Compounds and methods for modulating YAP / TEAD and their applications

Abstract

Formula (I) [Formula 1] JPEG2024517473000053.jpg5561 (In the formula, R 1 , R 2 , R 3 , R 4 , L and X are as described in any of the embodiments described in this disclosure), or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, compositions thereof, and uses thereof are disclosed.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 187,226, filed May 11, 2021, the entire teachings of which are incorporated herein by reference.

[0002] Field The present disclosure relates to organic compounds useful for therapy in mammals, in particular for modulating the interaction between YAP and TEAD for the treatment of various diseases associated with the Hippo signaling pathway. [Background technology]

[0003] YAP and TEAD are two proteins involved in the Hippo signaling pathway that regulates tissue homeostasis, cell proliferation, tumor transformation and apoptosis. This pathway involves a series of kinases that result in the phosphorylation of two transcriptional coactivators, YAP and TAZ. YAP / TAZ does not contain a DNA-binding domain, but binds to the TEAD transcription factor family (TEAD-1, TEAD-2, TEAD-3 and TEAD-4) to mediate target gene expression, such as connective tissue growth factor (CTGF), cysteine-rich angiogenic factor 61 (CYR61), and promotes cell growth, proliferation, migration and survival. (Gandhi TKBoopathy et al., Role of Hippo Pathway-YAP / TAZ Signaling in Angiogenesis, Front Cell Dev Biol. 2019, vol. 7, p. 49). When the upstream kinase is inactive, YAP and TAZ are not phosphorylated, translocate to the nucleus and bind to TEAD. Deregulation of the Hippo pathway is involved in a wide variety of tumors, including breast, and therefore its targeting represents an approach for the treatment of cancers with functional alterations of this pathway. (Dominguez-Berrocal et al., New Therapeutic Approach for Targeting Hippo Signalling Pathway. Sci Rep 9, 4771 (2019)). As an example, one of the small molecules used to target this signaling pathway is verteporfin, which associates with YAP and inhibits its binding to TEAD.

[0004] Compounds that modulate, and more specifically inhibit, the interaction between YAP and TEAD (i.e., YAP / TEAD inhibitors), thereby reducing the expression of YAP / TEAD target genes and exhibiting antiproliferative effects in cancer cell lines controlled by the Hippo signaling pathway, are a new class of potential therapeutic agents that can modulate tumor growth and other diseases. As there are no YAP / TEAD inhibitors currently approved for the treatment or prevention of human disease, there is an unmet need for novel compounds that can modulate YAP / TEAD. Summary of the Invention

[0005] One embodiment of the present disclosure relates to a novel compound, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, as described in any of the embodiments herein, that is capable of modulating YAP / TEAD.

[0006] Another embodiment of the present disclosure is a compound of formula (I) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , L and X are as described in any of the embodiments (including any of the subembodiments) of the present disclosure. or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof.

[0007] Other embodiments and subembodiments of formula (I) are further described herein in this disclosure.

[0008] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or any of the embodiments and subembodiments of formula (I) as described herein, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, and a pharma- ceutically acceptable carrier or excipient.

[0009] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), or any embodiment of formula (I), or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, as described in this disclosure, and another therapeutic agent.

[0010] Another embodiment of the present disclosure relates to a method of treating a subject having a disease or condition mediated at least in part by YAP / TEAD, comprising administering to the subject an effective amount of a compound according to Formula (I), or any embodiment of Formula (I) described in this disclosure, or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds described in this disclosure.

[0011] Also provided herein is the use of a compound according to Formula (I), or any embodiment of Formula (I) described in this disclosure, or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds described in this disclosure, for treating a disease or condition mediated by YAP / TEAD.

[0012] Further embodiments are further described in the detailed description of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] I. Definition As used herein, the following definitions apply unless otherwise stated.

[0014] Please note that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0015] Unless the point of attachment indicates otherwise, the chemical moieties listed in the definitions of the variables of formula (I) and all embodiments thereof in this disclosure are to be read from left to right, with the right hand side being directly attached to the defined parent structure. However, when a point of attachment (e.g., a dash "-") is indicated to the left of the chemical moiety (e.g., -C1-C6 alkyl-N(R 6 )2), the left side of this chemical moiety is directly attached to the parent moiety as defined.

[0016] Given the general description of compounds described herein for purposes of constructing compounds, it is believed that such construction will result in the generation of stable structures, i.e., one of skill in the art will recognize that, in theory, some constructs are not normally considered to be stable compounds (i.e., sterically practical and / or synthetically feasible).

[0017] "Alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 means 1-6 carbons). Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. For each of the definitions herein (e.g., alkyl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, and the like), when no prefix is ​​included to indicate the number of carbon atoms in the alkyl moiety, the alkyl moiety or portion thereof has 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms. For example, C1-C6 alkyl refers to a straight or branched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms, including, but not limited to, -CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C2 alkyl, C2 alkyl, C3 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C2-C3 alkyl, C2-C4 alkyl, C2-C5 alkyl, C2-C6 alkyl, C3-C4 alkyl, C3-C5 alkyl, C3-C6 alkyl, C4-C5 alkyl, C4-C6 alkyl, C5-C6 alkyl, and C6 alkyl.Substitutions are understood to be attached to any available atom to produce a stable compound, however, when optionally substituted alkyl is the R group of a moiety such as -OR (e.g., alkoxy), -SR (e.g., thioalkyl), -NHR (e.g., alkylamino), -C(O)NHR, etc., the substitution of the alkyl R group is such that substitution of an alkyl carbon bonded to any O, S or N of the moiety (except when N is a heteroaryl ring atom) excludes substitutions where any O, S or N of the substituent would be bonded to an alkyl carbon bonded to any O, S or N of the moiety (except when N is a heteroaryl ring atom).

[0018] "Alkylene" by itself or as part of another substituent means a straight or branched chain saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e., C1-C6 means 1 to 6 carbons. C1-C6 alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene, etc.). 1~4 Alkylene includes methylene -CH-, ethylene -CHCH-, propylene -CHCHCH-, and isopropylene -CH(CH)CH-, -CHCH(CH)-, -CH-(CH)CH-, -CH-CH(CH)CH-, -CH-C(CH)-CH-CHCH(CH)-. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms. If no prefix is ​​included to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or portion thereof has 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms, or 3 or fewer main chain carbon atoms, or 2 or fewer main chain carbon atoms, or 1 carbon atom.

[0019] "Alkoxy" or "alkoxyl" refers to an -O-alkyl group, where alkyl is as defined herein. By way of example, "C1-C6 alkoxy" refers to an -O-C1-C6 alkyl group, where alkyl is as defined herein. Substitution on alkoxy is understood to be attached to any available atom to produce a stable compound, but substitution on alkoxy is such that O, S, or N (except when N is a heteroaryl ring atom) is not attached to an alkyl carbon bonded to the alkoxy O. Additionally, when alkoxy is recited as a substituent on another moiety, the alkoxy oxygen is not bonded to a carbon atom bonded to an O, S, or N (except when N is a heteroaryl ring atom) of the other moiety, or to an alkene or alkyne carbon of the other moiety.

[0020] "Amino" or "amine" refers to an NH2 group.

[0021] "Aryl," by itself or as part of another substituent, refers to a monocyclic, bicyclic or polycyclic polyvalent unsaturated aromatic hydrocarbon group containing 6 to 14 ring carbon atoms, which may be a single ring or multiple rings (up to three rings) fused or covalently linked together, unless otherwise stated. However, aryl does not in any way encompass or overlap with heteroaryl, as defined below. When one or more aryl rings are fused with a heteroaryl ring, the resulting ring system is heteroaryl. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl and 2-naphthyl. The term "arylene" refers to a divalent aryl, where aryl is as defined herein.

[0022] "Cycloalkyl" or "carbocycle" or "carbocyclic", by itself or as part of another substituent, refers to a saturated or partially unsaturated non-aromatic monocyclic ring, bridged ring, spiro ring, fused ring (e.g., bicyclic or tricyclic carbocyclic ring systems) or cubane, unless otherwise stated, having the number of carbon atoms indicated by the prefix, or, if not specified, 3 to 6, further 4 to 6, further 5 to 6 ring members per ring, e.g., cyclopropyl, cyclopentyl, cyclohexyl, in which one or two ring carbon atoms may optionally be replaced by carbonyl. Additionally, the term cycloalkyl is intended to encompass ring systems fused to an aromatic ring (e.g., of an aryl or heteroaryl), regardless of the point of attachment to the remainder of the molecule. Cycloalkyl refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3~6 (Both cycloalkyl and 3-6 membered cycloalkyl refer to 3 to 6 ring carbon atoms.) The term "cycloalkenyl" refers to a cycloalkyl having at least one unit of unsaturation. A cycloalkyl or cycloalkenyl substituent may be at the point of attachment of the cycloalkyl or cycloalkenyl group, forming a quaternary center.

[0023] "Halogen" or "halo" refers to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br) or iodo (I).

[0024] "Heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).

[0025] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring group containing 5-9 ring atoms (including monocyclic aromatic ring groups containing 5 or 6 ring atoms (also referred to in this disclosure as 5-6 membered heteroaryl) and containing one or more, 14, 13 or 12 heteroatoms independently selected from the group consisting of O, S and N, also referred to in this disclosure as 5-9 membered heteroaryl). Any aromatic ring or ring system containing at least one heteroatom is heteroaryl regardless of the point of attachment (i.e., through any one of the fused rings). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl, triazinyl, quinoxalinyl, cinnolinyl, Examples of heteroaryls include, but are not limited to, phthalazinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl, pteridinyl, and thiadiazolyl. "Nitrogen-containing heteroaryl" refers to a heteroaryl in which at least one of the ring heteroatoms is N.

[0026] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, both terms as defined herein.

[0027] "Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic cycloalkyl group containing 1-5 heteroatoms selected from N, O, S (including S(O) and S(O)2) or P (including phosphine oxide), where the nitrogen, sulfur and phosphorus atoms are optionally oxidized, the nitrogen atom is optionally quaternized, the remaining ring atoms are C, and one or two C atoms may optionally be present as carbonyl. Furthermore, the term heterocycloalkyl is intended to encompass any ring or ring system containing at least one heteroatom that is not heteroaryl, regardless of the point of attachment to the rest of the molecule. Heterocycloalkyl groups include those with rings that have formally charge-separated aromatic resonance structures, e.g., N-methylpyridonyl. Heterocycloalkyls may be substituted with one or two oxo groups and may include sulfone and sulfoxide derivatives. Heterocycloalkyls can be monocyclic, fused bicyclic or fused polycyclic ring systems of 3-12, 4-10, 5-10 or 5-6 ring atoms, with 1-5 ring atoms being heteroatoms selected from -N=, -N-, -O-, -S-, -S(O)- or S(O)2-, and optionally with 1 or 2 ring atoms being replaced by -C(O)- groups. As an example, a 4-6 membered heterocycloalkyl is a heterocycloalkyl having 4-6 ring members with at least one heteroatom. A heterocycloalkyl can be a heterocyclic alkyl ring fused with a cycloalkyl. Non-limiting examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyl, pyridonyl, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom. "Heterocycloalkenyl" refers to a heterocycloalkyl having at least one unit of unsaturation. Substituents on a heterocycloalkyl or heterocycloalkenyl group at the point of attachment of the heterocycloalkyl or heterocycloalkenyl group can form a quaternary center.

[0028] The term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group. Examples include, but are not limited to, azetidinylmethyl, morpholinomethyl, and the like.

[0029] "Hydroxyl" or "hydroxy" refers to an OH group. The terms "hydroxyalkyl" or "hydroxyalkylene" refer to an alkyl or alkylene group, respectively, as defined herein, that is substituted with one to five hydroxy groups.

[0030] As used throughout this disclosure, "optionally substituted" or "optionally substituted" means that the compound may or may not be substituted, and the description includes both cases where substitution occurs and cases where no substitution occurs. For example, "1 to 3 T 1 The phrase "optionally substituted with a group" is intended to include 1 It means that the group can be present but does not have to be present. In this disclosure, any substitutions to the compounds are assumed to be made in a way that results in a stable compound.

[0031] As used herein in connection with compounds of the present disclosure, "synthesize" and like terms refer to chemical synthesis from one or more precursor materials.

[0032] As used herein, the term "composition" refers to a formulation suitable for administration to an animal subject intended for therapeutic purposes, which contains at least one pharma- ceutically active compound and at least one pharma- ceutically acceptable carrier or excipient.

[0033] The term "pharmaceutical acceptable" indicates that the indicated material does not possess properties that would cause a reasonably prudent physician to avoid administering the material to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, such materials are generally required to be essentially sterile, e.g., in the case of injectables.

[0034] "Pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (e.g., a salt that has acceptable mammalian safety for a given dosing regimen). Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of a compound without preventing the compound from exerting its physiological effect. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration, and increasing the solubility to facilitate administration of higher concentrations of the drug. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein.

[0035] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then evaporating the solution. In another example, salts can be prepared by reacting the free base with an acid in an organic solvent.

[0036] When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compound, neat or in a suitable inert solvent, with a sufficient amount of the desired base (i.e., a primary, secondary, tertiary, quaternary or cyclic amine, an alkali metal hydroxide, an alkaline earth metal hydroxide, etc.). The desired acid can be, for example, a pyranosidyl acid (glucuronic acid, galacturonic acid, etc.), an α-hydroxy acid (citric acid, tartaric acid, etc.), an amino acid (aspartic acid, glutamic acid, etc.), an aromatic acid (benzoic acid, cinnamic acid, etc.), a sulfonic acid (p-toluenesulfonic acid, ethanesulfonic acid, etc.), and the like. In some embodiments, the salt is selected from the group consisting of acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, sulfamic acid, It can be derived from pharma- ceutically acceptable acids such as hydroiodic, carbonic, tartaric, p-toluenesulfonic, pyruvic, aspartic, benzoic, cinnamic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, embonic (pamoic), ethanesulfonic, benzenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylsulfamic, cyclohexylaminosulfonic, quinic, argenic, hydroxybutyric, galactaric, and galacturonic acids.

