Compounds and methods for YAP / TEAD modulation and their indications

Abstract

Compounds of formula (I): [Case 1] JPEG2025503945000103.jpg3250 or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, 2 , R 3 , R 4 , Y 1 , Y 2 , X and Z are as described in any of the embodiments described in this disclosure); compositions thereof; and uses thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,504, filed January 28, 2022, and U.S. Provisional Patent Application No. 63 / 309,442, filed February 11, 2022, the entire teachings of which are incorporated herein by reference.

[0002] The present disclosure relates to organic compounds useful for mammalian therapy, 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 inducer 61 (CYR61), promoting cell growth, proliferation, migration and survival. (Gandhi TKBoopathy et al.,Role of Hippo Pathway-YAP / TAZ Signaling in Angiogenesis,Front Cell Dev Biol.2019;7:49). 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 is 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 in cancer cell lines controlled by the Hippo signaling pathway (i.e., YAP / TEAD inhibitors), thereby reducing the expression of YAP / TEAD target genes and exhibiting antiproliferative effects, 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 new compounds that can modulate YAP / TEAD. Summary of the Invention

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

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

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

[0008] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to Formula (I) or any of the embodiments and subembodiments of Formula (I) as described herein in this disclosure, 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 according to formula (I) or any embodiment of formula (I) as described herein in this disclosure, or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of these compounds, 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] Additional embodiments are further described in the detailed description of this disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0014] It should be noted 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 is otherwise indicated, 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 parent structure as defined. However, when a point of attachment (e.g., a dash "-") is indicated on the left hand side 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 constructing compounds, it is assumed that such constructs will produce stable structures, i.e., those skilled in the art will recognize that, in theory, some constructs would not normally be considered 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 to 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. In each of the definitions herein (e.g., alkyl, alkoxy, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, etc.), 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 chain 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.It is understood that substitutions are attached to any available atom to produce a stable compound, however, when an optionally substituted alkyl is the R group of a moiety such as, for example, -OR (e.g., alkoxy), -SR (e.g., thioalkyl), -NHR (e.g., alkylamino), -C(O)NHR, the substitution of the alkyl R group is such that replacement of an alkyl carbon bonded to any O, S or N (except when N is a heteroaryl ring atom) of the moiety excludes substitutions which result in any O, S or N (except when N is a heteroaryl ring atom) of the substituent being bonded to an alkyl carbon bonded to any O, S or N of the moiety.

[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 -CH2-, ethylene -CH2CH2-, propylene -CH2CH2CH2-, and isopropylene -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2-(CH2)2CH2-, -CH2-CH(CH3)CH2-, -CH2-C(CH3)2-CH2-CH2CH(CH3)-. Typically, alkyl (or alkylene) groups have 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, 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] "Alkenyl" refers to a linear or branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, C2-C6 alkenyl is meant to include ethenyl, propenyl, and the like.

[0020] "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. It is understood that substitutions on an alkoxy are attached to any available atom to produce a stable compound, but the substitutions on the alkoxy are such that no O, S, or N (except when N is a heteroaryl ring atom) is attached to the alkyl carbon attached to the alkoxy O. Additionally, when alkoxy is recited as a substituent on another moiety, the alkoxy oxygen is not attached to a carbon atom attached 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.

[0021] "Amino" or "amine" refers to the group NH2.

[0022] "Aryl," by itself or as part of another substituent, refers to a monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical 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 encompass or in any way 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.

[0023] "Arylalkyl" or "aralkyl" refers to -(alkylene)-aryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if not specified, up to 6 main chain carbon atoms or up to 4 main chain carbon atoms, and aryl is as defined herein. Examples of arylalkyl include benzyl, phenethyl, 1-methylbenzyl, and the like.

[0024] "Cycloalkyl" or "carbocycle" or "carbocyclic", by itself or as part of another substituent, unless otherwise stated, 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, e.g., cyclopropyl, cyclopentyl, cyclohexyl, having the number of carbon atoms indicated in the prefix or, if not specified, having 3 to 6, even 4 to 6, even 5 to 6 ring members per ring, in which one or two ring carbon atoms may be replaced by a 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., C3-6 cycloalkyl and 3-6 membered cycloalkyl both mean 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.

[0025] "Cycloalkylalkyl" refers to an -(alkylene)-cycloalkyl group, where alkylene as defined herein has the indicated number of carbon atoms, or if not specified, up to 6 carbon atoms, and cycloalkyl as defined herein has the indicated number of carbon atoms, or if not specified, 3 to 10, further 3 to 8, further 3 to 6 ring members per ring. By way of example, a 4-6 membered cycloalkyl-C1-C6 alkyl refers to a cycloalkyl having 4 to 6 carbon atoms attached to an alkylene chain having 1 to 6 carbon atoms, the alkylene chain being attached to the parent moiety. Other exemplary cycloalkyl alkyls include, for example, cyclopropyl methylene, cyclobutyl ethylene, cyclobutyl methylene, and the like.

[0026] "Halogen" or "halo" refers to any halogen, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

[0027] The term "haloalkyl" refers to an alkyl substituted with 1 to 7 halogen atoms. Haloalkyl includes monohaloalkyl or polyhaloalkyl. For example, the term "C1-C6 haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0028] The term "haloalkoxy" refers to an alkoxy substituted with 1 to 7 halogen atoms. Haloalkoxy includes monohaloalkoxy or polyhaloalkoxy. For example, the term "C1-C6 haloalkoxy" is meant to include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutoxy, 3-bromopropoxy, and the like.

[0029] "Heteroatom" is meant to include oxygen (O), nitrogen (N) and sulfur (S).

[0030] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring radical containing 5-9 ring atoms (also referred to in this disclosure as 5-9 membered heteroaryl), and encompasses monocyclic aromatic ring radicals containing 5 or 6 ring atoms (also referred to in this disclosure as 5-6 membered heteroaryl), containing one or more, 14, 13 or 12 heteroatoms independently selected from the group consisting of O, S and N. 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, but are not limited to, 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, quinoxalyl, and the like. "Nitrogen-containing heteroaryl" refers to a heteroaryl in which at least one of the ring heteroatoms is N.

[0031] "Heteroarylalkyl" refers to an -(alkylene)-heteroaryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if not specified, up to 6 main chain carbon atoms or up to 4 main chain carbon atoms, and heteroaryl is as defined herein.

[0032] "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 may be oxidized, the nitrogen atom may be quaternized, the remaining ring atoms are C, and one or two C atoms may 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 having rings with formally charge-separated aromatic resonance structures, e.g., N-methylpyridonyl. Heterocycloalkyls may be substituted by 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 further, 1 or 2 ring atoms may be 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 may 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. A heterocycloalkyl or heterocycloalkenyl substituent may be at the point of attachment of the heterocycloalkyl or heterocycloalkenyl group, forming a quaternary center.

[0033] "Heterocycloalkylalkyl" refers to -(alkylene)-heterocycloalkyl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if not specified, up to 6 main chain carbon atoms, or up to 4 main chain carbon atoms, and heterocycloalkyl is as defined herein.

[0034] "Hydroxyl" or "hydroxy" refers to the group OH. 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.

[0035] As used throughout this disclosure, "optionally substituted" or "optionally substituted" means that the compound may or may not be substituted, and the description includes cases where substitution occurs and cases where no substitution occurs. For example, "1 to 3 T 1 The phrase "optionally substituted by 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.

[0036] As used herein in connection with compounds of the present disclosure, the term "synthesize" and like terms refer to chemical synthesis from one or more precursor materials.

[0037] As used herein, the term "composition" refers to a formulation suitable for administration to an animal subject intended for treatment, which contains at least one pharma- ceutically active compound and at least one pharma- ceutically acceptable carrier or excipient.

[0038] The term "pharmaceutical acceptable" indicates that the indicated material does not possess properties that would cause a reasonably prudent physician to avoid administering it 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.

[0039] "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 characteristics 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 even 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 in the compounds described herein.

[0040] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then isolated by evaporating the solution. In another example, salts can be prepared by reacting the free base with an acid in an organic solvent.

[0041] When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of a 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 (such as glucuronic acid or galacturonic acid), an alpha-hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), and the like. In some embodiments, the salt is prepared from a pharma- ceutically acceptable acid, such as, for example, 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, or the like. , pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, sulfamic acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, embonic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, stearic acid, cyclohexylsulfamic acid, cyclohexylaminosulfonic acid, quinic acid, algenic acid, hydroxybutyric acid, galactaric acid, and galacturonic acid, and the like.

[0042] 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, 66:1-19). Certain specific 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.

[0043] The neutral forms of the compounds may 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.

[0044] Pharmaceutically acceptable salts of various compounds may exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (e.g., similar to dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex; dramamine), and various cyclodextrin inclusion complexes.

[0045] 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.

[0046] The present disclosure also includes the isotopically labeled compounds of the present disclosure, which are identical to those listed herein, but which have one or more atoms replaced by atoms with atomic masses or mass numbers different from those usually found in nature.All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be included 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, including, but not limited to, 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 I. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," the position is designated with its natural abundance isotopic composition or its isotopes, e.g., 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 be preferred in some circumstances, as it may provide certain therapeutic advantages resulting from superior metabolic stability (e.g., increased in vivo half-life, or reduced dosage requirements). Isotopically labeled compounds of the present disclosure may generally be prepared by following procedures similar to those described in the schemes and examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0047] "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 group, an amino group, a carboxyl group, or a sulfhydryl group in a compound of formula (I) is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, a free amino group, or a free 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 compounds. The preparation, selection and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0048] As described in Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories: biological precursor prodrugs and carrier prodrugs. In general, biological precursor prodrugs are compounds that contain one or more protective groups and have inactive or low activity compared to the corresponding active drug compound, which is converted to an active form by metabolism or solvolysis. In the active drug form and any released metabolites, toxicity should be acceptably low. Typically, the formation of an active drug compound involves a metabolic process or reaction that is one of the following types: (1) Oxidation Reactions: Oxidation reactions are exemplified for reactions such as, but not limited to, 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: Reduction reactions are exemplified for reactions such as, but not limited to, the reduction of carbonyl functional groups, the reduction of alcohol functional groups and carbon-carbon double bonds, the reduction of nitrogen-containing functional groups, and other reduction reactions. (3) Reactions that do not change the oxidation state: Reactions that do not change the oxidation state are exemplified, but not limited to, 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, elimination of hydrogen halide molecules, and other such reactions.

[0049] Carrier prodrugs are drug compounds that contain a transport moiety that improves, for example, 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, for example, certain polymers, or other moieties such as cyclodextrins. (See, for example, Cheng et al., U.S. Patent 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 drug formulation (e.g., stability, water solubility, suppression of undesirable organoleptic 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.

[0050] The term "carrier" is also meant to include microspheres, liposomes, micelles, nanoparticles (naturally equipped nanocarriers, e.g., exosomes), etc. It is known that exosomes can be extremely 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;219:396-405, the entire contents of which are incorporated by reference.

[0051] Metabolites, for example, active metabolites, overlap with the above-mentioned prodrugs, for example, biological precursor prodrugs. Thus, such metabolites are compounds that are further metabolized to pharmacologically active compounds, or derivatives that result from metabolic processes in the subject's body. Among these, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, the prodrug compounds are generally inactive or less active than the metabolites. In the case of active metabolites, the parent compound can be either an active compound or an inactive prodrug.

[0052] Prodrugs and active metabolites can be identified using routine techniques known in the art.See, for example, Bertolini et al., 1997, J. Med. Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230.

[0053] "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, Fourth Edition, John Wiley & Sons, pages 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 -N=C(H)-NH- ring atom arrangement, 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 thus include various isomers. One of ordinary skill in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0054] "Isomers" refer to compounds that have the same molecular formula but differ in the nature or sequence of bonding 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". A "stereoisomer" or "stereoisomers" refers 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 thus 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, 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 called dextrorotatory or levorotatory (i.e., (+) 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, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the 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) that differ in the chirality of one or more stereocenters.

[0055] "Hydrate" refers to a complex formed by the combination of water molecules with molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure.

[0056] 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 so that a potential binding interaction and / or chemical reaction between the compound and the other particular material can occur.

[0057] "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 may be assayed based on its ability to act on a detectable substrate. A compound may be assayed based on its ability to bind to a particular target molecule or molecules.

[0058] 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" is one that 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.

[0059] The term "bind" in reference to the interaction between a target and a potential binding compound indicates that the potential binding compound generally associates with the target to a statistically significant extent compared to its association with a protein (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 specific target. In the context of a compound that binds to a target, the terms "greater affinity" and "selective" indicate that the compound binds more tightly than a reference compound or more tightly than the same compound under reference conditions, i.e., with a reduced 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 the affinity.

[0060] 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, e.g., the interaction between YAP and TEAD, and such functions 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 feature associated with YAP / TEAD, either directly or indirectly, and / or upregulation or downregulation of the expression of YAP / TEAD, either directly or indirectly, as described herein. In another embodiment, the modulation is direct. An inhibitor or antagonist is, for example, a compound that binds to a stimulus, partially or completely blocks a stimulus, reduces activation, prevents activation, inhibits activation, delays activation, inactivates signaling, desensitizes signaling, or downregulates signaling. An activator or agonist is a compound that, for example, binds to activation, stimulates activation, increases activation, opens activation, activates activation, promotes activation, enhances activation, activates signaling, sensitizes signaling, or upregulates signaling.

[0061] As used herein, the terms "treat," "treating," "therapy," "therapies," and similar terms 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 similar terms 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.

[0062] 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 reacquiring 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.

[0063] As used herein, the terms "subject", "animal subject" and the like refer to organisms including, but not limited to, humans and non-human vertebrates, e.g., any mammals, e.g., humans, other primates, sports animals, and commercial animals, e.g., cows, horses, sheep or pigs, rodents, or pets, e.g., dogs and cats.

[0064] "Unit dosage form" refers to a composition intended for single administration to treat a subject suffering from a disease or condition. Each unit dosage form typically contains each of the active ingredients of the present disclosure and a pharma- ceutically acceptable excipient. Examples of unit dosage forms include individual tablets, individual capsules, bulk powders, liquid solutions, 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, one unit dosage form more than once a day, once with each meal, once at four hours or other intervals, or only once a day. The term "oral unit dosage form" refers to a unit dosage form designed to be taken orally.

[0065] The term "administer" refers to oral administration, administration as a suppository, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration 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, palate, 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.

[0066] In this context, the term "therapeutically effective" or "effective amount" indicates that the compound or material or the amount of the compound or material when administered is sufficient or effective to prevent, alleviate or ameliorate one or more symptoms of the disease, disorder or condition being treated and / or 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, a daily dosage of about 0.1 to about 10 g / kg of subject body weight is shown to produce satisfactory results in the subject. In some embodiments, the daily dosage ranges from about 0.10 to 10.0 mg / kg body weight, about 1.0 to 3.0 mg / kg body weight, about 3 to 10 mg / kg body weight, about 3 to 150 mg / kg body weight, about 3 to 100 mg / kg body weight, about 10 to 100 mg / kg body weight, about 10 to 150 mg / kg body weight, or about 150 to 1000 mg / kg body weight. The dosage may conveniently be administered in divided doses, for example, up to four times a day, or in sustained release form.

[0067] 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 YAP / TEAD interaction (such as YAP / TEAD-mediated transcription) alters the onset, course and / or symptoms. A YAP / TEAD-mediated disease or condition includes a disease or condition in which disruption of 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 a disease or condition. A disease or condition mediated by YAP / TEAD is intended to include cancers with loss-of-function mutations in YAP / TEAD or cancers in which there is activation of YAP / TEAD. A disease or condition mediated by YAP / TEAD 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.

[0068] Also, in the context of a compound that binds to a biomolecular target, the term "higher specificity" indicates that the compound binds to a specific 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 specific target.Typically, specificity refers to a limited set of other biomolecules, for example, in the case of YAP or TEAD.In certain embodiments, higher specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500 or 1000 times more specific.

[0069] As used herein in connection with binding compounds or ligands, 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. Also, when 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., enzyme activity inhibition, than it does to other enzymes. In some embodiments, the compounds described herein are specific for TEAD inhibition.

[0070] The term "first-line cancer therapy" refers to a therapy 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 a combination administered with one or more drugs.A summary of the currently accepted approach to first-line therapy for a particular disease can be found in the NCI guidelines for such disease.

[0071] The term "second-line cancer therapy" refers to a cancer treatment administered to subjects who do not respond to first-line therapy, i.e., 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 an earlier successful cancer therapy, which can be any of the treatments described under "first-line cancer therapy". A summary of the currently accepted approach to second-line therapy for a particular disease is described in the NCI guidelines for such disease.

