Compounds and methods for YAP / TEAD modulation and their indications

Abstract

Formula (I): JPEG2026503617000080.jpg27104 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof (wherein ring A, ring B, Q, G, R2, R3, R4, R 21 , p, q, v, Y1 and Y2 are as described in any of the embodiments described in this disclosure); compositions thereof; and uses thereof are disclosed.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 441,599, filed January 27, 2023, the entire teachings of which are incorporated herein by reference.

[0002] The present disclosure relates to organic compounds useful in mammalian therapy, particularly useful 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, which regulates tissue homeostasis, cell proliferation, tumor transformation and apoptosis. This pathway involves a series of kinases that phosphorylate 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 the expression of target genes, such as connective tissue growth factor (CTGF) and cysteine-rich angiogenic factor 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 kinases are inactive, YAP and TAZ are not phosphorylated, translocate to the nucleus, and bind to TEADs. Deregulation of the Hippo pathway is involved in a wide variety of tumors, including breast tumors, and therefore, its targeting represents an approach for treating cancers with functional alterations of this pathway (Dominguez-Berrocal et al., New Therapeutic Approach for Targeting Hippo Signaling Pathway. Sci Rep 9, 4771 (2019)). As an example, one small molecule used to target this signaling pathway is verteporfin, which associates with YAP and inhibits its binding to TEADs.

[0004] Compounds that modulate, or 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, represent a new class of potential therapeutic agents capable of modulating tumor growth and other diseases. Because no YAP / TEAD inhibitors are 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 described in any of the embodiments herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, or deuterated analogs 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 pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein ring A, ring B, Q, R2, R3, R4, Y1, Y2, G, R 21 , p, q, and v are as described in any of the embodiments (including any subembodiments thereof) in this disclosure.

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

[0008] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to Formula (I) or any embodiment and subembodiment of Formula (I) described herein in this disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog of any of these compounds, and a pharmaceutically 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) described herein in this disclosure, or a pharmaceutically 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 for 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 pharmaceutically 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 pharmaceutically 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 the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

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

[0014] 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 side being directly attached to the parent structure as defined, except that when a point of attachment (e.g., a dash "-") is indicated on the left 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.

[0015] When considering the general descriptions of compounds described herein for constructing compounds, it is assumed that such construction will produce stable structures; that is, one of skill in the art will recognize that, theoretically, some constructions would not normally be considered stable compounds (i.e., sterically practical and / or synthetically feasible).

[0016] "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 a prefix is ​​not 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 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, 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 said moiety excludes substituents that result in any O, S, or N (except when N is a heteroaryl ring atom) of that substituent being bonded to an alkyl carbon bonded to any O, S, or N of said moiety.

[0017] "Alkylene," by itself or as part of another substituent, means a straight-chain or branched 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.). C 1~4 Alkylene includes methylene -CH-, ethylene -CHCH-, propylene -CHCHCH-, and isopropylene -CH(CH)CH-, -CHCH(CH)-, -CH-(CH)CH-, -CH-CH(CH)CH-, -CH-C(CH)-CH-CHCH(CH)-. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, with groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms. When no prefix is ​​included to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or portion thereof has 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms, or 3 or fewer main chain carbon atoms, or 2 or fewer main chain carbon atoms, or 1 carbon atom.

[0018] "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.

[0019] "Alkoxy" or "alkoxyl" refers to an -O-alkyl group, where alkyl is as defined herein. By way of example, "C1-C6 alkoxy" refers to an -O-C1-C6 alkyl group, where alkyl is as defined herein. It is understood that substitution on the alkoxy is attached to any available atom to produce a stable compound, but substitution on the alkoxy is such that an O, S, or N (except when N is a heteroaryl ring atom) is not attached to the alkyl carbon attached to the alkoxy O. Furthermore, 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.

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

[0021] "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.

[0022] "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.

[0023] "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, 3 to 6, further 4 to 6, further 5 to 6 ring members per ring, in which one or two ring carbon atoms may be replaced by a carbonyl. Furthermore, 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 rest of the molecule. Cycloalkyl refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3~6 (Both cycloalkyl and 3- to 6-membered cycloalkyl refer to 3 to 6 ring carbon atoms.) The term "cycloalkenyl" refers to a cycloalkyl having at least one unit of unsaturation. A cycloalkyl or cycloalkenyl substituent may be at the point of attachment of the cycloalkyl or cycloalkenyl group, forming a quaternary center.

[0024] "Cycloalkylalkyl" refers to an -(alkylene)-cycloalkyl group where alkylene, as defined herein, has the designated number of carbon atoms, or if not specified, up to 6 carbon atoms, and cycloalkyl, as defined herein, has the designated number of carbon atoms, or if not specified, 3 to 10, further 3 to 8, and 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, where the alkylene chain is attached to the parent moiety. Other exemplary cycloalkylalkyls include, for example, cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and the like.