[0037] Also included are salts of amino acids, such as arginates, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts," J. Pharmaceutical Science, 1977, vol. 66, pp. 1-19).Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0038] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure.

[0039] Pharmaceutically acceptable salts of different compounds may exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (e.g., dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex, similar to dramamine) and various cyclodextrin inclusion complexes.

[0040] The term "deuterated" as used herein alone or as part of a group means a substituted deuterium atom. The term "deuterated analog" as used herein alone or as part of a group means a substituted deuterium atom in place of hydrogen. The deuterated analogs of the present disclosure can be fully or partially deuterium substituted derivatives. In some embodiments, the deuterium substituted derivatives of the present disclosure have alkyl, aryl or heteroaryl groups that are fully or partially deuterium substituted.

[0041] The present disclosure also encompasses the isotopically labeled compounds of the present disclosure, which are identical to those listed herein, but in fact have one or more atoms replaced by atoms with atomic masses or mass numbers different from those normally found in nature.All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g. 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P,35 S, 36 Cl and 125 Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is designated with its natural abundance isotopic composition or its isotopes, such as deuterium (D) or tritium ( 3 H). Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) and fluorine-18( 18 F) isotopes are useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes such as H may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by procedures similar to those described in the schemes and examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0042] "Prodrug" refers to any compound that releases an active parent drug according to formula (I) in vivo when such prodrug is administered to a subject. Prodrugs of compounds of formula (I) are prepared by modifying functional groups present in the compounds of formula (I) such that the modifications can be cleaved in vivo to release the parent compound, either by routine manipulation or in vivo. Prodrugs may progress from the prodrug form to the active form in a single step, or may have one or more intermediate forms that may themselves be active or inactive. Some prodrugs are enzymatically activated to produce active compounds, or compounds that produce active compounds upon further chemical reaction. Prodrugs include compounds of formula (I) in which a hydroxyl, amino, carboxyl or sulfhydryl group in a compound of formula (I) is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in the compounds of formula (I). Other examples of prodrugs include, but are not limited to, carbonates, ureides, solvates or hydrates of the active compound. The preparation, selection and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," the ACS Symposium Series, Vol. 14, "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0043] As described in The Practice of Medicinal Chemistry, Chapters 31-32 (Wermuth, ed., Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. In general, bioprecursor prodrugs are compounds that contain one or more protecting groups and are inactive or have low activity compared to the corresponding active drug compound that is converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolites should have acceptably low toxicity. Typically, the formation of an active drug compound involves a metabolic process or reaction that is one of the following types: (1) Oxidation Reactions. Examples of oxidation reactions include, but are not limited to, reactions such as the oxidation of alcohol, carbonyl and acid functional groups, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic and sulfur, oxidative N-dealkylation, oxidative O and S dealkylation, oxidative deamination, and other oxidation reactions. (2) Reduction reactions. Examples of reduction reactions include, but are not limited to, reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions. (3) Reactions that do not change the oxidation state. Examples of reactions that do not change the oxidation state include, but are not limited to, reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic bonds resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecules, and other such reactions.

[0044] Carrier prodrugs are, for example, drug compounds that include a transport moiety that improves uptake and / or localized delivery to the site of action. For such carrier prodrugs, the bond between the drug moiety and the transport moiety is covalent, the prodrug is inactive or less active than the drug compound, and it is desirable that the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides sustained release, such as certain polymers or other moieties such as cyclodextrins. (See, for example, Cheng et al., U.S. Patent Application Publication No. 2004 / 0077595, incorporated herein by reference.) Such carrier prodrugs are often advantageous for orally administered drugs. Carrier prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, reduced toxicity and adverse reactions, and / or improved formulation (e.g., stability, water solubility, suppression of undesirable functional or physicochemical properties). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or esterification of carboxylic acid groups with alcohols, such as aliphatic alcohols.

[0045] The term "carrier" is also meant to include microparticles, liposomes, micelles, nanoparticles (naturally equipped nanocarriers, e.g., exosomes), etc. It is known that exosomes can be very effective drug carriers, and there are various ways in which drugs can be loaded into exosomes, including the techniques described in J Control Release. 2015 December 10, Vol. 219, pp. 396-405, the entire contents of which are incorporated by reference.

[0046] Metabolites, such as active metabolites, overlap with the above-mentioned prodrugs, such as biological precursor prodrugs. Thus, such metabolites are compounds that are further metabolized to pharmacologically active compounds, or derivatives resulting from metabolic processes in the subject's body. Among these, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, prodrug compounds are generally inactive or less active than metabolites. In the case of active metabolites, parent compounds can be either active compounds or inactive prodrugs.

[0047] Prodrugs and active metabolites can be identified using routine techniques known in the art.See, for example, Bertolini et al., 1997, J.Med.Chem., vol. 40, pp. 2011-2016; Shan et al., 1997, J Pharm Sci, vol. 86(7), pp. 756-757; Bagshawe, 1995, Drug Dev.Res., vol. 34, pp. 220-230.

[0048] "Tautomer" refers to a compound produced by the phenomenon of a proton of one atom of a molecule moving to another atom. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 4th ed., John Wiley & Sons, pp. 69-74 (1992). Tautomer also refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. Examples include keto-enol tautomers, such as acetone / propen-2-ol, imine-enamine tautomers, ring-chain tautomers, such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, and tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom sequence, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Where a compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ("tautomerism") may occur. The compounds described herein may have one or more tautomers and therefore include various isomers. One of ordinary skill in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomers of these compounds are expressly included in the present disclosure.

[0049] "Isomers" refer to compounds that have the same molecular formula but differ in the nature or sequence of bonds of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms, for example, when they have one or more asymmetric centers or double bonds with asymmetric substitution, and therefore can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example an atom such as a carbon bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, and are referred to as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". As another example, stereoisomers include geometric isomers, such as cis or trans orientation of substituents on adjacent carbons of a double bond. Unless otherwise indicated, a description is intended to include individual stereoisomers as well as mixtures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 6th Edition, J. March, John Wiley and Sons, New York, 2007), which differ in the chirality of one or more stereocenters.

[0050] In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means that the compound is in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other particular material that a potential binding interaction and / or chemical reaction between the compound and the other particular material can occur.

[0051] "Assaying" refers to the creation of experimental conditions and the collection of data regarding the particular outcome of exposure to particular experimental conditions. For example, an enzyme can be assayed based on its ability to act on a detectable substrate. A compound can be assayed based on its ability to bind to a particular target molecule or molecules.

[0052] As used herein, the terms "ligand" and "modulator" are used equivalently to refer to compounds that alter (i.e., increase or decrease) the activity of a target biomolecule, e.g., an enzyme, such as those described herein. Generally, a ligand or modulator is a small molecule, where "small molecule" refers to a compound having a molecular weight of 1500 daltons or less, 1000 daltons or less, 800 daltons or less, or 600 daltons or less. Thus, an "improved ligand" has better pharmacological and / or pharmacokinetic properties than a reference compound, where "better" can be defined by one of skill in the art for a particular biological system or therapeutic use.

[0053] The term "bind" in reference to the interaction between a target and a potential binding compound indicates that the potential binding compound associates with the target to a statistically significant extent compared to association with proteins in general (i.e., non-specific binding). Thus, the term "binding compound" refers to a compound that has a statistically significant association with a target molecule. In some embodiments, a binding compound has a dissociation constant (K) of 10 mM or less, 1,000 μM or less, 100 μM or less, 10 μM or less, 1 μM or less, 1,000 nM or less, 100 nM or less, 10 nM or less, or 1 nM or less.D ) interacts with a particular target. In the context of a compound that binds to a target, the terms "greater affinity" and "selective" indicate that the compound binds more strongly than a reference compound or binds more strongly than the same compound under reference conditions, i.e., has a lower dissociation constant. In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000 times greater affinity.

[0054] The terms "modulate", "modulation" and the like refer to the ability of a compound to increase or decrease the function and / or expression of a target, such as the interaction between YAP and TEAD, and such function may include transcriptional regulatory activity and / or binding. Modulation may occur in vitro or in vivo. Modulation includes inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with YAP / TEAD, either directly or indirectly, and / or upregulation or downregulation of expression of YAP / TEAD, either directly or indirectly, as described herein. In another embodiment, the modulation is direct. Inhibitors or antagonists are compounds that, for example, bind, partially or completely block stimulation, reduce, prevent, inhibit, delay activation, inactivate, desensitize, or downregulate signaling. An activator or agonist is a compound that, for example, binds to, stimulates, increases, opens, activates, promotes, enhances activation, activates, sensitizes, or upregulates signal transduction.

[0055] As used herein, the terms "treat", "treating", "therapy", "therapies", and the like refer to the administration of a material, e.g., any one or more compounds described herein, in an amount effective to inhibit YAP / TEAD. In other embodiments, the terms "treat", "treating", "therapy", "therapies", and the like refer to the administration of a material, e.g., any one or more compounds described herein, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms, i.e., indications, of a disease or condition and / or prolong the survival of the subject being treated.

[0056] As used herein, the terms "prevent", "preventing", "prevention" and grammatical variations thereof refer to a method of partially or completely delaying or eliminating the onset or recurrence of a disease, disorder or condition and / or one or more of its attendant symptoms, or preventing a subject from acquiring or re-acquiring a disorder or condition, or reducing the risk that a subject will acquire or require a disorder or condition or one or more of its attendant symptoms.

[0057] As used herein, the terms "subject", "animal subject" and the like refer to organisms including, but not limited to, human and non-human vertebrates, e.g., any mammal, e.g., humans, other primates, sports animals and animals of commercial interest, e.g., cows, horses, sheep or pigs, rodents, or pets, e.g., dogs and cats.

[0058] "Unit dosage form" refers to a composition intended for single administration to treat a subject suffering from a disease or medical condition. Each unit dosage form typically contains each of the active ingredients of the present disclosure and pharma- ceutically acceptable excipients. Examples of unit dosage forms are individual tablets, individual capsules, bulk powders, liquids, ointments, creams, eye drops, suppositories, emulsions, or suspensions. Treatment of a disease or condition may require regular administration of a unit dosage form, for example, administration of one unit dosage form more than once a day, once with each meal, once every four hours or at other intervals, or only once a day. The term "oral unit dosage form" refers to a unit dosage form designed to be taken orally.

[0059] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration to a subject, or implantation of a sustained release device, such as a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0060] In this context, the term "therapeutically effective" or "effective amount" indicates that a compound or material, or an amount of a compound or material, when administered, is sufficient or effective to prevent, alleviate or ameliorate one or more symptoms of the disease, disorder or medical condition being treated, and / or to prolong the survival of the subject being treated. The therapeutically effective amount varies depending on the compound, the disease, disorder or condition and its severity, as well as the age, weight, etc., of the mammal being treated. In general, satisfactory results in a subject are indicated to be obtained at a daily dosage of about 0.1 to about 10 g / kg of subject body weight. In some embodiments, the daily dosage ranges from about 0.10 to 10.0 mg / kg of body weight, about 1.0 to 3.0 mg / kg of body weight, about 3 to 10 mg / kg of body weight, about 3 to 150 mg / kg of body weight, about 3 to 100 mg / kg of body weight, about 10 to 100 mg / kg of body weight, about 10 to 150 mg / kg of body weight, or about 150 to 1000 mg / kg of body weight. The dosage may conveniently be administered in divided doses, for example up to four times a day, or in sustained release form.

[0061] As used herein, the term "YAP / TEAD-mediated disease or condition" (also meant to mean "YAP or TEAD-mediated disease or condition" or "YAP and / or TEAD-mediated disease or condition") refers to a disease or condition in which the biological function of YAP / TEAD affects the onset and / or course of the disease or condition, and / or a disease or condition in which modulation of the YAP / TEAD interaction (such as YAP / TEAD-mediated transcription) alters the onset, course and / or symptoms. YAP / TEAD-mediated diseases or conditions include diseases or conditions in which disruption of the YAP / TEAD interaction (e.g., by TEAD inhibition) and / or inhibition of YAP / TEAD-mediated transcription provides a therapeutic benefit, e.g., treatment with a YAP / TEAD inhibitor, including a compound described herein, provides a therapeutic benefit to a subject suffering from or at risk for the disease or condition. YAP / TEAD-mediated diseases or conditions are intended to include cancers with loss-of-function mutations in YAP / TEAD or cancers in which there is activation of YAP / TEAD. A YAP / TEAD-mediated disease or condition is also intended to include various human carcinomas, including those of the colon, lung, pancreas, and ovary, and diseases or conditions associated with tumor angiogenesis and invasiveness.

[0062] Also, in the context of a compound that binds to a biomolecular target, the term "higher specificity" indicates that the compound binds to a particular target to a greater extent than another biomolecule or biomolecules that may be present under the relevant binding conditions, and that binding to such other biomolecules results in a biological activity that is different from binding to the particular target. Typically, the specificity refers to a limited set of other biomolecules, such as YAP or TEAD. In certain embodiments, the higher specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or 1000 times more specific.

[0063] As used herein in reference to a binding compound or ligand, the term "specific for YAP / TEAD" and terms of similar import mean that a particular compound binds to YAP or TEAD to a statistically greater extent than other epigenetic targets that may be present in a particular sample. In addition, where biological activities other than binding are indicated, the term "specific for YAP or TEAD" indicates that a particular compound has a greater biological effect associated with binding to YAP or TEAD, e.g., inhibition of enzyme activity, than it does to other enzymes.