[0072] The term "refractory" refers to a subject that does not respond to or is otherwise resistant to a cancer therapy or cancer treatment. The cancer therapy can be a first-line, second-line, or any subsequent 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 therapy, or a subject may be refractory due to acquired resistance that occurs during the course of a particular therapy.

[0073] Additionally, the abbreviations used herein have the following respective meanings: [Table 1]

[0074] II. Compounds Embodiment 1 of the present disclosure relates to a compound having formula (I): [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein Y 1 Ha-QR 1 and Y 2 is R 2 or Y 1 is R 2 and Y 2 Ha-QR 1 and; Q is a bond or -O-; R 1 is phenyl substituted with 0-4 G groups; Each G is a halogen, OH, CN, or one or more R 5 and one or more R 5 substituted alkoxy; Each R 2are independently H, halogen, -C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1-3 halogens, provided that not more than one R 2 is -C(O)O-alkyl; R 3 is H; halogen; alkenyl optionally substituted by cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted by -C(O)-alkyl; heterocycloalkenyl optionally substituted by C(O)-alkyl; heterocycloalkylalkyl optionally substituted by C(O)-alkyl; or heteroaryl optionally substituted by haloalkyl, cycloalkyl or cycloalkylalkyl; R 4 is H; alkyl; cycloalkyl optionally substituted by haloalkyl, or -C(O)-alkenyl; heterocycloalkyl optionally substituted by -C(O)-alkyl, -C(O)-alkenyl, or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted by -C(O)-alkyl, -C(O)-CH2-OH, or heteroaryl; R 5 is a halogen or OH; X is -(CH2) m -S(O)-2-, -(CH2) n -C(O)- or -C(O)O-, with the right side indicating the point of attachment to Z; Z is -NR 6 R 7 , 1 to 4 R 8 C1-C6 alkyl optionally substituted by -C(CH3)=CH2, -CH2-CH=C=O, 1 to 4 R 9 cycloalkyl optionally substituted by 1 to 4 R 10 heterocycloalkyl, optionally substituted by 1 to 4 R 10 or aryl optionally substituted by 1 to 4 R 10 or heteroaryl optionally substituted by; or XZ is -C(=NR 7 )2-NR 6 R 7 Is it; Or X is a bond and Z is CN, -C(O)-NR 14 R 15 , -S(O)2-C1-C3 alkyl, or -SO -2 -NR 14 R 15 is a 5-6 membered heteroaryl optionally substituted by R 6 is hydrogen, -S(O)2-C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being selected from 1 to 3 R 11 may be substituted by; R 7 is hydrogen or C1-C6 alkyl; or R 6 and R 7 together with the nitrogen to which they are attached form a heterocycloalkyl; R 8 -NR 6 R 7 , CN, hydroxy, alkoxy, haloalkoxy, -S-C1-C3 alkyl, -S(O)-C1-C3 alkyl, -S(O)2-C1-C3 alkyl, -S(O)2-C1-C3 haloalkyl, -S(O)2-NH2, -S(O)(NH)-C1-C3 alkyl, -C(O)-NH2, -C(O)OH, -C(O)O-C1-C3 alkyl, -C(O)C1-C3 haloalkyl, -N(H)-C(O)-NR 6 R 7 , -NR 12 R 13 Or CN -N(H)-C(O)-C1-C3 alkyl, -N(H)-C(O)-C2-C6 alkenyl, -N(H)-C(O)-C1-C3 haloalkyl, -N(H)-C(O)O-C1-C6 alkyl, -N(H)-C(NH)-NH2, -N(H)-S(O)2-NR 12 R 13 , -N(R 7 )-S(O)2-C1-C3 alkyl, -N(R 7 )-S(O)2-cycloalkyl, -N(H)-S(O)2-C1-C3 haloalkyl, -P(O)(OH)2, -P(O)(C1-C6 alkyl)2, 1 to 3 R 10 cycloalkyl optionally substituted by 1 to 3 R 10 or one to three R 10 or The Two R's 8 together with the carbon atoms to which they are attached, combine with each other to form a cycloalkyl; Each R 9 are independently CN, -S(O)2-C1-C3 alkyl, or -N(C 1~3 alkyl)2; Each R 10 are independently hydroxy, CN, C1-C6 alkyl, haloalkyl, -NH2, -C(O)-alkenyl, -C(O)-NH2, -C(O)O-alkyl, -NH-C(O)-alkenyl, -S(O)2-C1-C3 alkyl, -S(O)2-C2-C6 alkenyl, or -S(O)2-NH2; Each R 11 is independently hydroxy, CN, alkoxy, -S(O)2-C1-C3 alkyl, or cycloalkyl; Each R 12 and R 13 are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 14 and R 15 are independently hydrogen or C1-C6 alkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; however: when Z is -C(CH3)=CH2, X is -C(O)O-, or n is 1 or 2, or m is 1, 2 or 3; When XZ is -C(O)-C-1 alkyl, R 8 cannot be CN, hydroxy, alkoxy, or haloalkoxy; When X is -C(O)-, Z cannot be oxiranyl; X is -C(O)- or -S(O)2- and Z is one R 9 is a cycloalkyl substituted by R 9 If is CN, then R 9 cannot be bonded to the same ring atom of Z as the atom to which X is bonded; X is -C(O)- or -S(O)2- and Z is one R 10 is heterocycloalkyl substituted by R 10 When is hydroxy or CN, R 10 cannot be bonded to the same ring atom of Z as the atom to which X is bonded; When X is -C(O)-, or -S(O)2-, and Z is a partially saturated cycloalkyl or partially saturated heterocycloalkyl, the point of saturation of Z cannot be adjacent to X).

[0075] Embodiment 2 of the present disclosure relates to a compound having formula (Ia): [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, wherein R 1 is phenyl substituted with 0-4 G groups; Each G is a halogen, OH, CN, or one or more R 5 and one or more R 5 substituted alkoxy; Each R 2are independently H, halogen, -C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1-3 halogens, provided that not more than one R 2 is -C(O)O-alkyl; R 3 is H; halogen; alkenyl optionally substituted by cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted by -C(O)-alkyl; heterocycloalkenyl optionally substituted by C(O)-alkyl; heterocycloalkylalkyl optionally substituted by C(O)-alkyl; or heteroaryl optionally substituted by haloalkyl, cycloalkyl or cycloalkylalkyl; R 4 is H; alkyl; cycloalkyl optionally substituted by haloalkyl, or -C(O)-alkenyl; heterocycloalkyl optionally substituted by -C(O)-alkyl, -C(O)-alkenyl, or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted by -C(O)-alkyl, -C(O)-CH2-OH, or heteroaryl; R 5 is a halogen or OH; X is -(CH2) m -S(O)-2-, -(CH2) n -C(O)- or -C(O)O-, with the right side indicating the point of attachment to Z; Z is -NR 6 R 7 , 1 to 4 R 8 C1-C6 alkyl optionally substituted by -C(CH3)=CH2, -CH2-CH=C=O, 1 to 4 R 9 cycloalkyl optionally substituted by 1 to 4 R 10 heterocycloalkyl, optionally substituted by 1 to 4 R 10 or aryl optionally substituted by 1 to 4 R 10 or heteroaryl optionally substituted by; or XZ is -C(=NR 7 )2-NR 6 R 7 Is it; Or X is a bond and Z is CN, -C(O)-NR 14 R 15 , -S(O)2-C1-C3 alkyl, or -SO -2 -NR 14 R 15 is a 5-6 membered heteroaryl optionally substituted by R 6 is hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being selected from 1 to 3 R 11 may be substituted by; R 7 is hydrogen or C1-C6 alkyl; or R 6 and R 7 together with the nitrogen to which they are attached form a heterocycloalkyl; R 8 -NR 6 R 7 , CN, hydroxy, alkoxy, haloalkoxy, -S-C1-C3 alkyl, -S(O)-C1-C3 alkyl, -S(O)2-C1-C3 alkyl, -S(O)2-C1-C3 haloalkyl, -S(O)2-NH2, -S(O)(NH)-C1-C3 alkyl, -C(O)-NH2, -C(O)OH, -C(O)O-C1-C3 alkyl, -C(O)C1-C3 haloalkyl, -N(H)-C(O)-NR 6 R 7 , -NR 12 R 13 Or CN -N(H)-C(O)-C1-C3 alkyl, -N(H)-C(O)-C2-C6 alkenyl, -N(H)-C(O)-C1-C3 haloalkyl, -N(H)-C(O)O-C1-C6 alkyl, -N(H)-C(NH)-NH2, -N(H)-S(O)2-NR 12 R13 , -N(R 7 )-S(O)2-C1-C3 alkyl, -N(R 7 )-S(O)2-cycloalkyl, -N(H)-S(O)2-C1-C3 haloalkyl, -P(O)(OH)2, -P(O)(C1-C6 alkyl)2, 1 to 3 R 10 cycloalkyl optionally substituted by 1 to 3 R 10 or one to three R 10 or The Two R's 8 together with the carbon atoms to which they are attached, combine with each other to form a cycloalkyl; Each R 9 are independently CN, -S(O)2-C1-C3 alkyl, or -N(C 1~3 alkyl)2; Each R 10 are independently hydroxy, CN, C1-C6 alkyl, haloalkyl, -NH2, -C(O)-alkenyl, -C(O)-NH2, -C(O)O-alkyl, -NH-C(O)-alkenyl, -S(O)2-C1-C3 alkyl, -S(O)2-C2-C6 alkenyl, or -S(O)2-NH2; R 11 is CN; Each R 12 and R 13 are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 14 and R 15 are independently hydrogen or C1-C6 alkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; however: when Z is -C(CH3)=CH2, X is -C(O)O-, or n is 1 or 2, or m is 1, 2 or 3; When XZ is -C(O)-C-1 alkyl, R 8cannot be CN, hydroxy, alkoxy, or haloalkoxy; When X is -C(O)-, Z cannot be oxiranyl; X is -C(O)- or -S(O)2- and Z is one R 9 is a cycloalkyl substituted by R 9 If is CN, then R 9 cannot be bonded to the same ring atom of Z as the atom to which X is bonded; X is -C(O)- or -S(O)2- and Z is one R 10 is heterocycloalkyl substituted by R 10 When is hydroxy or CN, R 10 cannot be bonded to the same ring atom of Z as the atom to which X is bonded; When X is -C(O)-, or -S(O)2-, and Z is a partially saturated cycloalkyl or partially saturated heterocycloalkyl, the saturated point of Z cannot be adjacent to X).

[0076] Embodiment 3 of the present disclosure relates to a compound according to embodiment 1 or embodiment 2, wherein R 1 is phenyl substituted with 0-4 G groups; Each G is a halogen, OH, CN, or one or more R 5 and one or more R 5 substituted alkoxy; Each R 2 are independently H, halogen, -C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1-3 halogens, provided that not more than one R 2 is -C(O)O-alkyl; R 3is H; halogen; alkenyl optionally substituted by cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted by -C(O)-alkyl; heterocycloalkenyl optionally substituted by C(O)-alkyl; heterocycloalkylalkyl optionally substituted by C(O)-alkyl; or heteroaryl optionally substituted by haloalkyl, cycloalkyl or cycloalkylalkyl; R 4 is H; alkyl; cycloalkyl optionally substituted by haloalkyl, or -C(O)-alkenyl; heterocycloalkyl optionally substituted by -C(O)-alkyl, -C(O)-alkenyl, or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted by -C(O)-alkyl, -C(O)-CH2-OH, or heteroaryl; R 5 is a halogen or OH; X is -(CH2) m -S(O)-2-, -(CH2) n -C(O)- or -C(O)O-, with the right side indicating the point of attachment to Z; Z is -NR 6 R 7 , 1 to 4 R 8 C1-C6 alkyl optionally substituted by -CH2-CH=C=O, 1 to 4 R 10 or aryl optionally substituted by 1 to 4 R 10 or heteroaryl optionally substituted by; or XZ is -C(=NR 7 )2-NR 6 R 7 Is it; Or X is a bond and Z is CN, -C(O)-NR 14 R 15 , -S(O)2-C1-C3 alkyl, or -SO -2 -NR 14 R 15 is a 5-6 membered heteroaryl optionally substituted by R 6 is hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being selected from 1 to 3 R 11 may be substituted by; R 7 is hydrogen or C1-C6 alkyl; or R 6 and R 7 together with the nitrogen to which they are attached form a heterocycloalkyl; R 8 -NR 6 R 7 , -S-C1-C3 alkyl, -S(O)-C1-C3 alkyl, -S(O)2-C1-C3 alkyl, -S(O)2-C1-C3 haloalkyl, -S(O)2-NH2, -S(O)(NH)-C1-C3 alkyl, -C(O)-NH2, -C(O)OH, -C(O)O-C1-C3 alkyl, -C(O)C1-C3 haloalkyl, -N(H)-C(O)-NR 6 R 7 , -NR 12 R 13 or -N(H)-C(O)-C1-C3 alkyl, -N(H)-C(O)-C2-C6 alkenyl, -N(H)-C(O)-C1-C3 haloalkyl, -N(H)-C(O)O-C1-C6 alkyl, -N(H)-C(NH)-NH2, -N(H)-S(O)2-NR 12 R 13 , -N(R 7 )-S(O)2-C1-C3 alkyl, -N(R 7 )-S(O)2-cycloalkyl, -N(H)-S(O)2-C1-C3 haloalkyl, -P(O)(OH)2, -P(O)(C1-C6 alkyl)2, 1 to 3 R 10 cycloalkyl optionally substituted by 1 to 3 R 10 or one to three R 10 or The Two R's 8 together with the carbon atoms to which they are attached, combine with each other to form a cycloalkyl; Each R 9 are independently CN, -S(O)2-C1-C3 alkyl, or -N(C 1~3 alkyl)2; Each R 10 are independently hydroxy, CN, C1-C6 alkyl, haloalkyl, -NH2, -C(O)-alkenyl, -C(O)-NH2, -C(O)O-alkyl, -NH-C(O)-alkenyl, -S(O)2-C1-C3 alkyl, -S(O)2-C2-C6 alkenyl, or -S(O)2-NH2; R 11 is CN; Each R 12 and R 13 are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 14 and R 15 are independently hydrogen or C1-C6 alkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3).

[0077] Embodiment 4 of the present disclosure relates to a compound according to embodiment 1 or embodiment 2, wherein R 1 0 to 3 G 2 phenyl substituted by a group; Each G is a halogen, CN, or one to three R 5 independently selected from C1-C3 alkyl optionally substituted by Each R 2 is H, halogen or CH3; R 5 is a halogen or OH; X is -(CH2) m -S(O)-2-, or -(CH2) n -C(O)-; Z is -NR 6 R7 , 1 to 3 R 8 C1-C6 alkyl optionally substituted by 1 to 3 R 9 cycloalkyl optionally substituted by 1 to 3 R 10 heterocycloalkyl optionally substituted by one to three R 10 or aryl optionally substituted by 1 to 3 R 10 and R is an optionally substituted heteroaryl.

[0078] Embodiment 5 of the present disclosure relates to a compound according to embodiment 4, wherein: R 1 is phenyl substituted with 0 to 2 G groups; Each G is Cl, F, CN, and one to three R 5 independently selected from C1-C3 alkyl substituted by Each R 2 is H, Cl, F or CH3; R 5 is a halogen).

[0079] Embodiment 6 of the present disclosure relates to a compound of embodiment 5, wherein R 5 is Cl or F).

[0080] Embodiment 7 of the present disclosure relates to a compound of embodiment 1 or embodiment 2 or embodiment 3 having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of either formula (IIa) or (IIb), Each G is Cl, F, CN, and one to three R 5 independently selected from C1-C3 alkyl substituted by R 5 is a halogen).

[0081] Embodiment 8 of the present disclosure relates to a compound according to embodiment 7 having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (IIIa), (IIIb) or (IIIc), wherein G is Cl, F or CN.

[0082] Embodiment 9 of the present disclosure relates to a compound of embodiment 7 or embodiment 8, wherein R 3 is H; halogen; C2-C4 alkenyl optionally substituted by cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted by C(O)-CH3; heterocycloalkenyl optionally substituted by C(O)-CH3; heterocycloalkylalkyl optionally substituted by C(O)-CH3; or 5-6 membered heteroaryl optionally substituted by haloalkyl, cyclopropyl, or cyclopropyl-CH2-.

[0083] Embodiment 10 of the present disclosure relates to a compound of any one of embodiments 7 to 9, wherein R 4 is H; C1-C3 alkyl; cycloalkyl optionally substituted by haloalkyl, or -C(O)-alkenyl; heterocycloalkyl optionally substituted by -C(O)-CH3, -C(O)-CH=CH2, or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted by -C(O)-CH3; -C(O)-CH2-OH; or 5- to 6-membered heteroaryl).