[0025] "Halogen" or "halo" refers to any halogen, ie, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

[0026] 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.

[0027] 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, etc.

[0028] "Heteroatom" is intended to include oxygen (O), nitrogen (N) and sulfur (S).

[0029] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring radical containing one or more, 14, 13, or 12 heteroatoms independently selected from the group consisting of O, S, and N, containing 5 to 9 ring atoms (also referred to in this disclosure as 5- to 6-membered heteroaryl), including monocyclic aromatic ring radicals containing 5 or 6 ring atoms (also referred to in this disclosure as 5- to 9-membered heteroaryl). Any aromatic ring or ring system containing at least one heteroatom is heteroaryl regardless of the point of attachment (i.e., through any one of the fused rings). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, indole, and the like. thienyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl, triazinyl, quinoxalinyl, cinnolinyl, phthalazinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzyl "Nitrogen-containing heteroaryl" refers to a heteroaryl in which at least one of the ring heteroatoms is N.

[0030] "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.

[0031] "Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic cycloalkyl group containing 1 to 5 heteroatoms selected from N, O, S (including S(O) and S(O)), or P (including phosphine oxide), where the nitrogen, sulfur, and phosphorus atoms are optionally oxidized, the nitrogen atom is optionally quaternized, and the remaining ring atoms are C, with one or two C atoms optionally present as carbonyl. Furthermore, the term heterocycloalkyl is intended to encompass any ring or ring system containing at least one heteroatom that is not heteroaryl, regardless of the point of attachment to the rest of the molecule. Heterocycloalkyl groups include those with rings that have formally charge-separated aromatic resonance structures, e.g., N-methylpyridonyl. Heterocycloalkyls can be substituted with one or two oxo groups and can include sulfone and sulfoxide derivatives. Heterocycloalkyls can be monocyclic, fused bicyclic, or fused polycyclic ring systems of 3 to 12, 4 to 10, 5 to 10, or 5 to 6 ring atoms, in which 1 to 5 ring atoms are heteroatoms selected from -N=, -N-, -O-, -S-, -S(O)-, or -S(O)2-, and in which 1 or 2 ring atoms are optionally replaced by a -C(O)- group. For example, a 4- to 6-membered heterocycloalkyl is a heterocycloalkyl having 4 to 6 ring members with at least one heteroatom. A heterocycloalkyl can also be a heterocyclic alkyl ring fused to 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.

[0032] "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.

[0033] "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.

[0034] As used throughout this disclosure, "optionally substituted" or "optionally substituted" means that the compound may or may not be substituted, and that the description includes both substituted and unsubstituted cases. For example, "1 to 3 T 1 The phrase "optionally substituted with a group" is intended to include 1 This means that the group may be present but need not be present. In this disclosure, any substitution to a compound is assumed to be made in a way that results in a stable compound.

[0035] As used herein in connection with the compounds of the present disclosure, the term "synthesize" and like terms means chemical synthesis from one or more precursor materials.

[0036] 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 pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0037] The term "pharmaceutically acceptable" indicates that the indicated material does not possess properties that would cause a reasonably prudent physician, taking into account the disease or condition to be treated and the respective route of administration, to avoid administering the material to a patient. For example, such materials are generally required to be essentially sterile, e.g., in the case of injectables.

[0038] A "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 solubility to facilitate the administration of higher drug concentrations. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, depending on the specific substituents found on the compounds described herein.

[0039] 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 an appropriate 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.

[0040] When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound, 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), etc. In some embodiments, the salt is prepared from a pharmaceutically 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, pantothenic acid, phosphoric acid, succinic acid, or the like. The acid may be derived from, for example, acetic 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, alginic acid, hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0041] Also included are salts of amino acids, such as alginates, 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.

[0042] 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 may differ 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.

[0043] Pharmaceutically acceptable salts of various compounds may exist as complexes, such as 8-chlorotheophylline complex (e.g., similar to dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex; dramamine), and various cyclodextrin inclusion complexes.

[0044] The term "deuterated," as used herein alone or as part of a group, refers to a substituted deuterium atom. The term "deuterated analog," as used herein alone or as part of a group, refers to 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.

[0045] The present disclosure also encompasses the isotope-labeled compounds of the present disclosure that are identical to those listed herein, except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers that are different from the atomic masses or mass numbers that are 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, for example, 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 Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," the position is hydrogen or an isotope thereof, 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. Tritiation (i.e. 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 preferable in some circumstances as they may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures similar to those described in the following schemes and examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0046] "Prodrug" means 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 can progress from the prodrug form to the active form in a single step, or can have one or more intermediate forms that may themselves be active or inactive. Some prodrugs are enzymatically activated to yield the active compound, or to yield a compound that will yield the active compound upon further chemical reaction. Prodrugs include compounds of formula (I) in which a hydroxyl group, amino group, carboxyl group, or sulfhydryl group in a compound of formula (I) is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, free amino group, or 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 compound. The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, "Prodrugs 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.