[0064] The term "first-line cancer therapy" refers to a treatment administered to a subject as an initial regimen to reduce the number of cancer cells. First-line therapy is also called induction therapy, primary therapy and primary treatment. First-line therapy can be administered in combination with one or more drugs. A summary of the currently accepted approach to first-line treatment for a particular disease can be found in the NCI guidelines for such disease.

[0065] The term "second-line cancer therapy" refers to a cancer treatment administered to subjects who do not respond to first-line therapy, i.e., who are often administered first-line therapy or whose cancer has recurred after remission. In certain embodiments, the second-line therapy that can be administered includes a repeat of the initial successful cancer therapy, which can be any of the treatments described in "first-line cancer therapy." A summary of currently accepted approaches to second-line treatment for a particular disease is provided in the NCI guidelines for such disease.

[0066] The term "refractory" refers to a subject that does not respond to or is otherwise resistant to a cancer therapy or treatment. The cancer therapy may be a first-line, second-line, or any subsequently administered treatment. In certain embodiments, refractory refers to a state in which a subject is unable to achieve complete remission after two induction attempts. A subject may be refractory due to the inherent resistance of cancer cells to a particular treatment, or a subject may be refractory due to acquired resistance that develops during the course of a particular treatment.

[0067] Additionally, the abbreviations used herein have the following respective meanings: [Table 1]

[0068] II. Compounds Embodiment 1 of the present disclosure relates to a compound represented by formula (I): [ka] (In the formula, R 1 is phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl, where R 1 is 0 to 1 G 1 Group and 0 to 4 G 2 is substituted with a group, X is -C(O)- or -S(O)-; G 1 is -S(O)2 alkyl, one or more R 5 cycloalkyl optionally substituted with, or one or more R 5 is phenyl optionally substituted with each G 2 is halogen, OH, CN, one or more R 5 alkyl optionally substituted with one or more R 5 alkoxy optionally substituted with Each R 2 are independently H, halogen, -C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1-3 halogens, or two R 2 Groups, together with the carbon to which they are attached, can form -CO-, provided that no more than one R 2 is -C(O)O-alkyl, L is -O-, -OC(R 8 )2-, -N(R 6 )-, -N(R 6 )-C(R 8 )2, -[C(R 8 )2] 1~2 -, -C(R8 )2O- or C(R 8 )2-N(R 6 )-and R 3 is H, halogen, alkyl, hydroxyalkyl or haloalkyl; R 4 is H, halogen, alkyl, hydroxyalkyl, heterocycloalkylalkyl, heteroarylalkyl, or alkyl-N(R 6 )2, where each alkyl, hydroxyalkyl, heterocycloalkylalkyl, heteroarylalkyl, -alkyl-N(R 6 )2 is 1 to 3 R 7 and optionally substituted with Each R 5 are independently halogen or OH; Each R 6 are independently H or one or more R 5 is alkyl optionally substituted with Each R 7 is independently alkyl, alkoxy, hydroxyalkyl, halogen, or hydroxy; Each R 8 are independently H, halogen, or one or more R 5 is alkyl optionally substituted with or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof.

[0069] Embodiment 2 of the present disclosure relates to a compound according to embodiment 1, R 1 is phenyl, 5-6 membered heteroaryl, C4-C 10 cycloalkyl, or 5- to 6-membered heterocycloalkyl; Here, R 1 is 0 to 4 substituted G 2 It is based on each G 2 are independently halogen, OH, CN, or 1 to 3 R 5 C1-C6 alkyl optionally substituted with 1-3 R 5C1-C6 alkoxy optionally substituted with Each R 2 are independently H, halogen or CH3; R 3 is H, halogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, or C1-C3 haloalkyl; L is -O-, -OCH2-, -N(H)-, -N(CH3)-, -N(H)-C(R 8 )2, -[(CR 8 )2] 1~2 -, -C(R 8 )2O- or C(R 8 )2-N(H), R 4 is H, halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C1-C6 alkyl-N(R 6 )2, where each C1-C6 alkyl, C1-C6 hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or alkyl-N(R 6 )2 is 1 to 3 R 7 and optionally substituted with Each R 5 are independently halogen, C1-C3 haloalkyl, or OH; Each R 6 are independently H or 1 to 3 R 5 C1-C6 alkyl optionally substituted with Each R 7 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen or hydroxy; Each R 8 are independently H, halogen, or 1 to 3 R 5 is C1-C6 alkyl optionally substituted with

[0070] Embodiment 3 of the present disclosure relates to a compound according to embodiment 2, R 1 is phenyl, 5-6 membered heteroaryl, C4-C10 cycloalkyl, or 5-6 membered heterocycloalkyl, where R 1 is 0 to 3 substituted G 2 It is based on each G 2 are independently 1 to 3 R 5 Cl, F, OH, CN, C1-C4 alkyl, optionally substituted with 1-3 R 5 C1-C4 alkoxy optionally substituted with Each R 2 is independently H, Cl, F or CH3; R 3 is H, Cl, F, C1-C2 alkyl, C1-C2 hydroxyalkyl, or C1-C2 haloalkyl; L is -O-, -OCH2-, -N(H)- or N(H)C(H)2; R 4 is H, F, Cl, C1-C4 alkyl, C1-C4 hydroxyalkyl, 4-6 membered heterocycloalkylalkyl, 5-6 membered heteroarylalkyl, or C1-C4 alkyl-N(R 6 )2, where each C1-C4 alkyl, C1-C4 hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C1-C4 alkyl-N(R 6 )2 is 1 to 3 R 7 is optionally replaced by Each R 5 is independently Cl, F or OH; Each R 6 are independently H or 1 to 3 R 5 is a C1-C4 alkyl optionally substituted with Each R 7 are independently C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, Cl, F or hydroxy; Each R 8 are independently H, halogen, or 1 to 3 R 5 is C1-C4 alkyl optionally substituted with

[0071] Embodiment 4 of the present disclosure relates to a compound according to embodiment 1 having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula IIa, IIb, IIc, IId or IIe.

[0072] Embodiment 5 of the present disclosure relates to a compound according to embodiment 4, R 1 is phenyl, 5-6 membered heteroaryl, C4-C 10 cycloalkyl, or 5- to 6-membered heterocycloalkyl; Here, R 1 is 0 to 4 substituted G 2 It is based on each G 2 are independently halogen, OH, CN, one or more R 5 C1-C6 alkyl optionally substituted with 1-3 R 5 C1-C6 alkoxy optionally substituted with R 2 is H, halogen or CH3, R 4 is H, halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C1-C6 alkyl-N(R 6 )2, where each C1-C6 alkyl, C1-C6 hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or alkyl-N(R 6 )2 is 1 to 3 R 7 and optionally substituted with Each R 5 are independently halogen, C1-C3 haloalkyl, or OH; Each R 6 are independently H or 1 to 3 R 5 C1-C6 alkyl optionally substituted with Each R 7are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen or hydroxy; Each R 8 are independently H, halogen, or 1 to 3 R 5 is C1-C6 alkyl optionally substituted with

[0073] Embodiment 6 of the present disclosure relates to a compound according to embodiment 5, R 1 is phenyl, 5-6 membered heteroaryl, C4-C 10 cycloalkyl, or 5-6 membered heterocycloalkyl, where R 1 is 0 to 3 substituted G 2 It is based on each G 2 are independently Cl, F, OH, CN, or one or more R 5 C1-C4 alkyl optionally substituted with 1-3 R 5 C1-C4 alkoxy optionally substituted with R 2 is H, Cl, F or CH3, R 4 is H, F, Cl, C1-C4 alkyl, C1-C4 hydroxyalkyl, 4-6 membered heterocycloalkylalkyl, 5-6 membered heteroarylalkyl, or C1-C4 alkyl-N(R 6 )2, where each C1-C4 alkyl, C1-C4 hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C1-C4 alkyl-N(R 6 )2 is 1 to 3 R 7 and optionally substituted with Each R 5 is independently Cl, F or OH; Each R 6 are independently H or 1 to 3 R 5 is a C1-C4 alkyl optionally substituted with Each R 7are independently C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, Cl, F or hydroxy; Each R 8 are independently H, halogen, or 1 to 3 R 5 is C1-C4 alkyl optionally substituted with

[0074] Embodiment 7 of the present disclosure relates to a compound according to embodiment 6, wherein R 1 is phenyl or pyridyl substituted with 1 to 3 groups independently selected from Cl, F, CF3, and CN.

[0075] Embodiment 8 of the present disclosure relates to a compound according to embodiment 7, wherein R 1 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with one CF3 and optionally substituted with one to two F.

[0076] An embodiment 9 of the present disclosure relates to a formate salt according to any of the compounds of the previous embodiments.

[0077] Embodiment 10 of the present disclosure relates to a compound according to embodiment 1 selected from Table 1, or a pharma- ceutically acceptable salt thereof.

[0078] The compounds contemplated herein are described with reference to both general formulas and specific compounds. Furthermore, all compounds described herein may exist in several different forms or derivatives within the scope of this disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, prodrugs (e.g., carboxylic acid esters) and active metabolites.

[0079] It is understood that some compounds may show tautomerism.In such cases, the formula provided herein expressly shows only one possible tautomeric form.Therefore, it should be understood that the formula provided herein is intended to represent any tautomeric form of the compound shown, and is not limited to the specific tautomeric form shown by the formula drawing.

[0080] Likewise, some of the compounds according to the present disclosure may exist as stereoisomers as defined herein. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present disclosure. Unless otherwise specified, all such stereoisomers are included in the formulas provided herein.

[0081] In some embodiments, the chiral compounds of the present disclosure are in a form that contains at least 80% of a single isomer (60% enantiomeric excess ("ee") or diastereomeric excess ("de")), or at least 85% (70% ee or de), 90% (80% ee or de), 95% (90% ee or de), 97.5% (95% ee or de), or 99% (98% ee or de). As is generally understood by those of skill in the art, an optically pure compound having one chiral center is a compound that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having two or more chiral centers is a compound that is both diastereomerically pure and enantiomerically pure. In some embodiments, the compound is present in an optically pure form.

[0082] For compounds whose synthesis involves the addition of a single group at a double bond, particularly a carbon-carbon double bond, the addition can occur at either of the double bond linking atoms. For such compounds, the present disclosure includes both such positional isomers.

[0083] In addition to the formulas and compounds described herein, the present disclosure also includes prodrugs (generally pharma- ceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharma- ceutically acceptable salts thereof.

[0084] Unless otherwise specified, the specification of a compound herein includes the pharma- ceutically acceptable salts of such compounds.

[0085] In some embodiments, the compounds of the present disclosure are complexed with acids or bases, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine, acid addition salts such as acetate, acetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochloride, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, and tosylate, and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, etc. In some instances, the amorphous form of the complex is promoted by additional processing of the parent compound mixed with acid or base, for example, mechanochemical methods such as spray drying, roller compaction, or microwave irradiation. Such methods may also include the addition of ionic and / or non-ionic polymer systems, including but not limited to hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers (e.g., Eudragit® L100-55), which further stabilize the amorphous nature of the complex. Such amorphous complexes offer several advantages. For example, the reduced melting temperature relative to the free base facilitates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Also, amorphous complexes are easily friable, which improves compression for filling the solid into capsule or tablet forms.

[0086] III. Formulation and Administration An eleventh embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound of any one of the embodiments 1-10, or any of its subembodiments, and a pharma- ceutically acceptable carrier.

[0087] Embodiment 12 of the present disclosure relates to the pharmaceutical composition of embodiment 11, further comprising a second pharmaceutical agent.

[0088] The appropriate dosage form depends in part on the use or route of administration, for example, oral, transdermal, transmucosal, inhalant, or injection (parenteral). Such dosage form should allow the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that delay the compound or composition from exerting its effect. Techniques and formulations can generally be found in The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (incorporated herein by reference).

[0089] The compounds of the present disclosure (i.e., any of the compounds described in embodiments 1-9, including any of the subembodiments thereof) can be formulated as pharma- ceutically acceptable salts.

[0090] Carriers or excipients can be used to prepare compositions. Carriers or excipients can be selected to facilitate administration of compounds. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and types of physiologically compatible solvents. Examples of physiologically compatible solvents include sterile solutions of water for injection (WFI), physiological saline, and dextrose.

[0091] The compound can be administered by different routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant.In some embodiments, the compound can be administered by oral administration.For example, when administered orally, the compound can be formulated into conventional oral dosage forms, such as capsules, tablets, and liquid preparations, such as syrups, elixirs, and concentrated drops.

[0092] For inhalation, the compounds of the present disclosure can be formulated as dry powder or suitable solution, suspension or aerosol.Powder and solution can be formulated with suitable additives known in the art.For example, powder can contain suitable powder base such as lactose or starch, and solution can contain other additives such as propylene glycol, sterilized water, ethanol, sodium chloride, and acid, alkali and buffer salt.Such solution or suspension can be administered by inhalation through spray, pump, atomizer, or nebulizer, etc. The compounds of the present disclosure may also be used in combination with other inhalation therapies, for example, corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide and mometasone furoate, beta agonists such as albuterol, salmeterol, and formoterol, anticholinergics such as ipratropium bromide or tiotropium, vasodilators such as treprostinal and iloprost, enzymes such as DNAase, therapeutic proteins, immunoglobulin antibodies, oligonucleotides, e.g., single or double stranded DNA or RNA, siRNA, antibiotics such as tobramycin, muscarinic receptor antagonists, leukotriene antagonists, cytokine antagonists, protease inhibitors, cromolyn sodium, nedocryl sodium, and sodium cromoglycate.