[0084] Embodiment 11 of the present disclosure relates to a compound of embodiment 1 or embodiment 2 having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (IIIa), (IIIb) or (IIIc), wherein G is Cl, F or CN; R 3 is H; halogen; C2-C4 alkenyl optionally substituted by cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted by C(O)-CH3; heterocycloalkenyl optionally substituted by C(O)-CH3; heterocycloalkylalkyl optionally substituted by C(O)-CH3; or 5-6 membered heteroaryl optionally substituted by haloalkyl, cyclopropyl, or cyclopropyl-CH2-; R 4 is H; C1-C3 alkyl; cycloalkyl optionally substituted by haloalkyl or -C(O)-alkenyl; -C(O)-CH 3、 Heterocycloalkyl optionally substituted by -C(O)-CH=CH2 or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted by -C(O)-CH3; -C(O)-CH2-OH; or 5-6 membered heteroaryl; X is -S(O)-2- or -(CH2) n -C(O)-; Z is -NR 6 R 7 , 1 to 4 R 8 C1-C6 alkyl optionally substituted by 1 to 4 R 9 C3-C6 cycloalkyl optionally substituted by 1 to 4 R 10 5-10 membered heterocycloalkyl optionally substituted by 1-4 R 10 C6 to C which may be substituted 12 Aryl or 1-4 R 10 is a 5-10 membered heteroaryl optionally substituted by; Or X is a bond and Z is CN, -C(O)-NR 14 R 15, -S(O)2-C1-C3 alkyl, or -SO -2 -NR 14 R 15 is a 5-6 membered heteroaryl optionally substituted by where n is 0, 1 or 2).

[0085] Embodiment 12 of the present disclosure relates to a compound of embodiment 11, wherein: R 3 is H; R 4 is H; X is -S(O)-2- or -(CH2) n -C(O)-; Z is -NR 6 R 7 , 1 to 3 R 8 C1-C4 alkyl optionally substituted by 1 to 3 R 9 C3-C6 cycloalkyl optionally substituted by 1 to 3 R 10 5-7 membered heterocycloalkyl optionally substituted by 1-3 R 10 C6 to C which may be substituted 10 Aryl, or 1-3 R 10 is a 5-7 membered heteroaryl optionally substituted by where n is 0 or 1).

[0086] Embodiment 13 of the present disclosure relates to a compound of embodiment 11, wherein: X is -S(O)-2- or -(CH2) n -C(O)-; Z is -NR 6 R 7 , 1 to 3 R 8 C2-C4 alkyl optionally substituted by 1 to 3 R 10 C6 to C which may be substituted 12 Aryl, or 1-3 R 10 is a 5-10 membered heteroaryl optionally substituted by where n is 0 or 1).

[0087] Embodiment 14 of the present disclosure relates to a compound of embodiment 11, wherein: X is -S(O)-2- or -(CH2) n -C(O)-; Z-NR 6 R 7 and; where n is 0 or 1).

[0088] Embodiment 15 of the present disclosure relates to a compound of embodiment 11, wherein: X is -S(O)-2- or -(CH2) n -C(O)-; Z is 1 to 3 R 8 is a C2-C4 alkyl optionally substituted by where n is 0 or 1).

[0089] Embodiment 16 of the present disclosure relates to a compound of embodiment 11, wherein: X is -S(O)-2- or -(CH2) n -C(O)-; Z is 1 to 3 R 10 C6 to C which may be substituted 12 is aryl; where n is 0 or 1).

[0090] Embodiment 17 of the present disclosure relates to a compound of embodiment 11, wherein: X is -S(O)-2- or -(CH2) n -C(O)-; Z is 1 to 3 R 10 is a 5-10 membered heteroaryl optionally substituted by where n is 0 or 1).

[0091] Embodiment 18 of the present disclosure relates to a compound having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (IIIa), (IIIb) or (IIIc), wherein G is Cl, F or CN; R 3 is H; halogen; C2-C4 alkenyl optionally substituted by cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted by C(O)-CH3; heterocycloalkenyl optionally substituted by C(O)-CH3; heterocycloalkylalkyl optionally substituted by C(O)-CH3; or 5-6 membered heteroaryl optionally substituted by haloalkyl, cyclopropyl, or cyclopropyl-CH2-; R 4 is H; C1-C3 alkyl; cycloalkyl optionally substituted by haloalkyl, or -C(O)-alkenyl; heterocycloalkyl optionally substituted by -C(O)-CH3, -C(O)-CH=CH2, or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted by -C(O)-CH3; -C(O)-CH2-OH; or 5-6 membered heteroaryl; X is -S(O)-2- or -(CH2) n -C(O)-; Z is -NR 6 R 7 , 1 to 3 R 8 C2-C4 alkyl optionally substituted by 1 to 3 R 10 C6 to C which may be substituted 12 Aryl or 1-3 R 10 is a 5-10 membered heteroaryl optionally substituted by; Or X is a bond and Z is CN, C(O)-NR 14 R 15 , -S(O)2-C1-C3 alkyl, or -SO-2-NR 14 R 15 is a 5-6 membered heteroaryl optionally substituted by R6 is hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being selected from 1 to 3 R 11 may be substituted by; R 7 is hydrogen or C1-C6 alkyl; or R 8 -NR 6 R 7 , CN, hydroxy, alkoxy, haloalkoxy, -S-C1-C3 alkyl, -S(O)2-C1-C3 alkyl, -S(O)2-C1-C3 haloalkyl, -S(O)2-NH2, -S(O)(NH)-C1-C3 alkyl, -C(O)-NH2, -C(O)OH, -C(O)O-C1-C3 alkyl, -C(O)C1-C3 haloalkyl, -N(H)-C(O)-NR 6 R 7 , -NR 12 R 13 or -N(H)-C(O)-C1-C3 alkyl optionally substituted by CN; -N(H)-C(O)-C2-C6 alkenyl, -N(H)-C(O)-C1-C3 haloalkyl, -N(H)-C(O)O-C1-C6 alkyl, -N(H)-C(NH)-NH2, -N(H)-S(O)2-NR 12 R 13 , -N(R 7 )-S(O)2-C1-C3 alkyl, -N(H)-S(O)2-C1-C3 haloalkyl, -P(O)(OH)2, -P(O)(C1-C6 alkyl)2, 1 to 3 R 10 or one to three R 10 or The Two R's 8 together with the carbon atoms to which they are attached, combine with each other to form a cycloalkyl; Each R 10are independently hydroxy, CN, C1-C6 alkyl, haloalkyl, -NH2, -C(O)-alkenyl, -C(O)-NH2, -C(O)O-alkyl, -NH-C(O)-alkenyl, -S(O)2-C1-C3 alkyl, -S(O)2-C2-C6 alkenyl, or -S(O)2-NH2; R 11 is CN; Each R 12 and R 13 are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 14 and R 15 are independently hydrogen or C1-C6 alkyl; where n is 0 or 1).

[0092] Embodiment 19 of the present disclosure relates to a compound of embodiment 18, wherein: X is -S(O)-2-, or -C(O)-; Z is -(CH2)2-S(O)2-CH3, or -CH2-N(H)-C(O)-NH2).

[0093] Embodiment 20 of the present disclosure relates to a compound of one of embodiments 11 or 18, wherein X is a bond and Z is CN, C(O)-NR 14 R 15 , -S(O)2-C1-C3 alkyl, or -SO-2-NR 14 R 15 each R 14 and R 15 are independently hydrogen or C1-C3 alkyl.

[0094] Embodiment 21 of the present disclosure relates to a compound of embodiment 1 having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf), wherein Each G is Cl, F, CN, and one to three R 5 independently selected from C1-C3 alkyl substituted by R 5 is a halogen).

[0095] Embodiment 22 of the present disclosure relates to a compound having one of the following formulas: [ka] or a pharma- ceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (Va), (Vb) or (Vc), wherein G is Cl, F or CN; R 3 is H; halogen; C2-C4 alkenyl optionally substituted by cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted by C(O)-CH3; heterocycloalkenyl optionally substituted by C(O)-CH3; heterocycloalkylalkyl optionally substituted by C(O)-CH3; or 5-6 membered heteroaryl optionally substituted by haloalkyl, cyclopropyl, or cyclopropyl-CH2-; R 4 is H; C1-C3 alkyl; cycloalkyl optionally substituted by haloalkyl, or -C(O)-alkenyl; heterocycloalkyl optionally substituted by -C(O)-CH3, -C(O)-CH=CH2, or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted by -C(O)-CH3; -C(O)-CH2-OH; or 5-6 membered heteroaryl; X is -S(O)-2- or -(CH2) n -C(O)-; Z is -NR6 R 7 , 1 to 3 R 8 C2-C4 alkyl optionally substituted by 1 to 3 R 10 C6 to C which may be substituted 12 Aryl or 1-3 R 10 is a 5-10 membered heteroaryl optionally substituted by; Or X is a bond and Z is CN, C(O)-NR 14 R 15 , -S(O)2-C1-C3 alkyl, or -SO-2-NR 14 R 15 is a 5-6 membered heteroaryl optionally substituted by R 6 is hydrogen, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being selected from 1 to 3 R 11 may be substituted by; R 7 is hydrogen or C1-C6 alkyl; or R 8 -NR 6 R 7 , CN, hydroxy, alkoxy, haloalkoxy, -S-C1-C3 alkyl, -S(O)2-C1-C3 alkyl, -S(O)2-C1-C3 haloalkyl, -S(O)2-NH2, -S(O)(NH)-C1-C3 alkyl, -C(O)-NH2, -C(O)OH, -C(O)O-C1-C3 alkyl, -C(O)C1-C3 haloalkyl, -N(H)-C(O)-NR 6 R 7 , -NR 12 R 13 or -N(H)-C(O)-C1-C3 alkyl optionally substituted by CN; -N(H)-C(O)-C2-C6 alkenyl, -N(H)-C(O)-C1-C3 haloalkyl, -N(H)-C(O)O-C1-C6 alkyl, -N(H)-C(NH)-NH2, -N(H)-S(O)2-NR 12R 13 , -N(R 7 )-S(O)2-C1-C3 alkyl, -N(H)-S(O)2-C1-C3 haloalkyl, -P(O)(OH)2, -P(O)(C1-C6 alkyl)2, 1 to 3 R 10 or one to three R 10 or The Two R's 8 together with the carbon atoms to which they are attached, combine with each other to form a cycloalkyl; Each R 10 are independently hydroxy, CN, C1-C6 alkyl, haloalkyl, -NH2, -C(O)-alkenyl, -C(O)-NH2, -C(O)O-alkyl, -NH-C(O)-alkenyl, -S(O)2-C1-C3 alkyl, -S(O)2-C2-C6 alkenyl, or -S(O)2-NH2; R 11 is CN; Each R 12 and R 13 are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 14 and R 15 are independently hydrogen or C1-C6 alkyl; where n is 0 or 1).

[0096] Embodiment 23 of the present disclosure relates to a compound according to any of the preceding embodiments, wherein the compound is a formate salt.

[0097] Embodiment 24 of the present disclosure relates to a compound selected from Table 1, or a pharma- ceutically acceptable salt thereof.

[0098] Embodiment 25 of the present disclosure relates to a compound selected from Table 1A, or a pharma- ceutically acceptable salt thereof.

[0099] Embodiment 26 of the present disclosure relates to a compound according to any of the preceding embodiments, wherein the compound is a non-covalent inhibitor of TEAD.

[0100] The compounds contemplated herein are described with reference to both general formulas and specific compounds.In addition, any of the 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.

[0101] It is understood that some compounds may show tautomerism.In such cases, the formula provided herein expressly shows only one of possible tautomeric forms.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 drawing of the formula.

[0102] 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 stereoisomeric forms are included in the formulas provided herein.

[0103] 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 generally understood by those skilled 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 multiple 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.

[0104] For compounds where 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.

[0105] 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.

[0106] Unless otherwise specified, the specification of a compound herein includes the pharma- ceutically acceptable salts of such compounds.

[0107] In some embodiments, the compounds of the present disclosure are complexed with acids or bases, for example, base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine, and the like; 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, or valine. In some instances, the amorphous form of the complex is promoted by additional processing such as spray drying, roller compaction of the parent compound mixed with acid or base, or mechanochemical methods such as microwave irradiation. Such methods may also include adding 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, lowering the melting temperature relative to the free base facilitates further processing such as hot melt extrusion, further improving the biopharmaceutical properties of the compound. Also, amorphous complexes are easily friable, which improves compression for filling the solid into capsule or tablet forms.

[0108] III. Formulation and Administration Embodiment 27 of the present disclosure relates to a pharmaceutical composition comprising a compound of any one of embodiments 1-26 and a pharma- ceutically acceptable carrier.

[0109] Embodiment 28 of the present disclosure relates to the pharmaceutical composition of embodiment 27, further comprising a second pharmaceutical agent.

[0110] Suitable dosage forms depend, in part, on the use or route of administration, e.g., oral, transdermal, transmucosal, inhalant, or injection (parenteral). Such dosage forms should enable 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 are generally described in Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005, which is incorporated herein by reference.

[0111] The compounds of the present disclosure (i.e., any of the compounds described in embodiments 1-26, including any of the subembodiments thereof) can be formulated as a pharma- ceutically acceptable salt.

[0112] Carrier or excipient can be used to produce the composition. Carrier or excipient can be selected to facilitate administration of compound. Examples of carrier include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, or starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol and types of physiologically compatible solvents. Examples of physiologically compatible solvents include sterile solution of water for injection (WFI), physiological saline, and dextrose.

[0113] Compounds can be administered by different routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal or inhalant.In some embodiments, compounds can be administered by oral administration.For example, when administered orally, compounds can be formulated into conventional oral dosage forms, such as capsules, tablets, and liquid preparations, such as syrups, elixirs and concentrated drops.

[0114] For inhalation, the compound 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 propylene glycol, sterilized water, ethanol, sodium chloride and other additives such as acid, alkali and buffer salt.Such solution or suspension can be administered by inhalation through spray, pump, atomizer or nebulizer. The compounds of the present disclosure may also be used in combination with other inhalation therapies, such as 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, such as single-stranded or double-stranded DNA or RNA, siRNA; antibiotics, such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.

[0115] Pharmaceutical preparations for oral use can be obtained, for example, by combining active compound with solid excipient, optionally grinding the mixture obtained, and processing the mixture of granules after adding suitable auxiliary agents if desired, to obtain tablets or dragee cores.Suitable excipients are in particular fillers such as 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 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.

[0116] 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, which may optionally contain suitable organic solvents or solvent mixtures, may be used.Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0117] 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 ingredient 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 compound 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.

[0118] Alternatively, injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal and / or subcutaneous, may be used.For injection, the compound of the present disclosure is formulated in a physiologically compatible buffer or solution, for example, sterile liquid solution such as physiological saline, Hank's solution or Ringer's solution.In addition, the compound may be formulated in solid form and redissolved or suspended immediately before use.Lyophilized forms may also be produced.

[0119] Administration can also be by transmucosal, topical, transdermal or inhalant means.For transmucosal, topical or transdermal administration, a penetrant suitable for 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, detergents can be used to promote permeation.Transmucosal administration can be, for example, by nasal spray or suppository (rectal or vaginal).

[0120] The topical compositions of the present disclosure are formulated as oils, creams, lotions, ointments, etc., 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, moisturizers 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. Dosage administration is, of course, continuous rather than intermittent throughout the entire administration regimen, in order to administer in the form of a transdermal delivery system.

[0121] The amount of various compounds administered was determined based on the IC 50The dosage may 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 per kg of the subject being treated, or 0.1 to 20 mg per kg. Multiple doses may be used.

[0122] The compounds of the present disclosure may 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, dosage can be modified by methods well known to those skilled in the art to reduce the dosage of one or more of the compounds of the present disclosure or other therapeutic agents used in combination, for example, compared to the compound or therapy used alone.

[0123] Combinations include use with other therapies, drugs, medical procedures, and the like, and it is understood that the other therapy or procedure 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 even longer (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) or simultaneously with the compounds of the present disclosure. Combinations also include use with therapies or medical procedures, e.g., surgery, administered once or infrequently, with the compounds of the present disclosure administered within a short or longer time before or after the other therapy or procedure. 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 or the same route of administration. Combinations for any route of administration include 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, e.g., a formulation that is chemically linked so that the two compounds 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. Co-administration includes co-formulations administered by the same or different routes, or administration of a formulation of chemically linked compounds, or administration of two or more compounds in separate formulations within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours). Co-administration of separate formulations includes co-administration by delivery via one device, e.g., the same inhalant device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulation of a compound of the present disclosure with one or more additional drug therapies delivered by the same route includes preparation of materials together so that they can be administered by one device, including separate compounds combined in one formulation, or compounds modified so that they are chemically linked but 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.

