein each of R, R1, L1, and R5 is independently as defined and described in embodiments in the section of TBM of Formulas D, and D-1 to D-85. 18. The compound of any one of claims 1-4, wherein TBM is a moiety set forth in Table D, or a pharmaceutically acceptable salt thereof. 19. The compound of any one of claims 1-4, wherein TBM is a moiety of Formula E: thereby forming a compound of formula I-E:
Figure imgf000550_0001
Figure imgf000550_0002
or a pharmaceutically acceptable salt thereof, wherein L1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; Ring A is selected from
Figure imgf000550_0003
Figure imgf000550_0004
and each of which is optionally substituted;
Figure imgf000550_0005
Ring B is selected from
Figure imgf000550_0006
Figure imgf000550_0007
each Rw is independently selected from
Figure imgf000551_0001
; each R2 is independently selected from -OR, -C(O)NR2, optionally substituted -C1-6 aliphatic,
Figure imgf000551_0002
; each Y is independently N or CR5; each R3 is independently H or optionally substituted -C1-6 aliphatic; each R4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; p is 0, 1, or 2, and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 20. The compound of any one of claims 1-4, wherein TBM is a moiety elected from the following:
Figure imgf000551_0003
Figure imgf000552_0004
or a pharmaceutically acceptable salt thereof, wherein each of R1, L1, Rw, and n is independently as defined and as described in embodiments in the section of TBM of Formulas E, and E-1 to E- 204. 21. The compound of any one of claims 1-4, wherein TBM is a moiety set forth in Table E, or a pharmaceutically acceptable salt thereof. 22. The compound of any one of claims 1-21, wherein L is a covalent bond, or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 1-6 methylene units of L are independently and optionally replaced by –Cy-, -O-, -N(RI)-, -S-, -C(O)- , -S(O)-, -S(O)2-,
Figure imgf000552_0001
, wherein: each –Cy– is independently an optionally substituted bivalent ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, and a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RI is independently H or optionally substituted -C1-6 aliphatic; and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 23. The compound of any one of claims 1-21, wherein L is selected from
Figure imgf000552_0002
,
Figure imgf000552_0003
,
Figure imgf000553_0001
24. The compound of any one of claims 1-21, wherein L is selected from
Figure imgf000553_0002
,
Figure imgf000553_0003
25. The compound of any one of claims 1-21, wherein L is selected from
Figure imgf000553_0004
Figure imgf000553_0005
26. The compound of any one of claims 1-25, which is a compound selected from those in Table 1. 27. A pharmaceutical composition comprising the compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 28. A method for treating cancer in a patient, comprising administering to the patient the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27. 29. The method of claim 28, wherein the cancer is associated with increased TEAD expression. 30. The method of claims 28 or 29, wherein the cancer is associated with increased TEAD activity. 31. A method for inhibiting the progress of cancer in a patient, comprising administering to the patient the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27. 32. The method of claim 31, wherein the cancer is associated with increased TEAD expression. 33. The method of claims 31 or 32, wherein the cancer is associated with increased TEAD activity. 34. A method of treating a patient having a disease or disorder associated with increased TEAD expression comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27.
35. A method of treating a patient having a disease or disorder associated with increased TEAD activity comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27. 36. A method of treating a disease or disorder in which inhibition of TEAD activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27. 37. A method of treating a disease or disorder in which Hippo pathway inhibition is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27. 38. The method of any one of claims 34-37, wherein the disease or disorder is a cellular proliferative disorder. 39. The method of claim 38, wherein the cellular proliferative disorder is cancer. 40. The method of any one of claims 28-33 and 39, wherein the cancer is a cancer in which YAP is localized in the nucleus of cells of the cancer. 41. The method of any one of claims 29, 30, and 32-35, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity. 42. The method of any one of claims 29, 30, and 32-35, wherein the increased TEAD expression or increased TEAD activity is increased TEAD2 expression or increased TEAD2 activity.
43. The method of any one of claims 29, 30, and 32-35, wherein the increased TEAD expression or increased TEAD activity is increased TEAD3 expression or increased TEAD3 activity. 44. The method of any one of claims 29, 30, and 32-35, wherein the increased TEAD expression or increased TEAD activity is increased TEAD4 expression or increased TEAD4 activity. 45. The method of any one of claims 29, 30, and 32-35, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity; increased TEAD2 expression or increased TEAD2 activity; increased TEAD3 expression or increased TEAD3 activity; increased TEAD4 expression or increased TEAD4 activity; or any combination thereof. 46. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27, for treating cancer in a patient. 47. The use of claim 46, wherein the cancer is associated with increased TEAD expression. 48. The use of claims 46 or 47, wherein the cancer is associated with increased TEAD activity. 49. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27, for inhibiting the progress of cancer in a patient. 50. The use of claim 49, wherein the cancer is associated with increased TEAD expression. 51. The use of claims 49 or 50, wherein the cancer is associated with increased TEAD activity. 52. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 27, for treating a disease or disorder associated with increased TEAD expression. 53. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27, for treating a disease or disorder associated with increased TEAD activity. 54. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27, for treating a disease or disorder in which inhibition of TEAD activity is beneficial. 55. Use of a compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 27, for treating a disease or disorder in which Hippo pathway inhibition is beneficial. 56. The use of any one of claims 52-55, wherein the disease or disorder is a cellular proliferative disorder. 57. The use of claim 56, wherein the cellular proliferative disorder is cancer. 58. The use of any one of claims 46-51 and 57, wherein the cancer is a cancer in which YAP is localized in the nucleus of cells of the cancer. 59. The use of any one of claims 47, 48, and 50-53, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity. 60. The use of any one of claims 47, 48, and 50-53, wherein the increased TEAD expression or increased TEAD activity is increased TEAD2 expression or increased TEAD2 activity. 61. The use of any one of claims 47, 48, and 50-53, wherein the increased TEAD expression or increased TEAD activity is increased TEAD3 expression or increased TEAD3 activity.
62. The use of any one of claims 47, 48, and 50-53, wherein the increased TEAD expression or increased TEAD activity is increased TEAD4 expression or increased TEAD4 activity. 63. The use of any one of claims 47, 48, and 50-53, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity; increased TEAD2 expression or increased TEAD2 activity; increased TEAD3 expression or increased TEAD3 activity; increased TEAD4 expression or increased TEAD4 activity; or any combination thereof.
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