[0093] Pharmaceutical preparations for oral use can be obtained, for example, by combining active compounds with solid excipients, optionally grinding the mixture obtained, and processing the mixture of granules after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or fillers of polyvinylpyrrolidone (PVP, povidone).If desired, disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or its salts, such as sodium alginate, can be added.

[0094] Dragee cores are provided with suitable coatings.For this purpose, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may optionally contain suitable organic solvents or solvent mixtures may be used.Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0095] Pharmaceutical preparations that can be used orally include push-fit capsules ("gelcaps") made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compounds can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol (PEG). Additionally, stabilizers may be added.

[0096] Alternatively, injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal and / or subcutaneous, may be used. For injection, the compounds of the present disclosure are formulated in a physiologically compatible buffer or solution, such as physiological saline, Hank's solution or Ringer's solution, and other sterile liquid solutions. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately before use. Lyophilized forms may also be produced.

[0097] Administration may also be by transmucosal, topical, transdermal, or inhalation means. For transmucosal, topical, or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, surfactants may be used to facilitate permeation. Transmucosal administration may be, for example, by nasal spray or suppository (rectal or vaginal).

[0098] The topical compositions of the present disclosure are formulated as oils, creams, lotions, ointments, and the like, by selection of an appropriate carrier known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (C 12 In another embodiment, the carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants, as well as agents that impart color or fragrance if desired, may also be included. Creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredient dissolved in a small amount of solvent (e.g., oil) is mixed. Furthermore, administration by transdermal means may include a transdermal patch or dressing, such as a bandage, impregnated with the active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration is, of course, continuous rather than intermittent throughout the entire administration regimen.

[0099] The amount of various compounds administered was determined based on the IC 50The dosage can be determined by standard procedures taking into account factors such as the biological half-life of the compound, the age, size and weight of the subject, and the indication being treated. The importance of these and other factors is well known to those of skill in the art. In general, the dosage is about 0.01 to 50 mg / kg or 0.1 to 20 mg / kg of the subject being treated. Multiple doses may be used.

[0100] The compounds of the present disclosure can also be used in combination with other therapies to treat the same disease. Such combinations include administration of the compound and one or more other therapeutic agents at different times, or administration of the compound and one or more other therapeutic agents simultaneously. In some embodiments, dosages can be modified by methods well known to those skilled in the art to, for example, reduce the dosage of one or more of the compounds of the present disclosure or other therapeutic agents used in combination compared to the compound or treatment used alone.

[0101] Use in combination includes use with other treatments, drugs, medical procedures, etc., and it is understood that the other treatment or treatment may be administered at a different time (e.g., within a short time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours), or within a longer time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than the compounds of the present disclosure, or simultaneously with the compounds of the present disclosure. Use in combination also includes use in treatments or medical procedures, such as surgery, administered once or infrequently, with the compounds of the present disclosure administered within a short or longer time before or after the other treatment or treatment. In some embodiments, the present disclosure provides for the delivery of the compounds of the present disclosure and one or more other drug therapeutics delivered by different routes of administration or the same route of administration. Use in combination for any route of administration includes the delivery of the compounds of the present disclosure and one or more other drug therapeutics delivered together by the same route of administration in any formulation, including formulations in which the two compounds are chemically linked to maintain their therapeutic activity when administered. In one embodiment, other drug therapies may be co-administered with one or more compounds of the present disclosure. Use in combination by co-administration includes administration of co-formulations or formulations of chemically linked compounds, or administration of two or more compounds in separate formulations administered by the same or different routes within a short time of each other (e.g., within 1 hour, within 2 hours, within 3 hours, up to 24 hours). Co-administration of separate formulations includes co-administration by delivery via one device, such as the same inhalation device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulation of one or more additional drug therapies delivered by the same route as the compounds of the present disclosure includes preparing materials together so that they can be administered by one device, and includes separate compounds combined in one formulation, or compounds that are chemically linked but modified so that they still maintain their biological activity. Such chemically linked compounds may have bonds that are substantially maintained in vivo, or the bonds may degrade in vivo to separate the two active ingredients.

[0102] IV.How to use Disease Indications and Regulation of YAP / TEAD Exemplary YAP / TEAD-Related Diseases Polycystic kidney disease YAP and TAZ appear to play a role in the progression of polycystic kidney disease (PKD). Increased YAP expression was also observed in human PKD patients. TAZ forms a complex with polycystin-2 (PC2, the protein product of PKD1), thereby targeting it for ubiquitination and degradation. It was observed that TAZ knockout leads to PKD and also results in downregulation of other genes required for proper cilia development and function, implicating YAP as a potential therapeutic target for PKD (Steven W Plouffe et al., Disease Implications of the Hippo / YAP Pathway, Trends Mol Med. April 2015, Vol. 21(4), pp. 212-222).

[0103] Neurodegenerative diseases Hippo pathway components are involved in neurological diseases. For example, studies have reported that YAP / TAZ mediates gene transcription induced by AβPP, a precursor of amyloid β that is believed to be a driver of Alzheimer's disease, implying that YAP is a potential therapeutic target for Alzheimer's disease (Steven W Plouffe et al., 2015).

[0104] Arrhythmogenic cardiomyopathy and Holt-Oram syndrome The Hippo pathway plays a role in cardiac disease. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by thinning of the right ventricular wall, arrhythmias, and replacement of the myocardium by fibroadipocytes. It has been shown that YAP is phosphorylated in human ARVC hearts, and overexpression of a constitutively active YAP mutant in cardiomyocytes results in adipogenesis, further supporting the role of the Hippo pathway in ARVC and implicating YAP as a potential therapeutic target for ARVC (Steven W Plouffe et al., 2015).

[0105] Liver cancer YAP is frequently overexpressed in hepatocellular carcinoma (HCC) and is required to sustain increased cell proliferation and tumor growth. In addition, risk factors for HCC include hepatitis infection and exposure to xenobiotics, which are also involved in YAP activation. For example, hepatitis B virus X protein (HBx) directly increases YAP expression by enhancing YAP gene transcription. In another example, TCPOBOP is a xenobiotic mimic that activates the constitutive androstane receptor to increase YAP protein levels and induce HCC. Furthermore, it was observed that inducing YAP overexpression in a liver-specific transgenic model caused abnormal hepatocyte proliferation, inhibited apoptosis, increased liver size, and increased HCC, implicating YAP as a potential therapeutic target for HCC (Steven W Plouffe et al., 2015).

[0106] epithelioid hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is a vascular tumor commonly found in the lungs, bones, and skin. YAP / TAZ chromosomal translocations have been observed to occur in virtually all EHE cases, strongly suggesting that dysregulated YAP / TAZ fusion protein may act as a cancer driver in EHE, implicating YAP as a potential therapeutic target in EHE. (Steven W Plouffe et al., 2015).

[0107] Breast cancer YAP / TAZ activity correlates with increased risk of metastasis and reduced survival in various human breast cancer subtypes. TAZ is highly expressed in invasive breast cancer cell lines and primary breast cancers. Moreover, TAZ overexpression is sufficient to induce cell proliferation and transformation in breast cancer cell lines. Similarly, overexpression of YAP in breast cancer cell lines induces tumor formation and growth in xenograft experiments, and deletion of YAP prevents tumor growth in oncogene-induced breast cancer models, implicating YAP as a potential therapeutic target for breast cancer (Steven W Plouffe et al., 2015).

[0108] lung cancer Both YAP / TAZ are highly expressed in human non-small cell lung cancer (NSCLC). Knockdown of either YAP or TAZ in NSCLC cells suppresses proliferation, invasion, and tumor growth in mice. High YAP expression correlates with advanced stage, lymph node metastasis, and poor survival in lung cancer. Furthermore, knockdown of either YAP or TAZ has been shown to be sufficient to reduce cell migration in vitro and metastasis in vivo in lung cancer, implicating YAP as a potential therapeutic target for NSCLC (Steven W Plouffe et al., 2015).

[0109] Malignant mesothelioma It was observed that knockdown of YAP in malignant mesothelioma cells was sufficient to inhibit cell proliferation and anchorage-independent growth, implicating dysregulation of the Hippo pathway in malignant mesothelioma, implicating YAP as a potential therapeutic target for malignant mesothelioma (Steven W Plouffe et al., 2015).

[0110] Pancreatic cancer Pancreatic ductal adenocarcinoma (PDAC) often has elevated YAP expression, and increased YAP expression correlates with poor prognosis. Furthermore, it has been observed that YAP knockdown results in reduced proliferation and reduced anchorage-independent growth in pancreatic cancer cells, suggesting that YAP may play an important role in PDAC progression. It has also been reported that deleting YAP is sufficient to prevent PDAC in a mouse model expressing mutant KRAS (Steven W Plouffe et al., 2015).

[0111] Kaposi's Sarcoma YAP / TAZ plays a key role in Kaposi's sarcoma (KS). Tissue samples from human KS patients have been shown to have elevated levels of YAP / TAZ. Recently, it has been shown that KSHV encodes a viral GPCR (vGPCR) that activates YAP / TAZ, and that cells overexpressing vGPCRs fail to grow in xenograft mouse models when YAP / TAZ is depleted, indicating that YAP / TAZ is required for KSHV-induced tumorigenesis (Steven W Plouffe et al., 2015).

[0112] Uveal melanoma 80% of uveal melanoma (UM) cases are characterized by activating mutations in either GNAQ or GNA11, which encode Gq or G11 (Gq / 11), respectively. It has been shown that Gq / 11 can activate YAP, and treatment of UM with verteporfin, a drug that blocks the YAP-TEAD interaction, inhibits UM tumor growth in mice (Steven W Plouffe et al., 2015).

[0113] Renal Cell Carcinoma YAP is involved in renal cell carcinoma (RCC). Recent reports have found that YAP activity is increased in RCC, RCC tissues show elevated YAP levels, and knockdown of YAP in RCC cell lines blocks cell proliferation and increases apoptosis (Steven W Plouffe et al., 2015).

[0114] Colorectal cancer YAP is often overexpressed in colorectal cancer (CRC), and YAP / TAZ activity has been observed to correlate with reduced survival. In mice, induction of YAP overexpression in the intestine results in metaplasia after 2 days, but the intestine regenerates when induction is halted. Furthermore, in knockout mice that developed adenomas after 13 weeks and polyps after 13 months, it was observed that these phenotypes were blocked by deleting YAP, indicating that these pathologies are YAP-dependent. Furthermore, increased YAP protein levels were observed in human CRC liver metastases and correlated with CRC recurrence (Steven W Plouffe et al., 2015). Multiple myeloma The Hippo pathway plays an important role in regulating lymphocyte apoptosis. YAP acts as a tumor suppressor in several hematological cancers, including multiple myeloma (MM), lymphoma, and leukemia (Steven W Plouffe et al., 2015).

[0115] Nervous System Tumors The Hippo pathway is involved in several nervous system tumors. Loss-of-function mutations in NF2 cause neurofibromatosis type 2, a genetic disorder characterized by increased YAP expression and NF2 inhibiting YAP activity; since loss-of-function mutations in NF2 result in increased YAP accumulation, loss of NF2 and subsequent tumor growth may be due to abnormal YAP activity. In the central nervous system, expression of NF2 is also significantly reduced in human malignant gliomas, and expression of NF2 has been shown to inhibit human glioma growth both in vitro and in vivo. Similarly, YAP is highly expressed in many human brain tumors, including invasive gliomas, and overexpression of YAP promotes glioblastoma growth in vitro (Steven W Plouffe et al., 2015).

[0116] The methods and compounds are typically used to treat human subjects, however, they may also be used to treat similar or identical indications in other animal subjects.

[0117] In certain embodiments, the patient is 60 years or older and relapses after first-line cancer therapy. In certain embodiments, the patient is 18 years or older and relapses or is refractory after second-line cancer therapy. In certain embodiments, the patient is 60 years or older and is primarily refractory to first-line cancer therapy. In certain embodiments, the patient is 70 years or older and has not been previously treated. In certain embodiments, the patient is 70 years or older and is ineligible and / or unlikely to benefit from cancer therapy.

[0118] In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10 mg / day. In certain embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, or 2500 mg per day. In other embodiments, the therapeutically effective amount is greater than or equal to 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg per day. In certain embodiments, the compound is administered continuously.

[0119] In certain embodiments, provided herein is a method of treating a disease or condition mediated by YAP or TEAD, comprising administering to a mammal having the disease or condition at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day of a compound as described in any one of embodiments 1-10, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, wherein the compound is administered on an empty stomach.

[0120] Embodiment 13 of the present disclosure relates to a method of treating a subject having a disease or condition mediated by YAP / TEAD, comprising administering to the subject an effective amount of a compound of any one of embodiments 1-10, or any of its subembodiments, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of one of embodiments 11-12.

[0121] Embodiment 14 of the present disclosure relates to a method of treating a disease or condition according to embodiment 13, wherein the disease or condition is cancer, a neurodegenerative disease, a cardiac-related disorder, or a kidney-related disorder. Embodiment 15 of the present disclosure relates to a method of treating a disease or condition according to embodiment 13 or 14, wherein the disease or condition is polycystic kidney disease, Alzheimer's disease, arrhythmogenic cardiomyopathy, Holt-Oram syndrome, liver cancer, epithelioid hemangioendothelioma, breast cancer, lung cancer, malignant mesothelioma, pancreatic cancer, Kaposi's sarcoma, uveal melanoma, renal cell carcinoma, colorectal cancer, multiple myeloma, neurofibromatosis type 2, glioma, or glioblastoma.

[0122] V. Combination Therapy A YAP / TEAD modulator may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. In one embodiment, a composition comprises any one or more compounds described herein, together with one or more compounds that are therapeutically effective for the same disease indication, and the compounds have a synergistic effect on the disease indication. In one embodiment, a composition comprises any one or more compounds described herein that are effective in treating cancer, together with one or more other compounds that are effective in treating the same cancer, and the compounds are synergistically effective in treating cancer.