[0124] 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 multiple functions 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, which results in PKD, also results in downregulation of other genes required for proper microprojection 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.2015 Apr;21(4):212-222.).

[0125] Neurodegenerative diseases Hippo pathway components are involved in neurological diseases. For example, a study reported that YAP / TAZ mediates gene transcription induced by AβPP, a precursor of amyloid-β, which is believed to be a driver of Alzheimer's disease, implicating YAP as a potential therapeutic target for Alzheimer's disease (Steven W Plouffe et al., 2015).

[0126] Arrhythmogenic cardiomyopathy and Holt-Oram syndrome The Hippo pathway plays a role in cardiac disease. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular wall thinning, 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).

[0127] 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, in a liver-specific transgenic model, it was observed that inducing YAP overexpression 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).

[0128] epithelioid hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is a vascular tumor commonly found in the lung, bone, and skin. It has been observed that YAP / TAZ chromosomal translocations 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 for EHE (Steven W Plouffe et al., 2015).

[0129] Breast cancer In various human breast cancer subtypes, YAP / TAZ activity correlates with increased risk of metastasis and reduced survival. 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, in xenograft experiments, overexpression of YAP in breast cancer cell lines induced tumor formation and growth, and deletion of YAP prevented tumor growth in oncogene-induced breast cancer models, implicating YAP as a potential therapeutic target in breast cancer (Steven W Plouffe et al., 2015).

[0130] lung cancer In human non-small cell lung cancer (NSCLC), both YAP and TAZ are highly expressed. In mice, knockdown of either YAP or TAZ in NSCLC cells suppresses proliferation, invasion, and tumor growth. In lung cancer, high YAP expression correlates with advanced stage, lymph node metastasis, and poor survival. Furthermore, knockdown of either YAP or TAZ in lung cancer was shown to be sufficient to reduce cell migration in vitro and metastasis in vivo, implicating YAP as a potential therapeutic target in NSCLC (Steven W Plouffe et al., 2015).

[0131] 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 and YAP as a potential therapeutic target for malignant mesothelioma (Steven W Plouffe et al., 2015).

[0132] Pancreatic cancer Pancreatic ductal adenocarcinoma (PDAC) often has increased YAP expression, and increased YAP expression correlates with poor prognosis. Furthermore, it was observed that YAP knockdown results in decreased proliferation and decreased anchorage-independent growth in pancreatic cancer cells, suggesting that YAP may play an important role in PDAC progression. It was also reported that deleting YAP is sufficient to prevent PDAC in a mouse model expressing mutated KRAS (Steven W Plouffe et al., 2015).

[0133] Kaposi's Sarcoma In Kaposi's sarcoma (KS), YAP / TAZ plays a key role. 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 cannot 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).

[0134] Uveal melanoma 80% of uveal melanoma (UM) cases are characterized by activating mutations in either GNAQ or GNA11 (Gq / 11), which encode Gq or G11, respectively. Gq / 11 can activate YAP, and in mice, treatment of UM with verteporfin, a drug that blocks the YAP-TEAD interaction, has been shown to inhibit UM tumor growth (Steven W Plouffe et al., 2015).

[0135] Renal Cell Carcinoma YAP is involved in renal cell carcinoma (RCC). Recent reports have shown that YAP activity is increased in RCC, RCC tissues show elevated YAP levels, and knockdown of YAP in RCC cell lines inhibits cell proliferation and increases apoptosis (Steven W Plouffe et al., 2015).

[0136] Colorectal cancer It has been observed that YAP is often overexpressed in colorectal cancer (CRC), and YAP / TAZ activity correlates 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, these phenotypes were observed to be blocked by deletion of YAP, indicating that these pathologies are YAP-dependent. In addition, increased YAP protein levels were observed in human CRC liver metastases and correlated with CRC recurrence (Steven W Plouffe et al., 2015).

[0137] 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).

[0138] 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 YAP activation. Because NF2 inhibits YAP activity and loss-of-function mutations in NF2 increase YAP accumulation, loss of NF2, and subsequent tumor growth, may result from aberrant YAP activity. NF2 expression is also significantly decreased within the central nervous system in human malignant gliomas, and NF2 expression 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).

[0139] The methods and compounds are typically used to treat human subjects, although they may also be used to treat similar or identical indications in other animal subjects.

[0140] In certain embodiments, the patient is 60 years or older and has relapsed after first-line cancer therapy. In certain embodiments, the patient is 18 years or older and has relapsed or is refractory to 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 not suitable and / or unlikely to benefit from cancer therapy.

[0141] In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10mg per 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 2500mg 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.

[0142] In certain embodiments, provided herein is a method of treating a disease or condition mediated by YAP or TEAD by administering 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 per day of any of the compounds described in any of the embodiments 1-26, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof to a mammal having the disease or condition, wherein the compound is administered on an empty stomach.

[0143] Embodiment 29 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 1-26, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 27-28.

[0144] Embodiment 30 of the present disclosure relates to the method of embodiment 29, wherein the disease or condition is cancer, a neurodegenerative disease, a heart-related disorder, or a kidney-related disorder.

[0145] Embodiment 31 of the present disclosure relates to the method of embodiment 29, 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.

[0146] V. Combination Therapy YAP / TEAD modulators 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, the composition comprises any one or more compounds described herein 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, the composition comprises any one or more compounds described herein that are effective in treating cancer, and one or more other compounds that are effective in treating the same cancer, and further, the compounds are synergistically effective in treating cancer.

[0147] Embodiment 32 of the present disclosure relates to a method according to any one of embodiments 29-31, further comprising administering one or more additional therapeutic agents.

[0148] Embodiment 33 of the present disclosure is directed to a method for treating rheumatoid arthritis, comprising administering to the patient one or more of the following additional therapeutic agents: i) adozelin, altretamine, bizelin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, cis ... ii) an alkylating agent selected from platin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) azacitidine, capecitabine , cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) an immune checkpoint agent selected from PD-1 inhibitors, PD-L1 inhibitors and anti-CTLA4 inhibitors; v) a hormone or hormone antagonist selected from enzalutamide, abiraterone, anastrozole, androgen, 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) angiogenesis inhibitors 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) erlotinib, gefitinib, xii) kinase inhibitors selected from imatinib, 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-carboxyaldehyde thioacetate) Micarbazone, altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elescolomole, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase 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 CD39, CD38, A2AR and A2BR; or xxii) an agonist of a TNFA superfamily member; and xxiii) an anti-ErbB2 mAb.

[0149] In another embodiment, the present disclosure provides a method for treating cancer in a subject in need thereof by 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. The other therapies or medical procedures include suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, the one or more suitable anti-cancer therapies or medical procedures are selected from treatment with chemotherapeutic agents (e.g., chemotherapy drugs), radiation therapy (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle beams), hyperthermia heating (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 lutetium), surgery, or bone marrow and stem cell transplantation.

[0150] VI. Kit In another aspect, the present disclosure provides a kit comprising one or more compounds according to any one of embodiments 1-26, or a pharma- ceutically acceptable salt, deuterated analog, tautomer or stereoisomer thereof, or a pharmaceutical composition according to any one of embodiments 27-28. 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, for a disease or condition mediated by YAP / TEAD. The kits described herein may include instructions for use and / or other instructions that the compound or composition is suitable or approved for administration to a mammal, for example, a human, for a disease or condition mediated by YAP / TEAD. The compound or composition may be packaged in a unit dose or single dose form, for example, a single dose pill, capsule, etc.

[0151] VII. Binding Assays The method of the present disclosure can involve an assay that can detect the binding of a compound to a target molecule. Such binding is at a statistically significant level, with a confidence level of at least 90%, or at least 95, 97, 98, 99%, or more, that the assay signal represents binding to the target molecule, i.e., is distinguished from background. In some embodiments, a control is used to distinguish target binding from non-specific binding. A wide variety of assays that show binding are known for various target types and can be used in the present disclosure.

[0152] 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. 50or 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 increased compared 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.

[0153] "Background signal" in the context of a binding assay refers to the signal recorded under standard conditions for 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.

[0154] "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, which have a mean of 2, the variance is:

number

[0155] Surface plasmon resonance For example, surface plasmon resonance can be used to measure binding parameters using a BIAcore® chip (Biacore, Japan) coated with immobilized binding components. 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(R) analysis to test phosphopeptide-SH2 domain interactions,Methods in Molecular Biology.121:313-21;Liparoto et al.,(1999)Biosensor analysis of the interleukin-2 receptor complex,Journal of Molecular Recognition.12:316-21;Lipschultz et al. al.,(2000)Experimental design for analysis of complex kinetics using surface plasmon resonance,Methods.20(3):310-8;Malmqvist.,(1999)BIACORE:an affinity biosensor system for characterization of biomolecular interactions,Biochemical Society Transactions 27:335-40;Alfthan,(1998)Surface plasmon resonance biosensors as a tool in antibody engineering,Biosensors&Bioelectronics.13:653-63;Fivash et al.,(1998)BIAcore for macromolecular interaction,Current Opinion in Biotechnology.9:97-101;Price et al.;(1998)Summary report on the ISOBM TD-4 Workshop:analysis of 56 monoclonal antibodies against the MUC1 mucin.Tumour Biology 19 Suppl 1:1-20;Malmqvist et al,(1997)Biomolecular interaction analysis:affinity biosensor technologies for functional analysis of proteins,Current Opinion in Chemical Biology.1:378-83;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.236:275-83;Malmborg et al.,(1995)BIAcore as a tool in antibody engineering,Journal of Immunological Methods.183:7-13;Van Regenmortel,(1994)Use of biosensors to characterize recombinant proteins,Developments in Biological Standardization.83:143-51;および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.5:65-71.

[0156] BIAcore® uses the optical properties of surface plasmon resonance (SPR) to detect changes in protein concentration bound to a dextran matrix at the gold / glass sensor chip interface, a dextran biosensor matrix. Briefly, proteins are covalently bound to a dextran matrix at a known concentration, and a ligand for the protein is injected through the dextran matrix. Near-infrared light directed to the other side of the sensor chip surface is reflected, which 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 changes in surface protein concentration. These changes are displayed with respect to time along the y-axis of a sensorgram showing the association and dissociation of any biological reaction.

[0157] 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 assay thousands of different chemicals against each target molecule very rapidly, using robotic handling systems and automated analysis of the results.

[0158] 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.

[0159] To achieve high throughput screening, it is advantageous to accommodate samples on a multi-container carrier or platform. Multi-container carriers facilitate simultaneous measurement of the response of multiple candidate compounds. Multi-well microplates may be used as carriers. Such multi-well microplates and methods for using them in multiple assays are known in the art and commercially available.

[0160] Screening assays may include controls for calibration and confirmation of proper operation of the components of the assay. Blank wells containing all 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 comparative or control. It is understood that modulators can also be combined with enzyme activators or inhibitors to find modulators that inhibit enzyme activation or enzyme inhibition that would otherwise be caused by the presence of a known enzyme modulator.

[0161] Measurement of enzymatic and binding reactions during screening assays For example, techniques for measuring the progress of enzymatic and binding reactions within multi-container carriers are known in the art and include, but are not limited to, the following.

[0162] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxide, 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, Page 437.

[0163] Fluorescence spectroscopy may 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.

[0164] In spectrofluorimetry, 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, Amplex® Red reagent (Molecular Probes, Eugene, OR) can be used to detect SMase activity. 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 spectrofluorimetry.

[0165] Fluorescence polarization (FP) is based on the slowing of the molecular rotation rate of a fluorophore upon binding to a large 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 large polarized signal when bound to a large 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 depends on the maintenance of high affinity binding.

[0166] FP is a homogeneous technique and the reaction is extremely rapid, taking seconds to minutes to reach equilibrium. The reagents are stable and large batches may be prepared, resulting in high reproducibility. Because of these properties, FP has proven highly automatable and is often performed using 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, 17:27.

[0167] FP is particularly desirable because its 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. FP 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.

[0168] 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. U.S. 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.

[0169] Exemplary normal and polarized fluorescence readers include the POLARION® Fluorescence Polarization System (Tecan AG, Hombrechtikon, Switzerland). General 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).

[0170] 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 energy transfer between two fluorescent substances 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, for example, when the proteins specifically interact 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.).

[0171] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interaction 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 No. 4,626,513 and U.S. Patent No. 4,568,649 and European Patent No. 0154734. One commercially available system uses FLASHPLATE® scintillant-coated plates (NEN Life Science Products, Boston, MA).

[0172] Target molecules can be bound to scintillator plates by various well-known means. Scintillant plates are available that are derivatized to bind fusion proteins, such as GST, His6 or Flag fusion proteins. When target molecules are protein complexes or multimers, one protein or subunit can be attached to the plate first, and then other components of the complex can be added later under binding conditions to obtain bound complexes.

[0173] In a typical SPA assay, the gene products in the expression pool are radioactively labeled and added to the wells, where they are allowed to interact with the solid phase, which is the immobilized target molecule and the scintillant coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when the radioactive label is close enough 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.). When the radioactively labeled expression product binds to the target molecule, the radioactive label remains in close proximity to the scintillant long enough to generate a detectable signal.

[0174] In contrast, labeled proteins that do not bind to target molecules or bind only briefly do not remain near the scintillant long enough to generate a signal above background. Time spent near the scintillant caused by random Brownian motion also does not result in a significant amount of signal. Similarly, there may be residual unincorporated radiolabel used during the expression process, but it does not generate a significant signal because it is in solution rather than interacting with target molecules. 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. 257:112-119).

[0175] General Synthesis Compounds may 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 be used. The synthesis of typical compounds described herein may be accomplished as described in the following examples. When available, reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0176] 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 is understood that other process conditions can also be used unless otherwise stated. Although optimal reaction conditions may vary depending on the specific reactants or solvents used, such conditions can be determined by those skilled in the art by routine optimization procedures.

[0177] In addition, as will be apparent to those skilled in the art, conventional protective groups may be required to prevent certain functional groups from undergoing undesired reactions.Suitable protective 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, many protective groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein.

[0178] The compounds of the present disclosure may contain one or more asymmetric or chiral centers. Thus, if desired, such compounds may 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) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolving agents, and the like.

[0179] 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 Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0180] It is also understood that in each of the schemes, 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 enantiomerically pure or enriched compounds are 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.

[0181] Scheme 1 provides an exemplary synthetic route for synthesizing compounds provided herein (eg, compounds of Formula (Ia)). Scheme 1 [ka]

[0182] In Scheme 1, R 1 , R 2 , R 3 , R 4 , X and Z are as defined herein; PG, X a and X b is defined as follows:

[0183] In Scheme 1, compound Va-1 (wherein X a can be a leaving group suitable for cross-coupling reactions (e.g., halo, e.g., bromo, chloro, iodo), and PG can be a suitable amine protecting group (e.g., tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), which can be converted to compound Vb-1 under conditions known in the art. For example, compound Va-1 can be combined with bis(pinacolato)diboron under Miyaura boronation conditions including a coupling agent (e.g., Pd(dppf)Cl2, etc.) and a base (e.g., potassium acetate, triethylamine, etc.) in a suitable solvent (e.g., dioxane, etc.), followed by oxidation of the resulting boronic ester to compound Vb-1 under oxidation conditions including an oxidizing agent (e.g., hydrogen peroxide, etc.) and a base (e.g., sodium hydroxide, etc.).

[0184] The conversion of compound Vb-1 to compound Vd-1 can be achieved by standard coupling conditions. For example, compound Vb-1 can be reacted with compound Vc-1 in a suitable solvent (e.g., dichloromethane, etc.) under conditions known in the art, for example, under Chan-Lam coupling conditions including a catalyst (e.g., Cu(OAc)2, etc.) and a base (e.g., triethylamine, pyridine, etc.) to form compound Vd-1.

[0185] When PG is BOC, compound Ve-1 may be synthesized by deprotecting compound Vd under appropriate deprotection conditions, such as treatment with strong acid (e.g., TFA, HCl) in a suitable solvent (e.g., dichloromethane). Other protecting groups may be removed using standard deprotection conditions known to those skilled in the art.

[0186] Compound Ve-1 is then reacted with compound Vf-1 (wherein X b can be OH or LG) to provide a compound of formula I under standard conditions. For example, compound Vf-1 can be HO-(CH) n When the n is -C(O)-Z, standard conditions for the amide bond formation reaction between compound Ve-1 and compound Vf-1 may be used. These include, for example, a coupling agent (e.g., HATU, HBTU, EDC, DCC, etc.) for forming an amide bond, a base (e.g., diisopropylethylamine, triethylamine, pyridine, etc.), and a suitable solvent (e.g., a polar aprotic solvent such as DMF or pyridine). In another non-limiting example, compound Vf-1 is LG-(CH2) m When compound Ve-1 is -SO2-Z, where m is as defined herein and LG is a suitable leaving group (including but not limited to halo, e.g., chloro, bromo, and iodo), standard conditions for forming sulfonamide compounds of formula (Ia) from compound Ve-1 may be used. These include, for example, any coupling agent (e.g., HATU, etc.), a base (e.g., diisopropylethylamine, triethylamine, etc.) and a suitable solvent (e.g., a polar aprotic solvent such as DMF or dichloromethane). In another non-limiting example, compound Vf-1 is prepared by reacting compound X with X. b -Z(where X b When X is halo and Z is a 5-6 membered heteroaryl (i.e., X is a bond), standard conditions known in the art for palladium catalyzed couplings, including but not limited to Buchwald-type reactions, may be used to provide compounds of formula (Ia).