[0047] 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. Generally, biological precursor prodrugs are compounds that contain one or more protecting groups and are inactive or have low activity compared to the corresponding active drug compound, which is converted into an active form by metabolism or solvolysis. Both the active drug form and any released metabolites should have acceptably low toxicity. Typically, the formation of an active drug compound involves one of the following types of metabolic processes or reactions:

[0048] (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.

[0049] (2) Reduction Reactions: Reduction reactions are exemplified for reactions such as, but not limited to, reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.

[0050] (3) Reactions that do not change oxidation state: Reactions that do not change 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.

[0051] Carrier prodrugs are drug compounds containing a transport moiety that, for example, improves uptake and / or localized delivery to the site of action. In 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 the prodrug and any release transport moiety are desirably non-toxic. For prodrugs in which the transport moiety is intended to enhance uptake, the release of the transport moiety should typically be rapid. In other cases, it is desirable to utilize a moiety that provides sustained release, such as certain polymers or other moieties, such as cyclodextrins. (See, for example, U.S. Patent Publication No. 2004 / 0077595 to Cheng et al., 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 formulations (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, eg, aliphatic alcohols.

[0052] 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 highly effective drug carriers, and there are various methods by 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.

[0053] Metabolites, for example, active metabolites, overlap with the above-mentioned prodrugs, for example, biological precursor prodrugs.Therefore, such metabolites are compounds that are further metabolized into pharmacologically active compounds, or derivatives that are derived from metabolic processes in the subject's body.Among these, active metabolites are such pharmacologically active derivative compounds.In the case of prodrugs, prodrug compounds are generally inactive or less active than metabolites.In the case of active metabolites, parent compounds can be either active compounds or inactive prodrugs.

[0054] Prodrugs and active metabolites can be identified using conventional 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.

[0055] "Tautomer" refers to a compound formed 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). Tautomers also refer 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 arrangements, 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") can 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.

[0056] "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, if 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 each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, such as 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 chiral 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, descriptions are 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 the discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007), which differ in the chirality of one or more stereocenters.

[0057] "Hydrate" refers to a complex formed by the combination of water molecules with solute molecules or ions. "Solvate" refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvates are intended to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.

[0058] 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.

[0059] "Assaying" refers to the creation of experimental conditions and the collection of data regarding the specific results of exposure to particular experimental conditions. For example, enzymes can be assayed based on their ability to act on a detectable substrate. Compounds can be assayed based on their ability to bind to a specific target molecule or molecules.

[0060] 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.

[0061] The term "bind," in reference to the interaction between a target and a potential binding compound, indicates that the potential binding compound associates with the target to a statistically significant extent compared to association with proteins in general (i.e., non-specific binding). Thus, the term "binding compound" refers to a compound that has a statistically significant association with a target molecule. In some embodiments, a binding compound has a dissociation constant (K) of 10 mM or less, 1,000 μM or less, 100 μM or less, 10 μM or less, 1 μM or less, 1,000 nM or less, 100 nM or less, 10 nM or less, or 1 nM or less. D ) interacts with a 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 greater affinity.

[0062] The terms "modulate," "modulation," and the like refer to the ability of a compound to increase or decrease target function and / or expression, e.g., the interaction between YAP and TEAD; such function may include transcriptional regulatory activity and / or binding. Modulation can occur in vitro or in vivo. Modulation includes, as described herein, either direct or indirect inhibition, antagonism, partial antagonism, activation, agonism, or partial agonism of a function or characteristic associated with YAP / TEAD, and / or either direct or indirect upregulation or downregulation of expression YAP / TEAD. In another embodiment, 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 signal transduction, sensitizes signal transduction, or upregulates signal transduction.

[0063] 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.

[0064] As used herein, the terms "prevent," "preventing," "prevention," and grammatical variations thereof refer to a method of partially or completely delaying or eliminating the onset or recurrence of a disease, disorder, or condition, and / or one or more of its attendant symptoms, or preventing a subject from acquiring or re-acquiring a disorder or condition, or reducing the risk of a subject acquiring or requiring a disorder or condition, or one or more of its attendant symptoms.

[0065] 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 mammal, e.g., humans, other primates, sport animals, and commercial animals, e.g., cows, horses, sheep, or pigs, rodents, or pets, e.g., dogs and cats.

[0066] A "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 pharmaceutically 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 two or more times a day, once with each meal, once every 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.