[0123] Embodiment 16 of the present disclosure relates to a method according to any one of embodiments 13-15, further comprising administering one or more additional therapeutic agents.

[0124] Embodiment 17 of the present disclosure is directed to a method for treating cancer, the method comprising administering to the patient one or more additional therapeutic agents selected from the group consisting of i) an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and tresulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) azacitidine, capecitabine, antimetabolites selected from cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors and anti-CTLA4 inhibitors; v) hormones or hormone antagonists selected from enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen and toremifene; vi) DJ-927, docetaxel, TPI 287, a taxane selected from paclitaxel and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide;x) topoisomerase inhibitors selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan and 9-aminocamptothecin; xi) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxystaurosporine and vatalanib; xii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin and rapamycin; xiii) biological response modifiers selected from imiquimod, interferon-α and interleukin-2; xiv) IDO inhibitors; xv) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryomycin, bromoglucose ... xvi) BRAF inhibitors such as vemurafenib, dabrafenib or encorafenib; xvii) Mek inhibitors such as cobimetinib, trametinib, binimetinib or selumetinib; xviii) c-Kit mutant inhibitors; xix) EGFR inhibitors; xx) epigenetic modulators; xxi) other adenosine axis blockers selected from CD39, CD38, A2AR and A2BR; xxii) an agonist of a TNFA superfamily member; or xxiii) an anti-ErbB2 mAb.

[0125] In another embodiment, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising any one or more compounds described herein in combination with one or more other therapies or medical procedures effective in treating cancer, including suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiation therapy, hyperthermia heating, bone marrow or stem cell transplantation). In one embodiment, the one or more suitable anti-cancer therapies or medical procedures are selected from chemotherapeutic agents (e.g., chemotherapy drugs), radiation treatments (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle beams), hyperthermia (e.g., microwave, ultrasound, radiofrequency ablation), vaccine therapy (e.g., AFP gene hepatocellular carcinoma vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM-CSF secreting breast cancer vaccine, dendritic cell peptide vaccine), gene therapy (e.g., Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminolevulinic acid, motexatin luteinium), surgery, or treatment with bone marrow and stem cell transplantation.

[0126] VI. Kit In another aspect, the disclosure provides a kit comprising one or more compounds according to any one of the compounds of embodiments 1-10, or a pharma- ceutically acceptable salt, deuterated analog, tautomer or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 11-12. In some embodiments, the compound or composition is packaged, for example, in a vial, bottle, flask, which may be further packaged, for example, in a box, envelope, or bag. The compound or composition may be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal, for example, a human. The compound or composition may be approved for administration to a mammal, for example, a human, for a YAP / TEAD-mediated disease or condition. The kits described herein may include written instructions and / or other indications that the compound or composition is suitable or approved for administration to a mammal, for example, a human, for a YAP / TEAD-mediated disease or condition. The compound or composition may be packaged in a unit dose or single dose form, for example, a single dose pill, capsule, etc.

[0127] VII. Binding Assays The methods of the present disclosure can include assays that can detect binding of a compound to a target molecule. Such binding is at a statistically significant level, with a confidence level that the assay signal represents binding to the target molecule, i.e., is distinguished from background, at least 90%, or at least 95, 97, 98, 99% or more confidence level. In some embodiments, controls are used to distinguish target binding from non-specific binding. A wide variety of assays that indicate binding are known for various target types and can be used in the present disclosure.

[0128] Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, a "low activity" compound is one that has an inhibitory concentration (IC) of greater than 1 μM under standard conditions. 50 ) or effective concentration (EC 50 "Very low activity" means an IC50 activity greater than 100 μM under standard conditions. 50 or EC 50"Very low activity" means an IC50 activity of more than 1 mM under standard conditions. 50 or EC 50 "Moderate activity" means an IC of 200 nM to 1 μM under standard conditions. 50 or EC 50 "Moderately high activity" means an IC of 1 nM to 200 nM. 50 or EC 50 "High activity" means an IC of less than 1 nM under standard conditions. 50 or EC 50 It stands for IC 50 or EC 50 is defined as the concentration of a compound at which 50% of the activity of the target molecule (e.g., an enzyme or other protein) being measured is lost or gained relative to the range of activity observed in the absence of the compound. Activity can be measured using methods known to those of skill in the art, for example, by measuring any detectable product or signal generated by the occurrence of an enzymatic reaction or other activity by the protein being measured.

[0129] "Background signal" in the context of binding assays means the signal recorded under standard conditions of a particular assay in the absence of a test compound, molecular scaffold or ligand that binds to the target molecule. Those skilled in the art will appreciate that accepted methods exist and are widely available for determining background signal.

[0130] "Standard deviation" means the square root of the variance. Variance is a measure of how spread out a distribution is. It is calculated as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is:

number

[0131] Surface plasmon resonance Binding parameters can be measured using surface plasmon resonance, for example, using a BIAcore® chip (Biacore, Japan) coated with immobilized binding moieties. Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of the reaction between sFv or other ligands to target molecules. Such methods are generally described in the following references, which are incorporated herein by reference: Vely F. et al. (2000) BIAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. Vol. 121, pp. 313-21; Liparoto et al. (1999) Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. Vol. 12, pp. 316-21; Lipschultz et al. (2000) Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods. Vol. 20(3), pp. 310-8; Malmqvist. (1999) BIACORE, an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions Vol. 27, pp. 335-40; Alfthan, (1998) Surface plasmon resonance biosensors as a tool in antibody engineering,Biosensors&Bioelectronics. Vol. 13, pp. 653-63. Fivash et al. (1998) BIAcore for macromolecular interaction, Current Opinion in Biotechnology.9, pp. 97-101; Price et al., (1998) Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology vol. 19, Suppl. 1, pp. 1-20; Malmqvist et al., (1997) Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology. vol. 1, pp. 378-83; O'Shannessy et al., (1996) Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. vol. 236, pp. 275-83; Malmborg et al., (1995) BIAcore as a tool in antibody engineering, Journal of Immunological Methods. vol. 183, pp. 7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. Vol. 83, pp. 143-51; and O'Shannessy, (1994), Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology. Vol. 5, pp. 65-71. .

[0132] BIAcore® uses the optical properties of surface plasmon resonance (SPR) to detect changes in protein concentration bound to a dextran matrix, a dextran biosensor matrix, on the surface of a gold / glass sensor chip interface. Briefly, proteins are covalently bound to a dextran matrix at known concentrations, and ligands for the proteins are injected through the dextran matrix. Near-infrared light directed to the opposite side of the sensor chip surface is reflected and also induces an evanescent wave in the gold film, which produces an intensity dip in the reflected light at a specific angle, known as the resonance angle. A change in the refractive index of the sensor chip surface (e.g., by a ligand binding to a binding protein) causes a shift in the resonance angle. This angle shift can be measured, with 1000 RU corresponding to 1 ng / mm 2 These changes are expressed as resonance units (RU) to correspond to the change in surface protein concentration of 100 μg / mL. These changes are displayed with respect to time along the y-axis of a sensorgram showing the association and dissociation of any biological reaction.

[0133] High Throughput Screening (HTS) Assays HTS typically uses automated assays to search large numbers of compounds for a desired activity. Typically, HTS assays are used to find new drugs by screening chemicals that act on a specific enzyme or molecule. For example, if a chemical inactivates an enzyme, it may prove effective in preventing a process in the cell that causes disease. High-throughput methods allow researchers to very rapidly analyze thousands of different chemicals against each target molecule, using robotic handling systems and automated analysis of the results.

[0134] As used herein, "high throughput screening" or "HTS" refers to the rapid in vitro screening of large numbers of compounds (libraries), typically tens to hundreds of thousands of compounds, using robotic screening assays. Ultra high throughput screening (uHTS) generally refers to high throughput screening accelerated to over 100,000 tests per day.

[0135] To achieve high throughput screening, it is advantageous to accommodate samples on a multi-container carrier or platform. Multi-container carriers facilitate the simultaneous measurement of the response of multiple candidate compounds. Multi-well microplates may be used as carriers. Such multi-well microplates and methods for their use in multiple assays are known in the art and commercially available.

[0136] Screening assays may include controls for purposes of calibration and confirmation of proper operation of the components of the assay. Blank wells containing all of the reactants but no members of the chemical library are usually included. As another example, a known inhibitor (or activator) of the enzyme for which a modulator is sought can be incubated with one sample of the assay, and the resulting decrease (or increase) in enzyme activity can be used as a contrast or control. It will be appreciated that modulators can also be combined with enzyme activators or inhibitors to find modulators that inhibit enzyme activation or inhibition otherwise caused by the presence of a known enzyme modulator.

[0137] Measurement of enzyme and binding reactions during screening assays For example, techniques for measuring the progress of enzymatic and binding reactions in multi-container carriers are known in the art and include, but are not limited to, the following.

[0138] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, as described in Gordon, AJ and Ford, RA, (1972) The Chemist's Companion: A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, NY, p. 437.

[0139] Fluorescence spectroscopy can be used to monitor the formation of reaction products. Fluorescence methods are generally more sensitive than absorption methods. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al. (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd., and Bell, (1981) Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press.

[0140] In spectrofluorometry, an enzyme is exposed to a substrate that changes its intrinsic fluorescence when processed by a target enzyme. Typically, the substrate is non-fluorescent and is converted to a fluorophore by one or more reactions. As a non-limiting example, SMase activity can be detected using Amplex® Red reagent (Molecular Probes, Eugene, OR). To measure sphingomyelinase activity using Amplex® Red, the following reactions are performed: First, SMase hydrolyzes sphingomyelin to produce ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to produce choline. Third, choline is oxidized to betaine by choline oxidase. Finally, H2O2 reacts with Amplex® Red in the presence of horseradish peroxidase to produce the fluorescent product resorufin, the signal from which is detected using spectrofluorometry.

[0141] Fluorescence polarization (FP) is based on the slowing of the molecular rotation rate of a fluorophore upon binding to a larger molecule, such as a receptor protein, allowing for polarized fluorescence emission by the bound ligand. FP is determined empirically by measuring the vertical and horizontal components of fluorophore emission following excitation with plane polarized light. As the molecular rotation of the fluorophore decreases, the polarized emission increases. Fluorophores generate a larger polarized signal when bound to a larger molecule (i.e., a receptor), slowing the molecular rotation of the fluorophore. The magnitude of the polarized signal is quantitatively related to the degree of fluorescent ligand binding. Thus, the polarization of the "bound" signal is dependent on the maintenance of high affinity binding.

[0142] FP is a homogeneous technique and the reaction is very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable and large batches can be prepared, resulting in high reproducibility. Because of these properties, FP has proven highly automatable and is often performed in a single incubation with a single premixed tracer-receptor reagent. For a review, see Owicki et al. (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, Vol. 17, p. 27.

[0143] FPs are particularly desirable because their readout is independent of emission intensity (Checovich, WJ et al. (1995) Nature 375:254-256; Dandliker, WB et al. (1981) Methods in Enzymology 74:3-28) and therefore insensitive to the presence of colored compounds that quench the fluorescence emission. FPs and FRET (see below) are well suited to identifying compounds that block the interaction between sphingolipid receptors and their ligands. See, for example, Parker et al. (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase / phosphatase assays, J Biomol Screen 5:77-88.

[0144] Sphingolipid-derived fluorophores that can be used in FP assays are commercially available, for example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide fluorophore. These are N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosylphosphocholine (BODIPY® FL C5-sphingomyelin), N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosylphosphocholine (BODIPY® FL C12-sphingomyelin), and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine (BODIPY® FL C5-ceramide), respectively. US Patent No. 4,150,949 (Immunoassay for Gentamicin) discloses fluorescein-labeled gentamicin, including fluoresceinthiocarbanyl gentamicin. Additional fluorophores can be prepared using methods well known to those skilled in the art.

[0145] Exemplary normal-and-polarized fluorescence readers include the POLARION® Fluorescence Polarization System (Tecan AG, Hombrechtikon, Switzerland). General purpose multi-well plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multi-well plate spectrophotometer (both from Molecular Devices).

[0146] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interactions and has been described. See, for example, Heim et al. (1996) Curr. Biol. 6:178-182, Mitra et al. (1996) Gene 173:13-17, and Selvin et al. (1995) Meth. Enzymol. 246:300-345. FRET detects the energy transfer between two fluorophores in close proximity with known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in close proximity, such as when a protein specifically interacts with a target molecule, resonance energy can be transferred from one excited molecule to the other excited molecule. This results in a shift in the emission spectrum of the sample, which can be measured by a fluorometer such as an fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.).

[0147] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interactions with target molecules. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al. (1997) J. Lipid Res. 38:2365-2373; Kahl et al. (1996) Anal. Biochem. 243:282-283; Undenfriend et al. (1987) Anal. Biochem. 161:494-500). See also U.S. Patent Nos. 4,626,513 and 4,568,649, and European Patent No. 0,154,734. One commercially available system uses FLASHPLATE® scintillant-coated plates (NEN Life Science Products, Boston, MA).

[0148] The target molecule can be bound to the scintillator plate by various well-known means. Scintillant plates are available that are derivatized to bind fusion proteins, such as GST, His6 or Flag fusion proteins. If the target molecule is a protein complex or multimer, one protein or subunit can be attached to the plate first, and then the other components of the complex can be added later under binding conditions to obtain a bound complex.

[0149] In a typical SPA assay, gene products in the expression pool are radioactively labeled and added to the wells and allowed to interact with the solid phase, which is the immobilized target molecule in the well and the scintillant coating. The assay can be measured immediately or allowed to reach equilibrium. Either way, once the radioactive label is sufficiently close to the scintillant coating, a signal is generated that can be detected by an instrument such as the TOPCOUNT NXT® Microplate Scintillation Counter (Packard BioScience Co., Meriden Conn.). If the radioactively labeled expression product binds to the target molecule, the radioactive label will remain in close proximity to the scintillant long enough to generate a detectable signal.