[0187] Optionally, compounds of formula (Ia) can be further derivatized with Z. For example, in the formation of a sulfonamide from a free amine on substituent Z, conditions for the formation of sulfonamide compounds of formula (Ia) include treatment with a sulfonyl halide (e.g., chloro, bromo, etc.), an optional coupling agent (e.g., HATU, etc.), a base (e.g., diisopropylethylamine, triethylamine), and a suitable solvent (e.g., a polar aprotic solvent such as DMF or dichloromethane).

[0188] Scheme 2 provides a further exemplary synthetic route for synthesizing compounds provided herein (eg, compounds of Formula (Ib)). Scheme 2 [ka]

[0189] In Scheme 2, R 1 , R 2 , R 3 , R 4 , X and Z are as defined herein; R, X b , X c and X d is defined as follows:

[0190] In Scheme 2, compound Vg can be converted to compound Vh (wherein X is an integer from 1 to 10) in a suitable solvent (e.g., a polar aprotic solvent, such as DMF, DMSO, acetonitrile, etc.) under conditions known in the art, such as Ullmann-type copper catalyzed nucleophilic aromatic substitution conditions, including a cuprous catalyst (e.g., CuI, etc.), a suitable ligand (e.g., dimethylglycine, etc.), and a base (e.g., cesium carbonate, potassium phosphate, etc.). c Compound Vg can be converted to compound Vi by reacting with a suitable halide (e.g., iodo, bromo, chloro) dmay be converted to a suitable metal catalyzed cross coupling partner (which may be, for example, a halo, such as chloro, bromo or iodo, or a pseudohalide, such as a triflate).

[0191] Compound Vi may be converted to compound Vk by reacting with compound Vj, where R can be hydrogen or two R together with the oxygen to which they are attached form a cyclic boronic ester, such as pinacol boronic ester. The reaction of compound Vi with compound Vj is carried out under conditions suitable for cross-coupling, such as conditions described herein or known in the art. Non-limiting examples of suitable cross-coupling conditions include a palladium catalyst (e.g., Pd(PPh3)2Cl2, Pd(PPh3)4, etc.), a base (e.g., sodium carbonate), and a suitable solvent (e.g., dioxane / water). Compound Vk may also be formed by using other suitable metal-catalyzed cross-coupling reactions between compound Vi and compound Vj, such as, but not limited to, Stille coupling (compound Vj contains an organostannane (e.g., tributyltin, triphenyltin, etc.) instead of a boronic acid or ester), Hiyama coupling (compound Vj contains an organosilane (e.g., trimethylsilane, triethylsilane, etc.) instead of a boronic acid or ester), and Negishi coupling (compound Vj contains a zinc halide (e.g., chloro, bromo, iodo) instead of a boronic acid or ester), with the respective coupling conditions well known to those skilled in the art.

[0192] Compound Vk may then be converted to compound Vl under catalytic hydrogenation conditions, such as under an atmosphere of hydrogen gas, a metal catalyst (eg, palladium on carbon, platinum on carbon, etc.) and a conventional solvent (eg, methanol, etc.).

[0193] Compound Vl is then reacted with compound Vf-1 (wherein X bcan be OH or LG) under standard conditions to provide a compound of formula Ib. For example, compound Vf-1 can be HO-(CH) n When compound Vl is -C(O)-Z (wherein n is as described herein), standard conditions for the amide bond formation reaction between compound Vl and compound Vf-1 may be used. These include, for example, a coupling agent (e.g., HATU, HBTU, EDC, DCC, etc.) for forming an amide bond, a base (e.g., diisopropylethylamine, triethylamine, pyridine, etc.), and a suitable solvent (e.g., a polar aprotic solvent such as DMF or pyridine). In another non-limiting example, compound Vf-1 is LG-(CH2) m When compound Vf-1 is -SO2-Z, where m is as defined herein and LG is a suitable leaving group (including but not limited to halo, e.g., chloro, bromo, and iodo), standard conditions for forming sulfonamide compounds of formula Ib from compound Vl may be used. These include, for example, any coupling agent (e.g., HATU, etc.), a base (e.g., diisopropylethylamine, triethylamine, etc.) and a suitable solvent (e.g., a polar aprotic solvent such as DMF or dichloromethane). In another non-limiting example, compound Vf-1 is prepared by reacting compound Vf-2 with X b -Z(where X b When X is halo and Z is a 5-6 membered heteroaryl (i.e., X is a bond), standard conditions known in the art for palladium catalyzed couplings, including but not limited to Buchwald-type reactions, may be used to provide compounds of formula I'.

[0194] Optionally, compounds of formula Ib can be further derivatized at Z, for example, as described herein for compounds of formula Ia.

[0195] Scheme 3 provides an exemplary synthetic route for synthesizing compounds provided herein (eg, compounds of Formula (Ic) and Formula (Id)). Scheme 3 [ka]

[0196] In Scheme 3, R 1 , R 2 , R 3 , R 4 , X and Z are as defined herein; PG and X a is defined as follows:

[0197] In Scheme 3, compound Vm (wherein X a can be a leaving group suitable for cross-coupling reactions (e.g., halo, e.g., bromo, chloro, iodo), and PG can be a suitable amine protecting group (e.g., tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.), which can be converted to compound Vn under conditions known in the art. For example, compound Vm can be combined with bis(pinacolato)diboron under Miyaura boronation conditions including a coupling agent (e.g., Pd(dppf)Cl2, etc.) and a base (e.g., potassium acetate, triethylamine, etc.) in a suitable solvent (e.g., dioxane, etc.), followed by oxidation of the resulting boronate ester to compound Vn under oxidation conditions including an oxidizing agent (e.g., hydrogen peroxide, etc.) and a base (e.g., sodium hydroxide, etc.). Derivatization of compound Vn to form compound Ic can be performed as described herein, including, but not limited to, Scheme 1.

[0198] Compounds Vm (wherein X is an integer from 1 to 3) can be prepared by cross-coupling with a suitable boronic ester or the like in the presence of a suitable palladium catalyst, via standard cross-coupling conditions, including but not limited to Suzuki coupling conditions (e.g., with a suitable boronic ester in the presence of a suitable palladium catalyst, etc.). a may be converted to compound Vo by a leaving group suitable for cross-coupling reactions (e.g., halo or triflate). Deprotection of compound Vo by methods described herein (including but not limited to, Scheme 1) and subsequent introduction of -XZ provides compound Id.

[0199] Scheme 4 provides a further exemplary synthetic route for synthesizing compounds provided herein (eg, compounds of Formula (Ie)). Scheme 4 [ka]

[0200] In Scheme 4, R 1 , R 2 , R 3 , R 4 , X and Z are as defined herein; PG and X a is defined as follows:

[0201] In Scheme 4, compound Vp (wherein X is an integer from 1 to 3) can be prepared via standard cross-coupling conditions, including but not limited to Suzuki coupling conditions (e.g., with a suitable boronic ester in the presence of a suitable palladium catalyst, etc.). a may be converted to compound Vq by a leaving group suitable for cross-coupling reactions (e.g., halo or triflate). Deprotection of compound Vq by methods described herein (including but not limited to, Scheme 1) and subsequent introduction of -XZ provides compound Ie.

[0202] Alternatively, -XZ can be introduced into the deprotected analog of compound Vp according to standard methods known in the art and / or described herein, followed by the addition of R according to standard methods known in the art and / or described herein. 1 By introducing the following, compound Ie can be obtained.

[0203] One of skill in the art will appreciate that in certain embodiments, any of compounds Va-1, Vb-1, Vc-1, Vd-1, Ve-1, Vf-1, Vg, Vh, Vi, Vj, Vk, Vl, Vm, Vn, Vo, Vp, or Vq may be available from a commercial supplier. Alternative syntheses of compounds Va-1, Vb-1, Vc-1, Vd-1, Ve-1, Vf-1, Vg, Vh, Vi, Vj, Vk, Vl, Vm, Vn, Vo, Vp, or Vq may be as described herein or known to one of skill in the art.

[0204] example 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. From the structure of the desired product, the necessary starting materials will generally be apparent to those skilled in the art.

[0205] Synthesis of intermediate 1 [ka]

[0206] Step 1: Preparation of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3'): [ka]

[0207] To a solution of tert-butyl 7-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (compound 1', 53 g, 169.76 mmol, 1 equiv.) in dioxane (500 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (compound 2', 64.66 g, 254.64 mmol, 1.5 equiv.), Pd(dppf)Cl2 (6.21 g, 8.49 mmol, 0.05 equiv.) and AcOK (49.98 g, 509.29 mmol, 3 equiv.). The mixture was stirred at 90° C. under N2 for 15 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL×2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 0-10 / 1) to give compound 3'. LC-MS (ESI): RT=1.50 min, C 20 H 30 Calculated mass for BNO4: 359.23 m / z, measured mass: 305.10 [M-56+H] + Method: The gradient was 30-100% B in 1.5 min, 100-100% B in 1.0 min, and 100-30% B in 0.01 min. (flow rate 0.3 mL / min). Mobile phase A was 0.01% CF3COOH in water, and mobile phase B was 0.01% CF3COOH in CH3CN. The column used for chromatography was a Chromolith Flash waters-BEH-C18 1.7um, 2.1 x 50 mm column. The detection method was diode array (waters-UPLC-PDA) and positive electrospray ionization (waters-SQD-MS). 1 H NMR(400 MHz,CDCl3)δ 1.32(s,12 H),1.46(s,9 H),2.83(s,2 H),3.62(s,2 H),4.56(s,2 H),7.12(d,J=7.46 Hz,1 H),7.51-7.60(m,2 H).

[0208] Step 2: Preparation of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (4'): [ka]

[0209] The reaction was carried out in three batches of compound 3': 63g / 71g / 71g, which were combined upon completion. NaOH (6M, 116.90mL, 5eq) was added dropwise to a solution of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (compound 3', 63g, 140.29mmol, 80% purity, 1eq) in DCM (600mL) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes and then treated portionwise with H2O2 (135.18g, 1.19mol, 114.56mL, 30% purity, 8.5eq) at 0°C under N2. The resulting mixture was stirred for 16 hours with gradual warming to room temperature. LC-MS showed the reaction was complete. The reaction was quenched with Na2S2O3 (600 mL). The mixture was stirred for 1 h and then the pH was adjusted to about 6. The mixture was then diluted with water (600 mL) and extracted with DCM (600 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue of the three batches was combined. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 0-4 / 1) to give compound 4'. LC-MS (ESI): RT=1.13 min, C 14 H 19 Calculated mass for NO3 is 249.14 m / z, measured mass is 195.2 [M-56+H] +Method: The gradient was 30-100% B in 1.5 min, 100-100% B in 1.0 min, and 100-30% B in 0.01 min. (flow rate 0.3 mL / min). Mobile phase A was 0.01% CF3COOH in water, and mobile phase B was 0.01% CF3COOH in CH3CN. The column used for chromatography was a Chromolith Flash waters-BEH-C18 1.7um, 2.1 x 50 mm column. The detection method was diode array (waters-UPLC-PDA) and positive electrospray ionization (waters-SQD-MS). 1 H NMR(400 MHz,CDCl3)δ 1.49(s,9 H),2.73(t,J=5.8 Hz,2 H),3.61(t,J=6.0 Hz,2 H),4.50(s,2 H),6.61-6.73(m,2 H),6.96(d,J=8.20 Hz,1 H).

[0210] Step 3: Preparation of tert-butyl 7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (6'): [ka]

[0211] To a solution of tert-butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (compound 4', 80 g, 320.89 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (compound 5', 79.84 g, 420.37 mmol, 1.31 equiv.), TEA (129.88 g, 1.28 mol, 178.66 mL, 4 equiv.) and 4A molecular sieves (80 g) in DCM (1000 mL) was added Cu(OAc)2 (17.49 g, 96.27 mmol, 0.3 equiv.). The mixture was purged with O2 for 5 min and then stirred at 40 °C under O2 for 16 h. LC-MS showed that a portion of compound 4' remained and the desired compound was detected. The mixture was filtered. The filtrate was diluted with water (1000 mL) and extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give crude compound 6'. The combined crude tert-butyl 7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate was recrystallized from PE:EA (10:1) to give compound 6'. LC-MS (ESI): RT = 1.60 min, C 21 H 22 Calculated mass for F3NO3: 393.16 m / z, measured mass: 337.80 [M-56+H] + Method: The gradient was 30-100% B in 1.5 min, 100-100% B in 1.0 min, and 100-30% B in 0.01 min. (flow rate 0.3 mL / min). Mobile phase A was 0.01% CF3COOH in water, and mobile phase B was 0.01% CF3COOH in CH3CN. The column used for chromatography was a Chromolith Flash waters-BEH-C18 1.7um, 2.1 x 50 mm column. The detection method was diode array (waters-UPLC-PDA) and positive electrospray ionization (waters-SQD-MS). 1H NMR(400 MHz,CDCl3)δ 1.49(s,9 H),2.83(t,J=5.44 Hz,2 H),3.66(t,J=5.20 Hz,2 H),4.55(s,2 H),6.77-6.90(m,2 H),7.02(d,J=8.6 Hz,2 H),7.15(d,J=8.2 Hz,1 H),7.56(d,J=8.68 Hz,2 H).

[0212] Step 4: Preparation of 7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate 1): [ka]

[0213] A mixture of tert-butyl 7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate (compound 6', 35 g, 88.97 mmol, 1 equiv.), HCl / dioxane (4 M, 111.21 mL, 5 equiv.) in DCM (400 mL) was stirred at 25° C. for 2 h. LC-MS showed the reaction was complete. The mixture was concentrated by evaporation under reduced pressure to give intermediate 1HCl, which was used in the next step without purification. LC-MS (ESI): RT=0.48 min, C 16 H 14 Calculated mass for F3NO: 293.10 m / z, measured mass: 295.5 [M+H] + Method: The gradient was 5-95% B in 5 min, 95-95% B in 1.0 min, and 95-5% B in 0.01 min (flow rate 1.0 mL / min). Mobile phase A was 0.01% CF3COOH in water, and mobile phase B was 0.01% CF3COOH in CH3CN. The column used for chromatography was a Chromolith Flash waters-BEH-C18 1.7um, 2.1 x 50 mm column. The detection method was diode array (waters-UPLC-PDA) and positive electrospray ionization (waters-SQD-MS).

[0214] Example 1 [ka]

[0215] Step 1: Preparation of 1-chloro-7-(4-(trifluoromethyl)phenoxy)isoquinoline, 3: In a 50 mL flask, 1-chloroisoquinolin-7-ol (1, 180 mg, 1 mmol), 1-iodo-4-(trifluoromethyl)benzene (2, 408.9 mg, 1.5 mmol), CuI (38 mg, 0.2 mmol), dimethylglycine (31 mg, 0.3 mmol) and Cs2CO3 (0.65 g, 2 mmol) were mixed, then DMSO (10 mL) was added. The resulting mixture was stirred at 120° C. and monitored by LC-MS. After 4 h, the reaction was cooled. The reaction mixture was then diluted with 30 mL of EtOAc and the organic layer was washed twice with 30 mL of water and then with 30 mL of brine. The combined organic layers were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography to give 1-chloro-7-(4-(trifluoromethyl)phenoxy)isoquinoline (3).

[0216] Step 2: Preparation of cyclopropyl(4-(7-(4-(trifluoromethyl)phenoxy)isoquinolin-1-yl)-3,6-dihydropyridin-1(2H)-yl)methanone, 5: In a 40 mL vial, 1-chloro-7-[4-(trifluoromethyl)phenoxy]isoquinoline (3, 60 mg, 0.19 mmol), cyclopropyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]methanone (4, 77.06 mg, 0.28 mmol), Na2CO3 (117.89 mg, 1.11 mmol) and Pd(PPh3)2Cl2 (13.01 mg, 0.02 mmol) were mixed. Dioxane (3 mL) and water (0.3 mL) were then added to the mixture. The mixture was then heated to 90° C. and the reaction was monitored by LC-MS. After 1 h, LC-MS showed complete consumption of starting material. The mixture was cooled and then flushed through a short silica gel pad containing 20% ​​MeOH in DCM. The concentrated filtrate was then purified by RP-HPLC (HO / MeCN) to give cyclopropyl(4-(7-(4-(trifluoromethyl)phenoxy)isoquinolin-1-yl)-3,6-dihydropyridin-1(2H)-yl)methanone (5).