[0150] In contrast, labeled proteins that do not bind to the target molecule or that only bind briefly will not remain near the scintillant long enough to generate a signal above background. Any time spent near the scintillant caused by random Brownian motion will not result in a significant amount of signal. Similarly, there may be residual unincorporated radiolabel used during the expression step, but it will not generate a significant signal because it is in solution rather than interacting with the target molecule. Thus, these non-binding interactions cause a certain level of background signal that can be mathematically removed. If too much signal is obtained, salt or other modifiers can be added directly to the assay plate until the desired specificity is obtained (Nichols et al., (1998) Anal. Biochem. vol. 257, pp. 112-119).

[0151] General Synthesis Compounds can be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional well-known synthetic methods may also be used. The synthesis of typical compounds described herein can be accomplished as described in the following examples. Where available, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers.

[0152] The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0153] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW & Greene, TW (2006), Greene's protective groups in organic synthesis, Hoboken, NJ, Wiley-Interscience, and references cited therein.

[0154] The compounds of the present disclosure may contain one or more asymmetric or chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolving agents, and the like.

[0155] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989) organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th ed., 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0156] It will also be understood that in each scheme, the addition of any substituent may result in the production of several isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which may be isolated and purified using conventional techniques. Where an enantiomerically pure or enriched compound is desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be used as conventionally used in the art or as described in the examples. EXAMPLES

[0157] The compounds of the present disclosure can be synthesized according to the examples described below. The examples can be modified by replacing the starting materials with other materials having similar structures to obtain the corresponding products. The structure of the desired product will generally make the necessary starting materials clear to one skilled in the art.

[0158] Synthesis of intermediate 3 [ka]

[0159] Step 1: Preparation of tert-butyl 7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate 2. To a dry 20 mL microwave vial containing a dry microwave compatible flea stir bar was added tert-butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1,454 mg, 1.82 mmol), 1-iodo-4-(trifluoromethyl)benzene (296 μL, 548 mg, 2.01 mmol), N,N-dimethylglycine (125 mg, 1.22 mmol), cuprous iodide (70.3 mg, 0.369 mmol), cesium carbonate (1.20 g, 3.67 mmol) and DMSO (15.0 mL). The reaction was placed under nitrogen, sealed and heated to 130° C. for 8 h. The reaction was then added to 5.3 M ammonium chloride (250 mL) and extracted with ethyl acetate (2×250 mL). The organic fraction was washed with water (1×250 mL) and 5 M sodium chloride (1×250 mL), dried over sodium sulfate, filtered, evaporated, and purified by normal phase flash column chromatography (silica gel, 0-50% ethyl acetate in hexanes) to give tert-butyl 7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2, 545 mg). LC / ESI-MS [M-tBu+MeCN+2H] + = 379.0.

[0160] Step 2: Preparation of 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride 3. To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added tert-butyl 7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (2, 335 mg, 0.850 mmol) and HCl (4.0 M in 1,4-dioxane, 5.0 mL, 20.0 mmol). The reaction was placed under nitrogen and stirred at 20° C. for 5 min. The reaction was then evaporated and precipitated from ether (20 mL) to give 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (3, 252 mg). LC / ESI-MS [M+H] + = 294.4.

[0161] Example 1 [ka]

[0162] Step 1: Preparation of 1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0018). To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (3, 252 mg, 0.765 mmol) and acetonitrile (5.0 mL). The reaction was placed under nitrogen and cooled to 0° C., after which triethylamine (352 μL, 256 mg, 2.53 mmol) was added slowly dropwise via micropipettor. The reaction was stirred at 0° C. for 1 minute. To the reaction was then added acryloyl chloride (68.4 μL, 76.2 mg, 0.842 mmol) slowly dropwise via micropipettor. The reaction was stirred at 0° C. for 1 h. The reaction was then added to 5.3 M ammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL). The organic fraction was washed with water (1×100 mL) and 5 M sodium chloride (1×100 mL), dried over sodium sulfate, filtered, evaporated, and purified by normal phase flash column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give 1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0018, 164 mg). LC / ESI-MS [M+H] + = 348.0.

[0163] Example 2 [ka]

[0164] Step 1: Preparation of 2-acryloyl-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-1(2H)-one (P-0128). To a solution of 1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0018, 150 mg, 432 μmol) in dichloromethane (5 mL) was added meta-chloroperbenzoic acid (186 mg, 864 μmol, 80% purity). The mixture was stirred at 25° C. for 2 h and then at 40° C. for 3 days. The reaction was quenched by adding saturated aqueous Na2S2O3 solution (10 mL). The mixture was then extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude material, which was then purified by preparative HPLC (0-100% MeCN in water with 0.1% formic acid) to give 2-acryloyl-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-1(2H)-one (P-0128, 8.2 mg). LC / ESI-MS [M+H] + = 362.0.

[0165] Example 3 [ka]

[0166] Step 1: Preparation of 2-chloro-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0124). To a solution of 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (3, 0.69 g, 2.09 mmol) and triethylamine (0.87 mL, 6.28 mmol) in THF (20.0 mL) was added 2-chloroprop-2-enoyl chloride (0.23 mL, 2.51 mmol) dropwise at 0° C. The reaction was stirred at 0° C. for 45 min. The reaction mixture was diluted with saturated ammonium chloride (100 mL), extracted with ethyl acetate (2×30 mL), dried over magnesium sulfate, filtered, concentrated onto Celite, and purified by normal phase chromatography (24 g silica gel, 0-60% ethyl acetate in hexanes) to give a residue. The residue was redissolved in 20% water / dioxane (10 mL), frozen at −78° C., and placed under lyophilization conditions for 15 h. This procedure afforded 2-chloro-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0124, 668 mg). LC / ESI-MS [M+H] + = 382.1.

[0167] Example 4 [ka]

[0168] Step 1: Preparation of 2-(prop-1-en-2-ylsulfonyl)-7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline (P-0127). To a solution of 7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3, 200 mg, 608 μmol) in dichloromethane (5 mL), triethylamine (138 mg, 1.36 mmol) was added and the mixture was cooled to 0° C. Then, prop-1-ene-2-sulfonyl chloride (95.9 mg, 682 μmol) was added and the mixture was stirred at 0° C. for 5 minutes. The mixture was diluted with dichloromethane (20 mL) and washed with water (10 mL×2). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude mixture, which was purified by preparative HPLC (0-100% MeCN in water with 0.1% formic acid) to give 2-(prop-1-en-2-ylsulfonyl)-7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline (P-0127, 6.7 mg). LC / ESI-MS [M+H] + = 398.0.

[0169] Example 5 [ka]

[0170] Step 1: Preparation of (E)-4-bromo-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en-1-one 4. To a 100 mL round bottom flask under nitrogen was added (E)-4-bromobut-2-enoic acid (1.50 g, 9.10 mmol), dichloromethane (10 mL) and DMF (66.5 mg, 910 μmol, 70.0 μL). Oxalyl chloride (1.15 g, 9.10 mmol, 796 μL) was then added dropwise with stirring at 0° C. for 30 min. The resulting solution was stirred at 25° C. for an additional 60 min. The above reaction solution was added to a mixture of 7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3, 3.0 g, 9.10 mmol) and sodium carbonate (2.89 g, 27.3 mmol) in dichloromethane (30 mL) at 0° C., and the resulting mixture was stirred at temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated to give the crude material, which was then purified by column chromatography (silica gel column, 85-100% ethyl acetate in petroleum ether) to give (E)-4-bromo-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en-1-one (4, 2.8 g). LC / ESI-MS [M+H] + = 442.0.

[0171] Step 2: Preparation of (E)-4-(1H-imidazol-1-yl)-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en-1-one formate salt P-0119 (formate salt). A mixture of (E)-4-bromo-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en-1-one (4, 300 mg, 681 μmol) and 1H-imidazole (139 mg, 2.04 mmol) dissolved in dichloromethane (5 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated to give the crude material, which was then purified by preparative HPLC (0-100% MeCN in water with 0.1% formic acid) to give (E)-4-(1H-imidazol-1-yl)-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)but-2-en-1-one formate (P-0119 formate, 62.2 mg). LC / ESI-MS [M+H] + = 428.1.

[0172] Example 6 [ka]

[0173] Step 1: Preparation of tert-butyl 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate 5. To a dry 20 mL microwave vial containing a dry microwave compatible miniature stir bar was added tert-butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1, 499 mg, 2.00 mmol), 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (424 μL, 729 mg, 3.00 mmol), N,N-dimethylglycine (131 mg, 1.27 mmol), cuprous iodide (80.4 mg, 0.422 mmol), cesium carbonate (1.31 g, 4.02 mmol) and DMSO (15.0 mL). The reaction was placed under nitrogen, sealed and heated to 130° C. for 5 h. The reaction was then added to 5.3 M ammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL). The organic fraction was washed with water (1×100 mL) and 5 M sodium chloride (1×100 mL), dried over sodium sulfate, filtered, evaporated, and purified by normal phase flash column chromatography (silica gel, 0-25% ethyl acetate in hexanes). The material remained impure and was subsequently purified by reverse phase flash column chromatography (C18 column, 50-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to give tert-butyl 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (5, 291 mg). LC / ESI-MS [M-tBu+MeCN+2H] + = 397.4.

[0174] Step 2: Preparation of 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride 6. To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added tert-butyl 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (5, 291 mg, 0.707 mmol) and HCl (4.0 M in 1,4-dioxane, 2.0 mL, 8.00 mmol). The reaction was placed under nitrogen and stirred at 20° C. for 15 min. The reaction was then evaporated and precipitated from ether (20 mL) to give 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (6, 199 mg). LC / ESI-MS [M+H] + = 312.4.

[0175] Step 3: Preparation of 1-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one P-0045. To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (6, 199 mg, 0.573 mmol) and THF (5.0 mL). The reaction was placed under nitrogen and cooled to 0° C., after which triethylamine (240 μL, 174 mg, 1.72 mmol) was added slowly dropwise via micropipettor. The reaction was stirred at 0° C. for 1 min. The reaction was then slowly added dropwise with a micropipettor to acryloyl chloride (69.8 μL, 77.8 mg, 0.859 mmol). The reaction was stirred at 0 °C for 30 min. The reaction was then added to 5.3 M ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic fraction was dried over sodium sulfate, filtered, evaporated, and purified by reverse-phase flash column chromatography (C18 column, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to give 1-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0045, 150 mg). LC / ESI-MS [M+H] + = 366.4.

[0176] Example 7 [ka]

[0177] Step 1: Preparation of tert-butyl 7-(4-cyclopropyl-3-fluoro-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate 7. To a dry 5 mL microwave vial containing a dry microwave compatible miniature stir bar was added tert-butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1, 126 mg, 0.505 mmol), 4-bromo-1-cyclopropyl-2-fluoro-benzene (74.0 μL, 118 mg, 0.551 mmol), N,N-dimethylglycine (38.3 mg, 0.371 mmol), cuprous iodide (21.7 mg, 0.114 mmol), cesium carbonate (328 mg, 1.01 mmol) and DMSO (5.0 mL). The reaction was placed under nitrogen, sealed and heated to 130° C. for 17 h. The reaction was then added to 5.3 M ammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL). The organic fraction was washed with water (1×100 mL) and 5 M sodium chloride (1×100 mL), dried over sodium sulfate, filtered, evaporated, and purified by normal phase flash column chromatography (silica gel, 0-50% ethyl acetate in hexanes) to give tert-butyl 7-(4-cyclopropyl-3-fluoro-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate (7, 125 mg). LC / ESI-MS [M-tBu+MeCN+2H] + = 369.1.

[0178] Step 2: Preparation of 7-(4-cyclopropyl-3-fluoro-phenoxy)-1,2,3,4-tetrahydroisoquinoline 8. To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added tert-butyl 7-(4-cyclopropyl-3-fluoro-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate (7, 125 mg, 0.327 mmol) and dichloromethane (2.0 mL). The reaction was placed under nitrogen and stirred at 20° C. after which trifluoroacetic acid (2.0 mL, 2.98 g, 26.1 mmol) was added slowly dropwise via syringe. The reaction was stirred at 20° C. for 30 minutes. The reaction was then evaporated, added to 1.2 M sodium bicarbonate (10 mL) and extracted with ethyl acetate (2×10 mL). The organic fraction was dried over sodium sulfate, filtered and evaporated to give 7-(4-cyclopropyl-3-fluoro-phenoxy)-1,2,3,4-tetrahydroisoquinoline (8, 86.4 mg). LC / ESI-MS [M+H] + = 284.4.

[0179] Step 3: Preparation of 1-(7-(4-cyclopropyl-3-fluorophenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0050). To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added 7-(4-cyclopropyl-3-fluoro-phenoxy)-1,2,3,4-tetrahydroisoquinoline (8, 86.4 mg, 0.305 mmol) and dichloromethane (3.0 mL). The reaction was placed under nitrogen and cooled to 0° C., after which triethylamine (93.5 μL, 67.9 mg, 0.671 mmol) was added slowly dropwise via micropipettor. The reaction was stirred at 0° C. for 1 minute. The reaction was then slowly added dropwise with acryloyl chloride (27.3 μL, 30.4 mg, 0.336 mmol) via micropipettor. The reaction was stirred at 0° C. for 1 h. The reaction was then evaporated and purified by normal phase flash column chromatography (silica gel, 0-50% ethyl acetate in hexanes) and then reverse phase flash column chromatography (C18 column, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to give 1-(7-(4-cyclopropyl-3-fluorophenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0050, 4.9 mg). LC / ESI-MS [M+H] + = 338.1.

[0180] Example 8 [ka]

[0181] Step 1: Preparation of tert-butyl 7-[[4-fluoro-3-(trifluoromethyl)phenyl]-hydroxy-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate 10. To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added 1-fluoro-4-iodo-2-(trifluoromethyl)benzene (153 μL, 290 mg, 1.00 mmol) and THF (5.0 mL). The reaction was placed under nitrogen and cooled to 0° C., after which isopropylmagnesium chloride (2.0 M in THF, 500 μL, 1.00 mmol) was added slowly dropwise via syringe. The reaction was stirred at 0° C. for 30 minutes. To another dry 20 mL glass scintillation vial containing a dry miniature stir bar was added tert-butyl 7-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (9,266 mg, 1.02 mmol) and THF (5.0 mL). The reaction was placed under nitrogen and stirred at 0° C., after which the entire former halogen exchange solution was added slowly dropwise via syringe. The reaction was stirred at 0° C. for 1 h. The reaction was then quenched with acetic acid (117 μL, 123 mg, 2.05 mmol), added to 5.3 M ammonium chloride (100 mL), and extracted with ethyl acetate (2×100 mL). The organic fraction was dried over sodium sulfate, filtered, evaporated, and purified by reverse-phase flash column chromatography (C18 column, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) and then normal-phase flash column chromatography (silica gel, 0-50% ethyl acetate in hexanes) to give tert-butyl 7-[[4-fluoro-3-(trifluoromethyl)phenyl]-hydroxy-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (10, 130 mg). LC / ESI-MS [M-tBu+MeCN+2H] + = 411.0.

[0182] Step 2: Preparation of 7-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-1,2,3,4-tetrahydroisoquinoline 11. To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added tert-butyl 7-[[4-fluoro-3-(trifluoromethyl)phenyl]-hydroxymethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (10, 130 mg, 0.306 mmol), triethylsilane (500 μL, 364 mg, 3.13 mmol) and dichloromethane (2.0 mL). The reaction was placed under nitrogen and stirred at 20° C. after which trifluoroacetic acid (1.0 mL, 1.49 g, 13.1 mmol) was added slowly dropwise via syringe. The reaction was stirred at 20° C. for 5 days. The reaction was then evaporated and purified by reverse-phase flash column chromatography (C18 column, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to give 7-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-1,2,3,4-tetrahydroisoquinoline (11, 96.3 mg). LC / ESI-MS [M+H] + = 310.4.

[0183] Step 3: Preparation of 1-(7-(4-fluoro-3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0067). To a dry 20 mL glass scintillation vial containing a dry miniature stir bar was added 7-[[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-1,2,3,4-tetrahydroisoquinoline (11, 96.3 mg, 0.311 mmol) and THF (3.0 mL). The reaction was placed under nitrogen and cooled to 0° C., after which triethylamine (130 μL, 94.5 mg, 0.934 mmol) was added slowly dropwise via micropipettor. The reaction was stirred at 0° C. for 1 min. The reaction was then slowly added dropwise with a micropipettor to acryloyl chloride (38.0 μL, 42.3 mg, 0.468 mmol). The reaction was stirred at 0 °C for 30 min. The reaction was then added to 5.3 M ammonium chloride (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic fraction was dried over sodium sulfate, filtered, evaporated, and purified by reverse-phase flash column chromatography (C18 column, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)) to give 1-(7-(4-fluoro-3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0067, 17.1 mg). LC / ESI-MS [M+H] + = 364.4.

[0184] Example 9 [ka]

[0185] Step 1: Preparation of tert-butyl 7-[(3,3-difluorocyclobutyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate 12. To a solution of tert-butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1, 0.10 g, 0.40 mmol) in DMF (4.0 mL) was added NaH (60% in mineral oil, 0.024 g, 0.60 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min. Then, 3-(bromomethyl)-1,1-difluoro-cyclobutane (0.15 g, 0.80 mmol) was added and the mixture was heated in a 60° C. oil bath for 3.5 h. The reaction mixture was diluted with water, extracted with ethyl acetate (2×10 mL), dried over magnesium sulfate, filtered, concentrated onto Celite, and purified by normal phase chromatography (12 g silica gel, 0-60% ethyl acetate in hexanes) to give tert-butyl 7-[(3,3-difluorocyclobutyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (12, 89 mg).

[0186] Step 2: Preparation of 7-[(3,3-difluorocyclobutyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride 13. To a solution of tert-butyl 7-[(3,3-difluorocyclobutyl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (12, 0.089 g, 0.25 mmol) in dichloromethane (3.0 mL), HCl (4N in dioxane, 0.63 mL) was added and the reaction was stirred at room temperature for 2 h. The mixture was then concentrated in vacuo and dried to give 7-[(3,3-difluorocyclobutyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (13, 73 mg). LC / ESI-MS [M+H] + = 254.2.

[0187] Step 3: Preparation of 1-(7-((3,3-difluorocyclobutyl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0107). To a mixture of 7-[(3,3-difluorocyclobutyl)methoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (13, 0.073 g, 0.25 mmol) and triethylamine (0.10 mL, 0.75 mmol) at 0° C. was added prop-2-enoyl chloride (0.02 mL, 0.25 mmol). The reaction mixture was stirred at 0° C. for 20 min. The reaction was diluted with saturated aqueous ammonium chloride, extracted with ethyl acetate (2×10 mL), dried over magnesium sulfate, filtered, concentrated onto Celite, and purified by normal phase chromatography (4 g silica gel, 0-50% ethyl acetate in hexanes) to give 1-(7-((3,3-difluorocyclobutyl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0107, 58 mg). LC / ESI-MS [M+H] + = 308.2.

[0188] Example 10 [ka]

[0189] Step 1: Preparation of tert-butyl 7-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate 15. To a solution of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (14, 500 mg, 1.60 mmol) in toluene (10 mL) was added 6,6-difluorobicyclo[3.1.0]hexan-3-amine hydrochloride (407 mg, 2.40 mmol), Xphos-Pd-G2 (126 mg, 160 μmol) and sodium tert-butoxide (308 mg, 3.20 mmol). The mixture was stirred at 100° C. under nitrogen for 12 h. The mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL×3). The organic layer was dried over sodium sulfate, filtered and concentrated to give a residue which was subsequently purified by column chromatography (silica gel, 85-100% ethyl acetate in petroleum ether) to give tert-butyl 7-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15, 167 mg, 29%). LC / ESI-MS [M+H] + = 365.2.

[0190] Step 2: Preparation of N-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine trifluoroacetate salt 16. To a solution of tert-butyl 7-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15, 167 mg, 458 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at 25° C. for 30 min. The mixture was concentrated to give N-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine trifluoroacetate salt (16, 110 mg). LC / ESI-MS [M+H] + = 265.2.

[0191] Step 3: Preparation of 1-(7-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0087). To a solution of N-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine trifluoroacetate (16, 110 mg, 291 μmol) in dichloromethane (3 mL) was added triethylamine (58.8 mg, 581 μmol). The mixture was cooled to 0° C. and acryloyl chloride (15.8 mg, 174 μmol) was added slowly. The mixture was stirred at 0° C. for 5 min. The mixture was diluted with dichloromethane (5 mL) and washed with water (3 mL×2). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue which was then purified by preparative HPLC (0-100% MeCN in water with 0.1% formic acid) to give 1-(7-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0087, 14.7 mg). LC / ESI-MS [M+H] + = 319.1.

[0192] Example 11 [ka]

[0193] Step 1: Preparation of tert-butyl 7-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 17. To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (14, 10.0 g, 32.0 mmol) in THF (300 mL) at −78° C. under nitrogen was added n-BuLi (2.5 M in hexanes, 26.9 mL) dropwise. The mixture was stirred at −78° C. for 20 min. Then, 6-(trifluoromethyl)nicotinaldehyde (11.2 g, 64.1 mmol) was added in one portion. The mixture was stirred at −78° C. for 5 min. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (80 mL x 2), dried over sodium sulfate, filtered, and concentrated to give the crude material, which was purified by column chromatography (silica gel, 78-100% ethyl acetate in petroleum ether) to give tert-butyl 7-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (17, 2.73 g). LC / ESI-MS [M-tBu+H] + = 352.9.

[0194] Step 2: Preparation of tert-butyl 7-(6-(trifluoromethyl)nicotinoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 18. To a solution of tert-butyl 7-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (17, 2.73 g, 6.68 mmol) in dichloromethane (30 mL) was added Dess-Martin periodinane (4.25 g, 10.0 mmol, 3.10 mL) at 0° C. The mixture was stirred at 25° C. for 3 h. The mixture was diluted with dichloromethane (50 mL) and washed with water (25 mL×3). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude material, which was subsequently purified by silica gel chromatography (85-100% ethyl acetate in petroleum ether) to give tert-butyl 7-(6-(trifluoromethyl)nicotinoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (18, 2.53 g). LC / ESI-MS [M-tBu+H] + = 352.0.

[0195] Step 3: Preparation of tert-butyl 7-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate 19. To tert-butyl 7-(6-(trifluoromethyl)nicotinoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (18, 2.53 g, 6.23 mmol) was added DAST (25 mL) at 0° C. The mixture was stirred at 25° C. for 3 days and then at 30° C. for 1 day. The reaction was diluted with dichloromethane (30 mL) and the mixture was added to a saturated aqueous solution of ammonium chloride (50 mL) at 0° C. The mixture was then separated and extracted with ethyl acetate (80 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude material, which was purified by silica gel chromatography (85-100% ethyl acetate in petroleum ether) to give tert-butyl 7-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (19, 838 mg). LC / ESI-MS [M-tBu+H] + = 372.8.

[0196] Step 4: Preparation of 7-(difluoro(6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride 20. To a solution of tert-butyl 7-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (19, 838 mg, 1.96 mmol) in dichloromethane (6 mL) was added hydrochloric acid (4M in dioxane, 5 mL). The mixture was stirred at 25° C. for 30 min. The mixture was concentrated to give 7-(difluoro(6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (20, 710 mg). LC / ESI-MS [M+H] + = 328.5.

[0197] Step 5: Preparation of 1-(7-(difluoro(6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0106). To a solution of 7-(difluoro(6-(trifluoromethyl)pyridin-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (20, 710 mg, 1.95 mmol) in dichloromethane (10 mL) was added triethylamine (394 mg, 3.89 mmol). The mixture was cooled to 0° C. and acryloyl chloride (176 mg, 1.95 mmol) was added slowly. The mixture was stirred at temperature for 5 min. The mixture was concentrated and the residue was purified by preparative HPLC (0-100% MeCN in water with 0.1% formic acid) to give 1-(7-(difluoro(6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0106, 228 mg). LC / ESI-MS [M+H] + = 382.9.

[0198] Example 12 [ka]

[0199] Step 1: Preparation of tert-butyl 7-bromo-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 22. A mixture of 7-bromo-4-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (21,900 mg, 3.98 mmol), sodium bicarbonate (1.00 g, 11.9 mmol) and boc anhydride (1.30 g, 5.97 mmol) in ethyl acetate (10 mL) and water (10 mL) was stirred at 20° C. for 16 h. The reaction mixture was poured into water (10 mL) and the aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic solution was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-40% ethyl acetate in petroleum ether) to give tert-butyl 7-bromo-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (22, 1.07 g). LC / ESI-MS [M-tBu+H] + = 270.0.

[0200] Step 2: Preparation of tert-butyl 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 23. To a mixture of tert-butyl 7-bromo-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (22, 1.0 g, 3.07 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (934 mg, 3.68 mmol) in dioxane (10 mL) was added potassium acetate (903 mg, 9.20 mmol) and Pd(dppf)Cl2.CH2Cl2 (250 mg, 307 μmol) under nitrogen. The mixture was stirred at 100 °C for 16 h. The crude reaction was poured into water (10 mL) and the aqueous phase was extracted with ethyl acetate (10 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-100% ethyl acetate in petroleum ether) to give tert-butyl 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (23, 1.09 g). LC / ESI-MS [M-tBu+H] + = 318.0.

[0201] Step 3: Preparation of tert-butyl 7-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 24. To a mixture of tert-butyl 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (23, 1.0 g, 2.68 mmol) and NaOH (6 M aqueous, 2.23 mL) in dichloromethane (10 mL) was added hydrogen peroxide (2.46 g, 21.7 mmol, 2.08 mL, 30% in water) in one portion at 0° C. under nitrogen. The mixture was stirred at 20° C. for 1 h. The reaction was quenched by the addition of aqueous NaSO (50 mL) at 0° C., and the resulting mixture was stirred at temperature for 10 min. The aqueous phase was extracted with dichloromethane (10 mL x 2) and the combined organic solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-30% ethyl acetate in petroleum ether) to give tert-butyl 7-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (24, 0.46 g). LC / ESI-MS [M-tBu+H] + = 208.8.

[0202] Step 4: Preparation of tert-butyl 4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate 25. To a mixture of 5-iodo-2-(trifluoromethyl)pyridine (207 mg, 760 μmol) and tert-butyl 7-hydroxy-4-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (24,200 mg, 760 μmol) in DMSO (5 mL) was added N,N-dimethylglycine (54.8 mg, 532 μmol), CuI (28.9 mg, 152 μmol) and cesium carbonate (495 mg, 1.52 mmol). The mixture was stirred at 130° C. under nitrogen for 16 h. Water (10 mL) was added to the crude reaction mixture and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (0-30% ethyl acetate in petroleum ether) to give tert-butyl 4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (25, 0.20 g). LC / ESI-MS [M-tBu+H] + = 352.6.