[0217] Step 3: Preparation of cyclopropyl(4-(7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)piperidin-1-yl)methanone, 6: Cyclopropyl-[4-[7-[4-(trifluoromethyl)phenoxy]-1-isoquinolyl]-3,6-dihydro-2H-pyridin-1-yl]methanone (5, 70 mg, 0.16 mmol) was dissolved in MeOH (30 mL). The mixture was then hydrogenated at 40° C. and 20 bar using an H-Cube with a 10% Pd / C cartridge. The reaction was complete as confirmed by LC-MS. The reaction solution was then concentrated in vacuo to give cyclopropyl(4-(7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)piperidin-1-yl)methanone (6), which was used in the next step without further purification.

[0218] Step 4: Preparation of 1-(1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(methylsulfonyl)propan-1-one (P-0210): In a 10 mL vial, 3-methylsulfonylpropanoic acid (7, 48.61 mg, 0.32 mmol) and cyclopropyl-[4-[7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-piperidyl]methanone (6, 71 mg, 0.16 mmol) were dissolved in DMF (2 mL). To the mixture was then added DIPEA (0.08 mL, 0.48 mmol), followed by HATU (72.88 mg, 0.19 mmol). The reaction mixture was monitored by LC-MS. After about 30 min, LC-MS showed completion. The product was purified by RP-HPLC (HO / MeCN) to give 1-(1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(methylsulfonyl)propan-1-one (P-0210).

[0219] Example 2 [ka]

[0220] Step 1: Preparation of tert-butyl 3-(7-(4-(trifluoromethyl)phenoxy)isoquinolin-1-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate, 10: In a 40 mL vial, 1-chloro-7-[4-(trifluoromethyl)phenoxy]isoquinoline (3, 75 mg, 0.23 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (9, 102.59 mg, 0.35 mmol), Na2CO3 (147.36 mg, 1.39 mmol) and Pd(PPh3)2Cl2 (16.26 mg, 0.02 mmol) were mixed. Dioxane (3 mL) and water (0.3 mL) were then added to the mixture. The mixture was then heated to 90° C. and the reaction was monitored by LC-MS. After 1 h, LC-MS showed complete consumption of starting material. The mixture was cooled and then flushed through a short silica gel pad containing 20% ​​MeOH in DCM. The filtrate was then concentrated and purified by RP-HPLC (HO / MeCN) to give tert-butyl 3-(7-(4-(trifluoromethyl)phenoxy)isoquinolin-1-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10).

[0221] Step 2: Preparation of tert-butyl 3-(7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyrrolidine-1-carboxylate, 11: 85 mg of tert-butyl 3-[7-[4-(trifluoromethyl)phenoxy]-1-isoquinolyl]-2,5-dihydropyrrole-1-carboxylate (10) was dissolved in MeOH (30 mL). The solution was then hydrogenated at 40° C. and 20 bar using an H-Cube with a 10% Pd / C cartridge. The reaction was complete as confirmed by LC-MS. The reaction mixture was concentrated under vacuum to give tert-butyl 3-(7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyrrolidine-1-carboxylate (11), which was used in the next step without further purification.

[0222] Step 3: Preparation of tert-butyl 3-(2-(3-(methylsulfonyl)propanoyl)-7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyrrolidine-1-carboxylate, 12: In a 10 mL vial, 3-methylsulfonylpropanoic acid (7, 58 mg, 0.38 mmol) and tert-butyl 3-(7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyrrolidine-1-carboxylate (11, 86 mg, 0.19 mmol) were dissolved in DMF (2 mL). To the solution was then added DIPEA (0.1 mL, 0.56 mmol) followed by HATU (87 mg, 0.23 mmol). The reaction was monitored by LC-MS. After about 30 min, LC-MS showed completion. The title compound was purified by RP-HPLC (H2O / MeCN). The product is a mixture of two diastereomers.

[0223] Step 4: Preparation of 3-(methylsulfonyl)-1-(1-(pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one, 13: In a 10 mL vial, tert-butyl 3-[2-(3-methylsulfonylpropanoyl)-7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinolin-1-yl]pyrrolidine-1-carboxylate (12, 92.2 mg, 0.15 mmol) was dissolved in DCM (2 mL) and then TFA (0.2 mL, 2.6 mmol) was added. The resulting mixture was stirred at room temperature and monitored by LC-MS. After completion, the product was purified by RP-HPLC to give 3-(methylsulfonyl)-1-(1-(pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (13) as the TFA salt of a mixture of two diastereomers.

[0224] Step 5: Preparation of diastereomers 1 and 2 of 1-(3-(2-(3-(methylsulfonyl)propanoyl)-7-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (P-0217 and P-0218): To an ice-cold mixture of 3-methylsulfonyl-1-[1-pyrrolidin-3-yl-7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinolin-2-yl]propan-1-one TFA salt (13, 70 mg, 0.11 mmol) in anhydrous THF (2 mL) was slowly added acryloyl chloride (14, 0.02 mL, 0.23 mmol). After 5 min, additional acryloyl chloride (14, 0.01 mL, 0.11 mmol) was added, followed by DIPEA (0.06 mL, 0.34 mmol). The mixture was continued to stir at 0 °C for 10 min or upon completion as determined by monitoring by LC-MS. The mixture was concentrated, rediluted with DMF / water, and purified by RP-HPLC (0.1% HCOOH / MeCN, and 0.1% HCOOH / water, 0% to 80% gradient). Two diastereomers were collected as diastereomer 1 (P-0217, retention time 20.02 min) and diastereomer 2 (P-0218, retention time 20.98 min).

[0225] Example 3 [ka]

[0226] Preparation of 7-(3-fluoro-4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline HCl salt, intermediate 2: Follow the same synthetic route presented for the preparation of intermediate 1.

[0227] Step 1: Preparation of tert-butyl (2-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)carbamate, 18: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (17, 168.84 mg, 0.96 mmol) in DMF (4.8 mL) was added DIPEA (0.43 mL, 2.59 mmol), 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline (Intermediate 2, 300 mg, 0.96 mmol) and HATU (549.35 mg, 1.45 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with water and the resulting mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. Column purification gave tert-butyl N-[2-[7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxoethyl]carbamate (18).

[0228] Step 2: Preparation of 2-amino-1-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, 19: To a cooled (0° C.) solution of tert-butyl N-[2-[7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxoethyl]carbamate (18, 370 mg, 0.79 mmol) in DCM (3 mL) was slowly added a solution of 4 M HCl in dioxane (0.5 mL). After stirring at 25° C. for 1 h, the reaction mixture was concentrated in vacuo to give 2-amino-1-[7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinolin-2-yl]ethenon (19).

[0229] Step 3: Preparation of 1,1,1-trifluoro-N-(2-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)methanesulfonamide (P-0114): To a solution of 2-amino-1-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (19, 50 mg, 0.13 mmol) in DCM (2 mL) was added NEt3 (0.04 mL, 0.27 mmol). After cooling to -78 °C, trifluoromethanesulfonic anhydride (20, 0.02 mL, 0.13 mmol) was added dropwise with vigorous stirring. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was quenched by adding 1M HCl in H2O, and the resulting mixture was diluted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound (P-0114).

[0230] Example 4 [ka]

[0231] Step 1: Preparation of N-(4-cyanopyridin-3-yl)-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide (P-0064): To a solution of 3-aminopyridine-4-carbonitrile (22, 122 mg, 1.02 mmol, 2 equiv.), 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline (Intermediate 1, 150 mg, 455 μmol, 0.9 equiv., as HCl salt) and DIPEA (198 mg, 1.53 mmol, 267 μL, 3 equiv.) in THF (10 mL) was added triphosgene (290 mg, 977 μmol, 1.91 equiv.) in one portion at 0° C. After addition, the mixture was stirred at 25° C. for 16 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and H2O (10 mL). The organic phase was separated, washed with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC using a Welch Xtimate C18 150 x 30 mm x 5 μm (eluent: 53%-83% (v / v) CH3CN and H2O with 0.225% HCOOH) to give N-(4-cyano-3-pyridyl)-7-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carboxamide (P-0064).

[0232] Example 5 [ka]

[0233] Step 1: Preparation of N-ethyl-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (P-0017): To a mixture of ethylsulfamoyl chloride (24, 87 mg, 607 μmol) in DCM (1 mL), EtN (169 μL, 1.21 mmol) and a solution of 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline (Intermediate 1, 200 mg, 607 μmol, as HCl salt) in DCM (1 mL) were added in one portion at 0° C. under N2. The mixture was stirred at 0° C. for 1 h. LCMS showed the reaction was complete. The mixture was poured into water (2 mL). The aqueous phase was extracted with DCM (5 mL). The combined organic phase was washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC using Kromasil 150×30 mm×5 μm (eluent: 60%-100% (v / v) CH3CN and HO with 0.1% HCOOH) to give N-ethyl-7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)sulfonamide (P-0017).

[0234] Example 6 [ka]

[0235] Step 1: Preparation of 1-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-methylpiperazin-1-yl)propan-1-one (P-0095): To a solution of 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline HCl salt (Intermediate 2, 0.16 g, 0.46 mmol) in NMP (5.0 mL) was added 3-(4-methylpiperazin-1-yl)propanoic acid (26, 0.12 g, 0.7 mmol), HATU (0.35 g, 0.92 mmol) and DIPEA (0.4 mL, 2.3 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. Upon completion, the reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by reverse-phase C18 column chromatography eluting with 10% to 100% acetonitrile in water containing 0.1% formic acid to give the title product (P-0095).

[0236] Example 7 [ka]

[0237] Step 1: Preparation of tert-butyl 3-(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)azetidine-1-carboxylate, 29: To a stirred solution of 7-[3-fluoro-4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline HCl salt (Intermediate 2, 0.35 g, 1 mmol) in DMF (10 mL) at 0° C. was added 1-tert-butoxycarbonylazetidine-3-carboxylic acid (28, 0.25 g, 1.25 mmol), HATU (0.46 g, 1.2 mmol) and DIPEA (0.7 mL, 3.99 mmol) sequentially. The resulting mixture was stirred for 5 min, then the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 h. LCMS showed complete consumption of starting material and formation of product. The reaction was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in a rotovap, and purified by flash column chromatography (40 g silica gel column, 0-100% ethyl acetate in hexanes gradient in 18 min). The desired fractions were concentrated and dried to give the title compound (29).

[0238] Step 2: Preparation of azetidin-3-yl(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone, 30: To a stirred solution of tert-butyl 3-[7-[3-fluoro-4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinoline-2-carbonyl]azetidine-1-carboxylate (29, 0.25 g, 0.5 mmol) in methanol (5 mL) at 25° C. was added 4 M HCl (0.5 mL in dioxane). The mixture was stirred overnight. LCMS showed complete consumption of starting material and formation of product. The mixture was concentrated in a rotovap and dried under vacuum to give azetidin-3-yl(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone HCl salt (30).

[0239] Step 3: Preparation of (7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(vinylsulfonyl)azetidin-3-yl)methanone (P-0157): To a stirred solution of azetidin-3-yl(7-(3-fluoro-4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)methanone HCl salt (30, 0.05 g, 0.12 mmol) in DCM (5 mL) at 0° C. was added ethenesulfonyl chloride (31, 0.03 g, 0.24 mmol). The mixture was stirred for 5 min, then DIPEA (0.04 mL, 0.24 mmol) was added and the mixture was continued to stir for another 30 min. The cooling bath was removed and the mixture was continued to stir for another 2 h. LCMS showed complete consumption of the starting amine and formation of the product. The reaction was concentrated in a rotovap and purified by reverse-phase flash column chromatography (26 g, C18 column, 10-100% acetonitrile (with 0.1% formic acid) in water (with 0.1% formic acid) gradient in 18 min). The desired fractions were concentrated and lyophilized to give the title product (P-0157).

[0240] Example 8 [ka]

[0241] Step 1: Preparation of 3-(methylsulfonyl)-1-(7-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (P-0018): To a mixture of 7-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline HCl salt (Intermediate 1, 0.20 g, 0.61 mmol), 3-methylsulfonylpropanoic acid (7, 0.12 g, 0.79 mmol) and HATU (0.46 g, 1.21 mmol) in THF (5.0 mL), triethylamine (0.34 mL, 2.43 mmol) was added. The reaction was stirred at room temperature for 3.5 h. LCMS indicated completion of the reaction. The reaction mixture was diluted with saturated NH4Cl, extracted with EtOAc (2 x 10 mL), concentrated onto Celite, and purified by ISCO, silica gel 12 g column, eluting with 0-50% EtOAc / Hexane to give the desired product (P-0018).

[0242] Example 9 [ka]

[0243] Step 1: Preparation of tert-butyl 5-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 34: To a dry 100 mL heavy-walled pressure vessel containing a dried egg stir bar was added tert-butyl 5-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (32, 1.5 g, 6.0 mmol), 1-iodo-4-(trifluoromethyl)benzene (33, 2.5 g, 9.0 mmol), N,N-dimethylglycine (372 mg, 3.6 mmol), cuprous iodide (229 mg, 1.2 mmol), cesium carbonate (3.9 g, 12.0 mmol) and DMSO (30 mL). The reaction was placed under N2, sealed and heated to 130 °C for 4 h. LCMS analysis indicated product formation along with some by-product. The reaction was then added to 5.3 M NH4Cl (500 mL) and extracted with EtOAc (3 x 150 mL). The organic fraction was washed with H2O (2 x 100 mL) and 5 M NaCl (1 x 100 mL), dried over Na2SO4, filtered, evaporated, and purified by normal phase flash column chromatography (40 g SiO2, 0-50% EtOAc, hexanes) to give the desired product.

[0244] Step 2: Preparation of 5-(4-(trifluoromethyl)phenoxy)-1,2,3,4-tetrahydroisoquinoline, 35: 1.3 g of tert-butyl 5-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (34) was dissolved in 10 mL of DCM and 10 mL of 4 M HCl in dioxane was added. The mixture was stirred at room temperature for 90 min. LCMS showed complete conversion to the product. The reaction was concentrated to give the material (as the HCl salt) which was used in the subsequent reaction.

[0245] Step 3: Preparation of 4-oxo-4-(5-(4-(trifluoromethyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanenitrile (P-0239): To a dry 100 mL single neck round bottom flask containing a dried pea stir bar was added 5-[4-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydroisoquinoline hydrochloride (35, 50 mg, 0.152 mmol) and DMF (1 mL). The reaction was stirred at room temperature then DIEA (100 uL, 0.58 mmol) was added followed by 3-cyanopropanoic acid (36, 23 mg, 0.23 mmol) and HATU (81 mg, 0.23 mmol). The reaction was stirred at room temperature for 30 min. LCMS showed conversion to the desired product with some starting material. The reaction was directly purified by reverse phase chromatography (50 g C18 column, 0-100% MeCN in water with 0.1% formic acid). Purification afforded 4-oxo-4-[5-[4-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isoquinolin-2-yl]butanenitrile (P-0239).

[0246] Example 10 [ka]

[0247] Step 1: Preparation of tert-butyl 5-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 39: To a mixture of tert-butyl 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate (37, 2000 mg, 6.41 mmol), [4-(trifluoromethyl)phenyl]boronic acid (38, 1825.02 mg, 9.61 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.52 ml, 0.64 mmol) in dioxane (60 ml) was added 2.5 M aqueous K2CO3 (7.69 ml). The resulting mixture was stirred at 90°C for 2 hours or upon completion and monitored by LC-MS. The mixture was diluted with ethyl acetate, which was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated. The sample was purified by normal phase chromatography eluting with 10-20% ethyl acetate in hexanes to give tert-butyl 5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (39).

[0248] Step 2: Preparation of 5-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline, 40: To a mixture of tert-butyl 5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (39, 2400 mg, 6.36 mmol) in dioxane (6 ml) was added 4M HCl in dioxane (15.9 ml). The mixture was stirred at room temperature for 2 hours or upon completion. The mixture was concentrated and zeotroped with toluene (x2) to give 5-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline HCl salt (40), which was used in the next step without purification.

[0249] Step 3: Preparation of 4-oxo-4-(5-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)butanenitrile (P-0273): To a mixture of 3-cyanopropanoic acid (36, 24.63 mg, 0.25 mmol) and HATU (87.26 mg, 0.23 mmol) in DMF (2 mL) was added 5-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline HCl salt (40, 60 mg, 0.19 mmol) followed by DIEA (0.1 ml, 0.57 mmol). The mixture was stirred at room temperature for 5 min or upon completion and monitored by LC-MS. The mixture was concentrated, rediluted with DMF / water and purified by preparative HPLC (0.1% HCOOH / MeCN, and 0.1% HCOOH / water). The fractions were collected, reduced, and dried overnight by lyophilization to give 4-oxo-4-[5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanenitrile (P-0273).