[0203] Step 5: Preparation of 4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate 26. To a mixture of tert-butyl 4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (25,200 mg, 490 μmol) in dichloromethane (4 mL) was added trifluoroacetic acid (55.8 mg, 490 μmol, 36.3 μL) at 20° C. The mixture was stirred for 30 minutes. The suspension was concentrated by evaporation under reduced pressure to give 4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (26, 0.20 g). LC / ESI-MS [M+H] += 309.4.

[0204] Step 6: Preparation of 1-(4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0093). To a mixture of 4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline trifluoroacetate (26, 200 mg, crude) in dichloromethane (1 mL) was added a solution of triethylamine (95.8 mg, 947 μmol, 132 μL) and acryloyl chloride (42.9 mg, 474 μmol) in dichloromethane (1 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h. The reaction was then quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was extracted with dichloromethane (5 mL) and the combined organic layers were washed with brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under reduced pressure to give the crude material. This material was then purified by preparative HPLC (0-100% MeCN in water with 0.1% formic acid) to give 1-(4-methyl-7-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-en-1-one (P-0093, 41.9 mg). LC / ESI-MS [M+H] + = 363.0.

[0205] All compounds in Table 1 listed below can be prepared by following the synthetic examples described in this disclosure and making any necessary substitutions of starting materials that can be obtained commercially or otherwise by one of ordinary skill in the art. [Table 2-1] [Table 2-2] [Table 2-3]

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

[0206] Table 2 below provides data showing the biochemical and / or cellular inhibitory activity of exemplary compounds described in Table 1 herein. In Table 2 below, activity is indicated as follows: +++=0.001 μM <IC 50 <0.5μM, ++=0.5μM <IC 50 <20 μM, +=IC 50 >20μM, X=>20μM [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0207] All patents and other references cited in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains, and are incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference was individually incorporated by reference in its entirety.

[0208] Those skilled in the art will readily appreciate that the present disclosure is well adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variations, and compositions described herein as currently representative of the embodiments described herein are exemplary and are not intended as limitations on the scope of the disclosure. Modifications therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the disclosure and defined by the scope of the claims.

[0209] It will be readily apparent to those skilled in the art that various substitutions and modifications can be made to the present disclosure described herein without departing from the scope and spirit of the present disclosure. For example, modifications can be made to provide additional compounds of the present disclosure and / or various administration methods can be used. Thus, such additional embodiments are within the scope of the present disclosure and the following claims.

[0210] The present disclosure illustratively described herein may be suitably implemented in the absence of any element or elements, or any limitation or limitations not specifically described herein. The terms and expressions used are used as terms of description and not of limitation, and in the use of such terms and expressions, it is not intended to exclude any equivalents of the features shown and described, or any portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, although the present disclosure has been specifically described by the embodiments and optional features, it is to be understood that modifications and variations of the concepts described herein may be used by those skilled in the art, and such modifications and variations are considered to be within the scope of the present disclosure as defined by the appended claims.

[0211] Furthermore, when features or aspects of the disclosure have been described in terms of groupings of alternatives, those skilled in the art will recognize that the disclosure is thereby also described in terms of any individual members or subgroups of members of the group described herein.

[0212] Also, unless indicated to the contrary, when various numerical values ​​are provided for an embodiment, further embodiments are described by taking any two different values ​​as the end points of a range, such ranges are also within the scope of the present disclosure.

[0213] Accordingly, additional embodiments are within the scope of this disclosure and the following claims.

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, R １ is phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl, where R １ is 0 to 1 G １ group and 0 to 4 G ２ is substituted with a group, X is -C(O)- or S(O) ２ - and G １ is -S(O) ２ alkyl, one or more R ５ cycloalkyl optionally substituted with, or one or more R ５ is phenyl optionally substituted with Each G ２ is halogen, OH, CN, one or more R ５ alkyl optionally substituted with one or more R ５ alkoxy optionally substituted with Each R ２ are independently H, halogen, —C(O)O-alkyl, or C(O) optionally substituted with 1 to 3 halogens. １ ~C ３ alkyl, or two R ２ Groups can be taken together with the carbon to which they are attached to form -CO-, provided that no more than one R ２ is —C(O)O-alkyl, L is -O-, -OC(R ８ ) ２ -, -N(R ６ ) -, -N(R ６ )-C(R ８ ) ２ , -[C(R ８ ) ２ ] １～２ -, -C(R ８ ) ２ O- or C(R ８ ) ２ -N(R ６ ) - and R ３ is H, halogen, alkyl, hydroxyalkyl or haloalkyl; R ４ is H, halogen, alkyl, hydroxyalkyl, heterocycloalkylalkyl, heteroarylalkyl, or alkyl-N(R ６ ) ２ where each alkyl, hydroxyalkyl, heterocycloalkylalkyl, heteroarylalkyl, -alkyl-N(R ６ ) ２ is 1 to 3 R ７ and optionally substituted with Each R ５ are independently halogen or OH; Each R ６ are independently H or one or more R ５ is alkyl optionally substituted with Each R ７ is independently alkyl, alkoxy, hydroxyalkyl, halogen, or hydroxy; and Each R ８ are independently H, halogen, or one or more R ５ is alkyl optionally substituted with or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof.

2. R １ is phenyl, 5-6 membered heteroaryl, C ４ ~C １０ cycloalkyl, or 5- to 6-membered heterocycloalkyl; Here, R １ 0 to 4 G substituted with ２ It is based on Each G ２ are independently halogen, OH, CN, 1 to 3 R ５ C optionally substituted with １ ~C ６ Alkyl, 1 to 3 R ５ C optionally substituted with １ ~C ６ alkoxy; Each R ２ are independently H, halogen or CH ３ and R ３ H, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Hydroxyalkyl, or C １ ~C ３ is haloalkyl, L is -O-, -OCH ２ -, -N(H)-, -N(CH ３ )-, -N(H)-C(R ８ ) ２ , -[(CR ８ ) ２ ] １～２ -, -C(R ８ ) ２ O- or C(R ８ ) ２ -N(H), R ４ H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C １ ~C ６ Alkyl-N(R ６ ) ２ where each C １ ~C ６ Alkyl, C １ ~C ６ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or alkyl-N(R ６ ) ２ But 1 to 3 R ７ and optionally substituted with Each R ５ are independently halogen C １ ~C ３ haloalkyl, or OH; Each R ６ are independently H or 1 to 3 R ５ C optionally substituted with １ ~C ６ is alkyl, Each R ７ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ hydroxyalkyl, halogen or hydroxy, and Each R ８ are independently H, halogen, or 1 to 3 R ５ C optionally substituted with １ ~C ６ is alkyl, The compound of claim 1.

3. R １ is phenyl, 5-6 membered heteroaryl, C ４ ~C １０ cycloalkyl, or 5-6 membered heterocycloalkyl, where R １ is substituted with 0 to 3 G ２ It is based on Each G ２ are independently Cl, F, OH, CN, 1 to 3 R ５ C optionally substituted with １ ~C ４ Alkyl, 1 to 3 R ５ C optionally substituted with １ ~C ４ alkoxy; Each R ２ are independently H, Cl, F or CH ３ and R ３ H, Cl, F, C １ ~C ２ Alkyl, C １ ~C ２ Hydroxyalkyl, or C １ ~C ２ is haloalkyl, L is -O-, -OCH ２ -, -N(H)- or N(H)C(H) ２ and R ４ H, F, Cl, C １ ~C ４ Alkyl, C １ ~C ４ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C １ ~C ４ Alkyl-N(R ６ ) ２ where each C １ ~C ４ Alkyl, C １ ~C ４ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C １ ~C ４ Alkyl-N(R ６ ) ２ But 1 to 3 R ７ is optionally replaced by Each R ５ is independently Cl, F or OH; Each R ６ are independently H or 1 to 3 R ５ C optionally substituted with １ ~C ４ is alkyl, Each R ７ But independently, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C １ ~C ４ hydroxyalkyl, Cl, F or hydroxy, and Each R ８ are independently H, halogen, or 1 to 3 R ５ C optionally substituted with １ ~C ４ is alkyl, The compound according to claim 2.

4. The following formula: 【Chemistry 2】 or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formulae IIa, IIb, IIc, IId or IIe.

5. R １ is phenyl, 5-6 membered heteroaryl, C ４ ~C １０ cycloalkyl, or 5-6 membered heterocycloalkyl, where R １ 0 to 4 G substituted with ２ It is based on Each G ２ are independently halogen, OH, CN, one or more R ５ C optionally substituted with １ ~C ６ Alkyl, 1 to 3 R ５ C optionally substituted with １ ~C ６ alkoxy; R ２ is H, halogen or CH ３ and R ４ H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C １ ~C ６ Alkyl-N(R ６ ) ２ where each C １ ~C ６ Alkyl, C １ ~C ６ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or alkyl-N(R ６ ) ２ But 1 to 3 R ７ and optionally substituted with Each R ５ are independently halogen, C １ ~C ３ haloalkyl, or OH; Each R ６ are independently H or 1 to 3 R ５ C optionally substituted with １ ~C ６ is alkyl, Each R ７ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ hydroxyalkyl, halogen or hydroxy, and Each R ８ are independently H, halogen, or 1 to 3 R ５ C optionally substituted with １ ~C ６ is alkyl, The compound according to claim 4.

6. R １ is phenyl, 5-6 membered heteroaryl, C ４ ~C １０ cycloalkyl, or 5-6 membered heterocycloalkyl, where R １ is substituted with 0 to 3 G ２ It is based on Each G ２ are independently Cl, F, OH, CN, one or more R ５ C optionally substituted with １ ~C ４ Alkyl, 1 to 3 R ５ C optionally substituted with １ ~C ４ alkoxy; R ２ is H, Cl, F or CH ３ and R ４ H, F, Cl, C １ ~C ４ Alkyl, C １ ~C ４ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C １ ~C ４ Alkyl-N(R ６ ) ２ where each C １ ~C ４ Alkyl, C １ ~C ４ hydroxyalkyl, 4- to 6-membered heterocycloalkylalkyl, 5- to 6-membered heteroarylalkyl, or C １ ~C ４ Alkyl-N(R ６ ) ２ But 1 to 3 R ７ and optionally substituted with Each R ５ is independently Cl, F or OH; Each R ６ are independently H or 1 to 3 R ５ C optionally substituted with １ ~C ４ is alkyl, Each R ７ But independently, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C １ ~C ４ hydroxyalkyl, Cl, F or hydroxy, and Each R ８ are independently H, halogen, or 1 to 3 R ５ C optionally substituted with １ ~C ４ is alkyl, The compound according to claim 5.

7. R １ But Cl, F, CF ３ 7. The compound of claim 6, which is phenyl or pyridyl substituted with 1 to 3 groups independently selected from:

8. R １ is phenyl or pyridyl, and the phenyl or pyridyl is one CF ３ 8. The compound of claim 7, substituted with and optionally substituted with 1-2 F.

9. 2. A formate salt according to claim 1.

10. A compound selected from Table 1, or a pharma- ceutically acceptable salt thereof.

11. 13. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11, further comprising a second pharmaceutical agent.

13. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharma- ceutical acceptable salt, deuterated analog, tautomer or stereoisomer thereof, or a pharmaceutical composition of claim 11 or 12, for treating a subject having a disease or condition mediated by YAP / TEAD.

14. 14. The pharmaceutical composition of claim 13, wherein the disease or condition is cancer, a neurodegenerative disease, a heart-related disorder, or a kidney-related disorder.

15. 14. The pharmaceutical composition of claim 13, wherein the disease or condition is polycystic kidney disease, Alzheimer's disease, arrhythmogenic cardiomyopathy, Holt-Oram syndrome, liver cancer, epithelioid hemangioendothelioma, breast cancer, lung cancer, malignant mesothelioma, pancreatic cancer, Kaposi's sarcoma, uveal melanoma, renal cell carcinoma, colorectal cancer, multiple myeloma, neurofibromatosis type 2, glioma, or glioblastoma.

16. 14. The pharmaceutical composition of claim 13, further comprising one or more additional therapeutic agents.

17. The one or more additional therapeutic agents are: i) adozelesin, altretamine, bizeresin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine ii) an alkylating agent selected from the group consisting of bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin and plicamycin; iii) an antibiotic selected from the group consisting of azacitidine, capecitabine, cladribine, clofaxine, cyclospor ... an antimetabolite selected from the group consisting of rabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) an immune checkpoint agent selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors and anti-CTLA4 inhibitors; v) a hormone or hormone antagonist selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen and toremifene; vi) DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) retinoids selected from the group consisting of alitretinoin, bexarotene, fenretinide, isotretinoin and tretinoin; viii) alkaloids selected from the group consisting of etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine and vinorelbine; ix) AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide;and thalidomide; x) topoisomerase inhibitors selected from the group consisting of amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan and 9-aminocamptothecin; xi) erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, 7-hydroxylase inhibitors, cyclosporine ... xii) kinase inhibitors selected from the group consisting of xistaurosporine and vatalanib, xii) targeted signal transduction inhibitors selected from the group consisting of bortezomib, geldanamycin and rapamycin, xiii) biological response modifiers selected from the group consisting of imiquimod, interferon-α and interleukin-2, xiv) IDO inhibitors, xv) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors and aromatase inhibitors (anastrozole 17. The pharmaceutical composition of claim 16, wherein the therapeutic agent is one or more of: xvi) a chemotherapeutic agent selected from the group consisting of letrozole, exemestane, xvi) a BRAF inhibitor, xvii) a Mek inhibitor, xviii) a c-Kit mutant inhibitor, xix) an EGFR inhibitor, xx) an epigenetic modulator, xxi) another adenosine axis blocker selected from the group consisting of CD39, CD38, A2AR and A2BR, or xxii) an agonist of a TNFA superfamily member, and xxiii) an anti-ErbB2 mAb.

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