[0250] Example 11 [ka]

[0251] Step 1: Preparation of 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-3-(methylsulfonyl)propan-1-one, 43: To 7-bromo-1,2,3,4-tetrahydroisoquinoline (41, 2 g, 9.43 mmol) was added 3-methylsulfonylpropanoic acid (42, 1.5 g, 9.86 mmol), HATU (7 g, 18.41 mmol) and N-ethyl-N-isopropyl-propan-2-amine (5 ml, 28.71 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by reverse phase C18 column chromatography eluting with 10%-100% acetonitrile in water containing 0.1% formic acid to give the product.

[0252] Step 2: Preparation of 3-(methylsulfonyl)-1-(7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)propan-1-one (P-0277): In a 40 mL vial, 1-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-3-methylsulfonyl-propan-1-one (43, 52 mg, 0.15 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (44, 33.98 mg, 0.17 mmol), Na2CO3 (77 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.02 mmol) were combined, to which dioxane (3 ml) and water (0.3 ml) were added. The mixture was heated to 90° C. and monitored by LC-MS. After 1 h, LC-MS showed complete consumption of starting material. The reaction mixture was cooled and flushed through a short silica gel pad containing 20% ​​MeOH in DCM. The filtrate was concentrated and purified by RP-HPLC (H2O / MeCN) to give the desired product.

[0253] All of the compounds in Table 1 and Table 1A listed below can be made 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

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

[0254] Also provided are the compounds of Table 1A listed below. [Table 3-1] [Table 3-2]

[0255] Biological examples Biological Test Methods Determine inhibitor activity against TEAD-dependent transcription in a cell-based reporter assay Lipofectamine transfection reagent (Thermo Fisher) was used to transfect the luciferase reporter gene 1The human mesothelioma cell line MSTO-211H was stably transfected with the pGL4.21 plasmid, which contains 12 copies of a synthetic promoter with a GTIIC TEAD response element driving expression of GTIIC. Transfected cells were selected using puromycin, and single cell clones expressing this construct (termed MSTO-211H+12XGTIIC) were generated by limiting dilution. MSTO-211H cells express the Hippo pathway, which leads to upregulation of YAP / TEAD-mediated transcription. 2 We characterized genetic alterations in key components of TEAD expression. Stable expression of the 12XGTIIC reporter construct in MSTO-211H cells resulted in constitutive luciferase expression. Treatment of these cells with inhibitors targeting TEAD reduced luciferase expression. To evaluate TEAD inhibitors, the MSTO-211H+12XGTIIC cell line was cultured in 50 μL of culture medium at 1 × 10 cells / well in 96-well plates. 4 Cells / well were seeded and incubated overnight at 37° C. Serial dilutions of compounds (in a total volume of 50 μL of culture medium) were added to the cells and incubated for 24 hours at 37° C. Each plate also contained cells treated with DMSO as a high control and 20 μM of the reference compound K-975 (a known TEAD inhibitor) as a low control. 3 Cell viability was assayed by adding 25 μL of CellTiter-Fluor reagent (Promega) followed by incubation at 37°C for 30 minutes and quantifying the fluorescent signal (Ex400 / Em505). Luciferase expression was then assayed by adding 25 μL of ONE-Glo reagent (Promega) followed by incubation at room temperature for 10 minutes and quantifying the luminescent signal. The luminescent signal was normalized to the fluorescent signal to correct for any loss of cell viability over the 24-hour compound incubation period. Percent inhibition of normalized luminescent signal was calculated, indicating compound-mediated inhibition of TEAD-dependent transcription at individual compound concentrations compared to high and low controls. Data was analyzed using nonlinear regression to determine the IC of individual compounds. 50 Generated a value. References

number

[0256] Table 2 below provides data showing the biochemical and / or cell inhibitory activity of exemplary compounds described herein in Table 1. In Table 2 below, activity is provided as follows: +++=0.001 μM <IC 50 <10 μM;++=10 μM <IC 50 <100 μM, +=IC 50 >100 μM. The absence of data in Table 2 indicates that the data is not available and is not an indication of activity. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0257] 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.

[0258] 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 that are encompassed within the spirit of the disclosure as defined by the scope of the claims.

[0259] 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, changes can be made to provide additional compounds of the present disclosure and / or various administration methods can be used.Therefore, such additional embodiments are within the scope of the present disclosure and the appended claims.

[0260] The present disclosure illustratively described herein may be suitably implemented without any element or elements, or limitations not specifically described herein. The terms and expressions used are used as terms of description, not of limitation, and when using such terms and expressions, it is not intended to exclude the features shown and described or equivalents of some of them, but it is recognized that various modifications are possible within the scope of the present disclosure as 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.

[0261] Additionally, 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 also described with respect to any individual members or subgroups of members of the group described herein.

[0262] Also, unless indicated to the contrary, when various numerical values ​​are provided for an embodiment, additional embodiments are described by taking any two different values ​​as the endpoints of a range, and such ranges are also within the scope of the present disclosure.

[0263] Accordingly, additional embodiments are within the scope of this disclosure and the following claims.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y １ Ga-Q-R １ and Y ２ is R ２ or Y １ is R ２ and Y ２ Ga-Q-R １ and Q is a bond or —O—; R １ is phenyl substituted with 0-4 G groups; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted by one or more R ５ independently selected from alkoxy optionally substituted by Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted by 1 to 3 halogens; １ ~C ３ alkyl, provided that not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted by cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted by —C(O)-alkyl; heterocycloalkenyl optionally substituted by C(O)-alkyl; heterocycloalkylalkyl optionally substituted by C(O)-alkyl; or heteroaryl optionally substituted by haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted by haloalkyl, or —C(O)-alkenyl; heterocycloalkyl optionally substituted by —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ -OH, or heterocycloalkylalkyl optionally substituted by heteroaryl; R ５ is halogen or OH; X is -(CH ２ ) ｍ -S(O) ２ -, -(CH ２ ) ｎ -C(O)- or -C(O)O-, where the right side indicates the point of attachment to Z; Z is -NR ６ R ７ , 1 to 4 R ８ C optionally substituted by １ ~C ６ Alkyl, —C(CH ３ ) = CH ２ , -CH ２ -CH=C=O, 1 to 4 R ９ cycloalkyl optionally substituted by 1 to 4 R １０ heterocycloalkyl optionally substituted by 1 to 4 R １０ or aryl optionally substituted by 1 to 4 R １０ or heteroaryl optionally substituted by Or X-Z is -C(=NR ７ ) ２ -NR ６ R ７ Is it; Or X is a bond and Z is CN, —C(O)—NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl or -SO ２ -NR １４ R １５ is a 5-6 membered heteroaryl optionally substituted by R ６ is hydrogen, -S(O) ２ -C １ ~C ３ Alkyl, C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is 1 to 3 R １１ may be substituted by R ７ is hydrogen or C １ ~C ６ is alkyl; or R ６ and R ７ together with the nitrogen to which they are attached form a heterocycloalkyl; R ８ But, -NR ６ R ７ , CN, hydroxy, alkoxy, haloalkoxy, -S-C １ ~C ３ Alkyl, —S(O)—C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Haloalkyl, —S(O) ２ -NH ２ , -S(O)(NH)-C １ ~C ３ Alkyl, —C(O)—NH ２ , -C(O)OH, -C(O)OC １ ~C ３ Alkyl, —C(O)C １ ~C ３ Haloalkyl, —N(H)—C(O)—NR ６ R ７ , -NR １２ R １３ or —N(H)—C(O)—C optionally substituted by CN １ ~C ３ Alkyl, —N(H)—C(O)—C ２ ~C ６ Alkenyl, —N(H)—C(O)—C １ ~C ３ Haloalkyl, —N(H)—C(O)O—C １ ~C ６ Alkyl, —N(H)—C(NH)—NH ２ , -N(H)-S(O) ２ -NR １２ R １３ , -N(R ７ )-S(O) ２ -C １ ~C ３ Alkyl, —N(R ７ )-S(O) ２ -cycloalkyl, -N(H)-S(O) ２ -C １ ~C ３ Haloalkyl, —P(O)(OH) ２ , -P(O)(C １ ~C ６ alkyl) ２ , 1 to 3 R １０ cycloalkyl optionally substituted by one to three R １０ or one to three R １０ or is heteroaryl optionally substituted by Two R's ８ together with the carbon atoms to which they are attached, combine to form a cycloalkyl; Each R ９ are independently CN, -S(O) ２ -C １ ~C ３ Alkyl, or -N(C １～３ alkyl) ２ and Each R １０ are independently hydroxy, CN, C １ ~C ６ Alkyl, haloalkyl, -NH ２ , —C(O)-alkenyl, —C(O)—NH ２ , —C(O)O-alkyl, —NH—C(O)-alkenyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C ２ ~C ６ alkenyl, or —S(O) ２ -NH ２ and Each R １１ are independently hydroxy, CN, alkoxy, —S(O) ２ -C １ ~C ３ alkyl, or cycloalkyl; Each R １２ and R １３ are independently hydrogen, C １ ~C ６ Alkyl or C ３ ~C ６ is cycloalkyl; Each R １４ and R １５ are independently hydrogen or C １ ~C ６ is alkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; however: Z is -C(CH ３ ) = CH ２ when X is —C(O)O—, or n is 1 or 2, or m is 1, 2, or 3; X-Z is -C(O)-C １ When R is alkyl, ８ cannot be CN, hydroxy, alkoxy or haloalkoxy; When X is —C(O)—, then Z cannot be oxiranyl; X is -C(O)- or -S(O) ２ - and Z is one R ９ is a cycloalkyl substituted by R ９ If is CN, then R ９ cannot be attached to the same ring atom of Z as the atom to which X is attached; X is -C(O)- or -S(O) ２ - and Z is one R １０ and R is a heterocycloalkyl substituted by １０ When R is hydroxy or CN, １０ cannot be attached to the same ring atom of Z as the atom to which X is attached; X is -C(O)- or -S(O) ２ - and when Z is a partially saturated cycloalkyl or a partially saturated heterocycloalkyl, the point of saturation of Z cannot be adjacent to X).

2. Compounds of formula (Ia): 【Chemistry 2】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: R １ is phenyl substituted with 0-4 G groups; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted by one or more R ５ independently selected from alkoxy optionally substituted by Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted by 1 to 3 halogens; １ ~C ３ alkyl, provided that not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted by cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted by —C(O)-alkyl; heterocycloalkenyl optionally substituted by C(O)-alkyl; heterocycloalkylalkyl optionally substituted by C(O)-alkyl; or heteroaryl optionally substituted by haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted by haloalkyl, or —C(O)-alkenyl; heterocycloalkyl optionally substituted by —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ -OH, or heterocycloalkylalkyl optionally substituted by heteroaryl; R ５ is halogen or OH; X is -(CH ２ ) ｍ -S(O) ２ -, -(CH ２ ) ｎ -C(O)- or -C(O)O-, where the right side indicates the point of attachment to Z; Z is -NR ６ R ７ , 1 to 4 R ８ C optionally substituted by １ ~C ６ Alkyl, —C(CH ３ ) = CH ２ , -CH ２ -CH=C=O, 1 to 4 R ９ cycloalkyl optionally substituted by 1 to 4 R １０ heterocycloalkyl optionally substituted by 1 to 4 R １０ or aryl optionally substituted by 1 to 4 R １０ or heteroaryl optionally substituted by Or X-Z is -C(=NR ７ ) ２ -NR ６ R ７ Is it; Or X is a bond and Z is CN, —C(O)—NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl or -SO ２ -NR １４ R １５ is a 5-6 membered heteroaryl optionally substituted by R ６ But hydrogen, C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is 1 to 3 R １１ may be substituted by R ７ is hydrogen or C １ ~C ６ is alkyl; or R ６ and R ７ together with the nitrogen to which they are attached form a heterocycloalkyl; R ８ But, -NR ６ R ７ , CN, hydroxy, alkoxy, haloalkoxy, -S-C １ ~C ３ Alkyl, —S(O)—C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Haloalkyl, —S(O) ２ -NH ２ , -S(O)(NH)-C １ ~C ３ Alkyl, —C(O)—NH ２ , -C(O)OH, -C(O)OC １ ~C ３ Alkyl, —C(O)C １ ~C ３ Haloalkyl, —N(H)—C(O)—NR ６ R ７ , -NR １２ R １３ or —N(H)—C(O)—C optionally substituted by CN １ ~C ３ Alkyl, —N(H)—C(O)—C ２ ~C ６ Alkenyl, —N(H)—C(O)—C １ ~C ３ Haloalkyl, —N(H)—C(O)O—C １ ~C ６ Alkyl, —N(H)—C(NH)—NH ２ , -N(H)-S(O) ２ -NR １２ R １３ , -N(R ７ )-S(O) ２ -C １ ~C ３ Alkyl, —N(R ７ )-S(O) ２ -cycloalkyl, -N(H)-S(O) ２ -C １ ~C ３ Haloalkyl, —P(O)(OH) ２ , -P(O)(C １ ~C ６ alkyl) ２ , 1 to 3 R １０ cycloalkyl optionally substituted by one to three R １０ or one to three R １０ or is heteroaryl optionally substituted by Two R's ８ together with the carbon atoms to which they are attached, combine to form a cycloalkyl; Each R ９ are independently CN, -S(O) ２ -C １ ~C ３ Alkyl, or -N(C １～３ alkyl) ２ and Each R １０ are independently hydroxy, CN, C １ ~C ６ Alkyl, haloalkyl, -NH ２ , —C(O)-alkenyl, —C(O)—NH ２ , —C(O)O-alkyl, —NH—C(O)-alkenyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C ２ ~C ６ alkenyl, or —S(O) ２ -NH ２ and R １１ is CN; Each R １２ and R １３ are independently hydrogen, C １ ~C ６ Alkyl or C ３ ~C ６ is cycloalkyl; Each R １４ and R １５ are independently hydrogen or C １ ~C ６ is alkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; however: Z is -C(CH ３ ) = CH ２ when X is —C(O)O—, or n is 1 or 2, or m is 1, 2, or 3; X-Z is -C(O)-C- １ When R is alkyl, ８ cannot be CN, hydroxy, alkoxy or haloalkoxy; When X is —C(O)—, then Z cannot be oxiranyl; X is -C(O)- or -S(O) ２ - and Z is one R ９ is a cycloalkyl substituted by R ９ If is CN, then R ９ cannot be attached to the same ring atom of Z as the atom to which X is attached; X is -C(O)- or -S(O) ２ - and Z is one R １０ and R is a heterocycloalkyl substituted by １０ When R is hydroxy or CN, １０ cannot be attached to the same ring atom of Z as the atom to which X is attached; X is -C(O)- or -S(O) ２ - and when Z is a partially saturated cycloalkyl or a partially saturated heterocycloalkyl, the point of saturation of Z cannot be adjacent to X).

3. R １ is phenyl substituted with 0-4 G groups; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted by one or more R ５ independently selected from alkoxy optionally substituted by Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted by 1 to 3 halogens; １ ~C ３ alkyl, provided that not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted by cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted by —C(O)-alkyl; heterocycloalkenyl optionally substituted by C(O)-alkyl; heterocycloalkylalkyl optionally substituted by C(O)-alkyl; or heteroaryl optionally substituted by haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted by haloalkyl, or —C(O)-alkenyl; heterocycloalkyl optionally substituted by —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ -OH, or heterocycloalkylalkyl optionally substituted by heteroaryl; R ５ is halogen or OH; X is -(CH ２ ) ｍ -S(O) ２ -, -(CH ２ ) ｎ -C(O)- or -C(O)O-, where the right side indicates the point of attachment to Z; Z is -NR ６ R ７ , 1 to 4 R ８ C optionally substituted by １ ~C ６ Alkyl, —CH ２ -CH=C=O, 1 to 4 R １０ or aryl optionally substituted by 1 to 4 R １０ or heteroaryl optionally substituted by Or X-Z is -C(=NR ７ ) ２ -NR ６ R ７ Is it; Or X is a bond and Z is CN, —C(O)—NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl or -SO －２ -NR １４ R １５ is a 5-6 membered heteroaryl optionally substituted by R ６ But hydrogen, C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is 1 to 3 R １１ may be substituted by R ７ is hydrogen or C １ ~C ６ is alkyl; or R ６ and R ７ together with the nitrogen to which they are attached form a heterocycloalkyl; R ８ But, -NR ６ R ７ , -SC １ ~C ３ Alkyl, —S(O)—C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Haloalkyl, —S(O) ２ -NH ２ , -S(O)(NH)-C １ ~C ３ Alkyl, —C(O)—NH ２ , -C(O)OH, -C(O)OC １ ~C ３ Alkyl, —C(O)C １ ~C ３ Haloalkyl, —N(H)—C(O)—NR ６ R ７ , -NR １２ R １３ or —N(H)—C(O)—C optionally substituted by CN １ ~C ３ Alkyl, —N(H)—C(O)—C ２ ~C ６ Alkenyl, —N(H)—C(O)—C １ ~C ３ Haloalkyl, —N(H)—C(O)O—C １ ~C ６ Alkyl, —N(H)—C(NH)—NH ２ , -N(H)-S(O) ２ -NR １２ R １３ , -N(R ７ )-S(O) ２ -C １ ~C ３ Alkyl, —N(R ７ )-S(O) ２ -cycloalkyl, -N(H)-S(O) ２ -C １ ~C ３ Haloalkyl, —P(O)(OH) ２ , -P(O)(C １ ~C ６ alkyl) ２ , 1 to 3 R １０ cycloalkyl optionally substituted by one to three R １０ or one to three R １０ or is heteroaryl optionally substituted by Two R's ８ together with the carbon atoms to which they are attached, combine to form a cycloalkyl; Each R ９ are independently CN, -S(O) ２ -C １ ~C ３ Alkyl, or -N(C １～３ alkyl) ２ and Each R １０ are independently hydroxy, CN, C １ ~C ６ Alkyl, haloalkyl, -NH ２ , —C(O)-alkenyl, —C(O)—NH ２ , —C(O)O-alkyl, —NH—C(O)-alkenyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C ２ ~C ６ alkenyl, or —S(O) ２ -NH ２ and R １１ is CN; Each R １２ and R １３ are independently hydrogen, C １ ~C ６ Alkyl or C ３ ~C ６ is cycloalkyl; Each R １４ and R １５ are independently hydrogen or C １ ~C ６ is alkyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; A compound according to claim 1 or claim 2.

4. R １ But 0 to 3 G ２ phenyl substituted by a group, Each G is selected from halogen, CN, and 1 to 3 R ５ C optionally substituted by １ ~C ３ independently selected from alkyl; Each R ２ is H, halogen or CH ３ and R ５ is halogen or OH; X is -(CH ２ ) ｍ -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ , 1 to 3 R ８ C optionally substituted by １ ~C ６ alkyl, 1 to 3 R ９ cycloalkyl optionally substituted by one to three R １０ heterocycloalkyl optionally substituted by 1 to 3 R １０ or aryl optionally substituted by 1 to 3 R １０ is heteroaryl optionally substituted by A compound according to claim 1 or claim 2.

5. R １ is phenyl substituted with 0 to 2 G groups; Each G is selected from Cl, F, CN, and 1 to 3 R ５ C replaced by １ ~C ３ independently selected from alkyl; Each R ２ is H, Cl, F or CH ３ and R ５ is a halogen, The compound of claim 4.

6. R ５ The compound of claim 5 , wherein is Cl or F.

7. 3. A compound according to claim 1 or claim 2 having one of the following formulae: 【Transformation 3】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of either formula (IIa) or (IIb), wherein: Each G is selected from Cl, F, CN, and 1 to 3 R ５ C replaced by １ ~C ３ independently selected from alkyl; R ５ are halogens).

8. 8. The compound of claim 7 having one of the following formulas: 【Chemistry 4】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (IIIa), (IIIb) or (IIIc), wherein: G is Cl, F or CN).

9. R ３ is optionally substituted by H; halogen; cyclopropyl or heterocycloalkyl; ２ ~C ４ Alkenyl; C(O)-CH ３ heterocycloalkyl optionally substituted by C(O)—CH ３ heterocycloalkenyl optionally substituted by C(O)—CH ３ or haloalkyl, cyclopropyl, or cyclopropyl-CH ２ The compound of claim 7, wherein the heteroaryl is a 5- or 6-membered heteroaryl optionally substituted by -.

10. R ４ But H;C １ ~C ３ Alkyl; haloalkyl, or cycloalkyl optionally substituted by —C(O)-alkenyl; —C(O)—CH ３ , -C(O)-CH=CH ２ or heterocycloalkyl optionally substituted by —C(O)-cyclopropyl; —C(O)—CH ３ heterocycloalkylalkyl optionally substituted by -C(O)-CH ２ or 5-6 membered heteroaryl.

11. 10. The compound of claim 1 having one of the following formulas: 【Transformation 5】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (IIIa), (IIIb) or (IIIc), wherein: G is Cl, F or CN; R ３ is optionally substituted by H; halogen; cyclopropyl or heterocycloalkyl; ２ ~C ４ Alkenyl; C(O)-CH ３ heterocycloalkyl optionally substituted by C(O)—CH ３ heterocycloalkenyl optionally substituted by C(O)—CH ３ or haloalkyl, cyclopropyl, or cyclopropyl-CH ２ - is a 5- to 6-membered heteroaryl optionally substituted by -; R ４ But H;C １ ~C ３ Alkyl; haloalkyl, or cycloalkyl optionally substituted by —C(O)-alkenyl; —C(O)—CH ３、 -C(O)-CH=CH ２ or heterocycloalkyl optionally substituted by —C(O)-cyclopropyl; —C(O)—CH ３ heterocycloalkylalkyl optionally substituted by -C(O)-CH ２ -OH; or 5-6 membered heteroaryl; X is -S(O) ２ - or - (CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ , 1 to 4 R ８ C optionally substituted by １ ~C ６ alkyl, 1 to 4 R ９ C optionally substituted by ３ ~C ６ cycloalkyl, 1 to 4 R １０ 5-10 membered heterocycloalkyl optionally substituted by 1 to 4 R １０ C optionally substituted by ６ ~C １２ aryl, or 1 to 4 R １０ is a 5-10 membered heteroaryl optionally substituted by Or X is a bond and Z is CN, —C(O)—NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl or -SO ２ -NR １４ R １５ is a 5-6 membered heteroaryl optionally substituted by n is 0, 1 or 2).

12. R ３ is H; R ４ is H; X is -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ , 1 to 3 R ８ C optionally substituted by １ ~C ４ alkyl, 1 to 3 R ９ C optionally substituted by ３ ~C ６ cycloalkyl, 1 to 3 R １０ 5- to 7-membered heterocycloalkyl optionally substituted by 1 to 3 R １０ C optionally substituted by ６ ~C １０ aryl, or 1 to 3 R １０ is a 5-7 membered heteroaryl optionally substituted by n is 0 or 1; The compound of claim 11.

13. X is -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ , 1 to 3 R ８ C optionally substituted by ２ ~C ４ alkyl, 1 to 3 R １０ C optionally substituted by ６ ~C １２ aryl, or 1 to 3 R １０ is a 5-10 membered heteroaryl optionally substituted by n is 0 or 1; The compound of claim 11.

14. X is -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ and n is 0 or 1; The compound of claim 11.

15. X is -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is 1 to 3 R ８ C optionally substituted by ２ ~C ４ is alkyl; n is 0 or 1; The compound of claim 11.

16. X is -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is 1 to 3 R １０ C optionally substituted by ６ ~C １２ is aryl; n is 0 or 1; The compound of claim 11.

17. X is -S(O) ２ - or -(CH ２ ) ｎ -C(O)-; Z is 1 to 3 R １０ is a 5-10 membered heteroaryl optionally substituted by n is 0 or 1; The compound of claim 11.

18. A compound having one of the following formulas: 【Transformation 6】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (IIIa), (IIIb) or (IIIc), wherein: G is Cl, F or CN; R ３ is optionally substituted by H; halogen; cyclopropyl or heterocycloalkyl; ２ ~C ４ Alkenyl; C(O)-CH ３ heterocycloalkyl optionally substituted by C(O)—CH ３ heterocycloalkenyl optionally substituted by C(O)—CH ３ or haloalkyl, cyclopropyl, or cyclopropyl-CH ２ - is a 5- to 6-membered heteroaryl optionally substituted by -; R ４ But H;C １ ~C ３ Alkyl; haloalkyl, or cycloalkyl optionally substituted by —C(O)-alkenyl; —C(O)—CH ３ , -C(O)-CH=CH ２ or heterocycloalkyl optionally substituted by —C(O)-cyclopropyl; —C(O)—CH ３ heterocycloalkylalkyl optionally substituted by -C(O)-CH ２ -OH; or 5-6 membered heteroaryl; X is -S(O) ２ - or - (CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ , 1 to 3 R ８ C optionally substituted by ２ ~C ４ alkyl, 1 to 3 R １０ C optionally substituted by ６ ~C １２ aryl, or 1 to 3 R １０ is a 5-10 membered heteroaryl optionally substituted by Or X is a bond and Z is CN, C(O)-NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl or -SO ２ -NR １４ R １５ is a 5-6 membered heteroaryl optionally substituted by R ６ But hydrogen, C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one to three R １１ may be substituted by R ７ is hydrogen or C １ ~C ６ is alkyl; or R ８ But, -NR ６ R ７ , CN, hydroxy, alkoxy, haloalkoxy, -S-C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Haloalkyl, —S(O) ２ -NH ２ , -S(O)(NH)-C １ ~C ３ Alkyl, —C(O)—NH ２ , -C(O)OH, -C(O)OC １ ~C ３ Alkyl, —C(O)C １ ~C ３ Haloalkyl, —N(H)—C(O)—NR ６ R ７ , -NR １２ R １３ or —N(H)—C(O)—C optionally substituted by CN １ ~C ３ Alkyl, —N(H)—C(O)—C ２ ~C ６ Alkenyl, —N(H)—C(O)—C １ ~C ３ Haloalkyl, —N(H)—C(O)O—C １ ~C ６ Alkyl, —N(H)—C(NH)—NH ２ , -N(H)-S(O) ２ -NR １２ R １３ , -N(R ７ )-S(O) ２ -C １ ~C ３ Alkyl, —N(H)—S(O) ２ -C １ ~C ３ Haloalkyl, —P(O)(OH) ２ , -P(O)(C １ ~C ６ alkyl) ２ , 1 to 3 R １０ or one to three R １０ or is heteroaryl optionally substituted by Two R's ８ together with the carbon atoms to which they are attached, combine to form a cycloalkyl; Each R １０ are independently hydroxy, CN, C １ ~C ６ Alkyl, haloalkyl, -NH ２ , —C(O)-alkenyl, —C(O)—NH ２ , —C(O)O-alkyl, —NH—C(O)-alkenyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C ２ ~C ６ alkenyl, or —S(O) ２ -NH ２ and R １１ is CN; Each R １２ and R １３ are independently hydrogen, C １ ~C ６ Alkyl or C ３ ~C ６ is cycloalkyl; Each R １４ and R １５ are independently hydrogen or C １ ~C ６ is alkyl; n is 0 or 1).

19. X is -S(O) ２ - or -C(O)-; Z is -(CH ２ ) ２ -S(O) ２ -CH ３ , or -CH ２ -N(H)-C(O)-NH ２ That is, 19. The compound of claim 18.

20. X is a bond and Z is CN, C(O)-NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl, or —SO ２ -NR １４ R １５ and each R is a 5- to 6-membered heteroaryl optionally substituted by １４ and R １５ are independently hydrogen or C １ ~C ３ 20. The compound of claim 11 or 18, wherein the compound is alkyl.

21. 10. The compound of claim 1 having one of the following formulas: 【Transformation 7】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf), wherein: Each G is selected from Cl, F, CN, and 1 to 3 R ５ C replaced by １ ~C ３ independently selected from alkyl; R ５ are halogens).

22. A compound having one of the following formulas: 【Transformation 8】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of formula (Va), (Vb) or (Vc), wherein: G is Cl, F or CN; R ３ is optionally substituted by H; halogen; cyclopropyl or heterocycloalkyl; ２ ~C ４ Alkenyl; C(O)-CH ３ heterocycloalkyl optionally substituted by C(O)—CH ３ heterocycloalkenyl optionally substituted by C(O)—CH ３ or haloalkyl, cyclopropyl, or cyclopropyl-CH ２ - is a 5- to 6-membered heteroaryl optionally substituted by -; R ４ But H;C １ ~C ３ Alkyl; haloalkyl, or cycloalkyl optionally substituted by —C(O)-alkenyl; —C(O)—CH ３ , -C(O)-CH=CH ２ or heterocycloalkyl optionally substituted by —C(O)-cyclopropyl; —C(O)—CH ３ heterocycloalkylalkyl optionally substituted by -C(O)-CH ２ -OH; or 5-6 membered heteroaryl; X is -S(O) ２ - or - (CH ２ ) ｎ -C(O)-; Z is -NR ６ R ７ , 1 to 3 R ８ C optionally substituted by ２ ~C ４ alkyl, 1 to 3 R １０ C optionally substituted by ６ ~C １２ aryl, or 1 to 3 R １０ is a 5-10 membered heteroaryl optionally substituted by Or X is a bond and Z is CN, C(O)-NR １４ R １５ , -S(O) ２ -C １ ~C ３ Alkyl or -SO ２ -NR １４ R １５ is a 5-6 membered heteroaryl optionally substituted by R ６ But hydrogen, C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each C １ ~C ６ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one to three R １１ may be substituted by R ７ is hydrogen or C １ ~C ６ is alkyl; or R ８ But, -NR ６ R ７ , CN, hydroxy, alkoxy, haloalkoxy, -S-C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C １ ~C ３ Haloalkyl, —S(O) ２ -NH ２ , -S(O)(NH)-C １ ~C ３ Alkyl, —C(O)—NH ２ , -C(O)OH, -C(O)OC １ ~C ３ Alkyl, —C(O)C １ ~C ３ Haloalkyl, —N(H)—C(O)—NR ６ R ７ , -NR １２ R １３ or —N(H)—C(O)—C optionally substituted by CN １ ~C ３ Alkyl, —N(H)—C(O)—C ２ ~C ６ Alkenyl, —N(H)—C(O)—C １ ~C ３ Haloalkyl, —N(H)—C(O)O—C １ ~C ６ Alkyl, —N(H)—C(NH)—NH ２ , -N(H)-S(O) ２ -NR １２ R １３ , -N(R ７ )-S(O) ２ -C １ ~C ３ Alkyl, —N(H)—S(O) ２ -C １ ~C ３ Haloalkyl, —P(O)(OH) ２ , -P(O)(C １ ~C ６ alkyl) ２ , 1 to 3 R １０ or one to three R １０ or is heteroaryl optionally substituted by Two R's ８ together with the carbon atoms to which they are attached, combine to form a cycloalkyl; Each R １０ are independently hydroxy, CN, C １ ~C ６ Alkyl, haloalkyl, -NH ２ , —C(O)-alkenyl, —C(O)—NH ２ , —C(O)O-alkyl, —NH—C(O)-alkenyl, —S(O) ２ -C １ ~C ３ Alkyl, —S(O) ２ -C ２ ~C ６ alkenyl, or —S(O) ２ -NH ２ and R １１ is CN; Each R １２ and R １３ are independently hydrogen, C １ ~C ６ Alkyl or C ３ ~C ６ is cycloalkyl; Each R １４ and R １５ are independently hydrogen or C １ ~C ６ is alkyl; n is 0 or 1).

23. 3. A formic acid salt of the compound of claim 1 or 2.

24. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

25. A compound selected from Table 1A or a pharmaceutically acceptable salt thereof.

26. 3. The compound of claim 1 or 2, which is a non-covalent inhibitor of TEAD.

27. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

28. 28. The pharmaceutical composition of claim 27, further comprising a second pharmaceutical agent.

29. 28. A method for treating a subject having a disease or condition mediated by YAP / TEAD, comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of claim 27.

30. 30. The method of claim 29, wherein the disease or condition is cancer, a neurodegenerative disease, a heart-related disorder, or a kidney-related disorder.

31. 30. The method of claim 29, 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.

32. 30. The method of claim 29, further comprising administering one or more additional therapeutic agents.

33. the one or more additional therapeutic agents are: 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 treosulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antibiotic selected from azacitidine, capecitabine, cladrifin, iv) an antimetabolite selected from rifabutin, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an immune checkpoint agent selected from PD-1 inhibitors, PD-L1 inhibitors, and anti-CTLA4 inhibitors; v) a hormone or hormone antagonist selected from enzalutamide, abiraterone, anastrozole, androgen, 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) 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 angiogenesis inhibitor 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, asparagine, ginase, bryostatin-1, cilengitide, elescolomole, 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, letrozole and and 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 CD39, CD38, A2AR, and A2BR; or xxii) an agonist of a TNFA superfamily member; and xxiii) an anti-ErbB2 mAb.

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