[0067] The term "administering" 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 can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0068] In this context, the term "therapeutically effective" or "effective amount" indicates that a compound or material, or amount of a compound or material, when administered is sufficient or effective to prevent, alleviate, or ameliorate one or more symptoms of the disease, disorder, or condition being treated and / or prolong the survival of the subject being treated. A therapeutically effective amount will vary depending on the compound, the disease, disorder, or condition and its severity, and the age, weight, etc., of the mammal being treated. Generally, satisfactory results are obtained in subjects at daily dosages of about 0.1 to about 10 g / kg of subject body weight. In some embodiments, the daily dosage ranges from about 0.10 to 10.0 mg / kg 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.

[0069] 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 influences 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. YAP / TEAD-mediated diseases or conditions include diseases or conditions in which disrupting YAP / TEAD interaction (e.g., by TEAD inhibition) and / or inhibiting YAP / TEAD-mediated transcription provides a therapeutic benefit, e.g., treatment with a YAP / TEAD inhibitor, including a compound described herein, provides a therapeutic benefit to a subject suffering from or at risk for the disease or condition. YAP / TEAD-mediated diseases or conditions are intended to include cancers with loss-of-function mutations in YAP / TEAD or cancers in which YAP / TEAD activation is present. YAP / TEAD-mediated diseases or conditions are also intended to include various human carcinomas, including those of the colon, lung, pancreas, and ovary, as well as diseases or conditions associated with tumor angiogenesis and invasiveness.

[0070] Also, in the context of compounds that bind to biomolecular targets, the term "higher specificity" indicates that the compound binds to a particular target to a greater extent than another biomolecule or biomolecules that may be present under the relevant binding conditions, and that binding to such other biomolecules results in a biological activity that is different from binding to the particular target. Typically, 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.

[0071] As used herein in reference to a binding compound or ligand, the term "specific for YAP / TEAD" and terms of similar import mean that a particular compound binds to YAP or TEAD to a statistically greater extent than to other epigenetic targets that may be present in a particular sample. Additionally, when a biological activity other than binding is indicated, the term "specific for YAP or TEAD" indicates that a particular compound has a greater biological effect, e.g., enzyme activity inhibition, associated with binding to YAP or TEAD than to other enzymes. In some embodiments, the compounds described herein are specific for TEAD inhibition.

[0072] The term " first-line cancer therapy " refers to the therapy that is administered to the subject as the 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 that is administered with one or more drugs.The currently accepted approach to first-line treatment for specific diseases can be found in the NCI guidelines for such diseases.

[0073] The term "second-line cancer therapy" refers to a cancer treatment administered to a subject who does not respond to first-line therapy, i.e., who has often received first-line therapy or whose cancer has recurred after remission. In certain embodiments, the second-line therapy that can be administered includes a repeat of the initial successful cancer therapy, which can be any of the treatments listed under "first-line cancer therapy." A summary of the currently accepted approach to second-line therapy for a particular disease can be found in the NCI guidelines for such disease.

[0074] The term "refractory" refers to a subject that does not respond to or is otherwise resistant to cancer therapy or cancer treatment.Cancer therapy can be first-line, second-line, or any subsequent treatment.In certain embodiments, refractory refers to a state in which a subject cannot achieve complete remission after two induction therapy attempts.A subject can be refractory due to the inherent resistance of cancer cells to a particular therapy, or the subject can be refractory due to acquired resistance that occurs during the course of a particular therapy.

[0075] As used herein, any variable followed by either a subscript or a superscript, e.g., R x or R x (where x is an integer) are intended to be interchangeable and synonymous. Additionally, the abbreviations used herein have the following respective meanings: [Table 0-1] [Table 0-2]

[0076] II. Compounds Embodiment 1 of the present disclosure relates to a compound of formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y1 is NR 24 and Y2 is N; or Y1 is N and Y2 is NR 24 is; R 24 is H or C1-C3 alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is -O-, -NR 20 -, -CR 22 R 23 -, -CR 22 R 23 O- or -CR 22 R 23 NH-;R 20 is H or alkyl, and R 22 is H, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, and R 23 is H, halogen or C1-C3 alkyl, or R 22 and R 23 together with the carbon atom to which they are attached to form a carbonyl; R 21 is C1-C6 alkyl; Each G is a halogen, OH, CN, or one or more R 5 alkyl optionally substituted with, and one or more R 5 independently selected from alkoxy optionally substituted with Each R 2 are independently H, halogen, —C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1 to 3 halogens, provided that not more than one R 2 is —C(O)O-alkyl; R 3 is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with -C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R 4is H; alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-alkyl, -C(O)-alkenyl or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted with -C(O)-alkyl, -C(O)-CH2-OH or heteroaryl; R 5 is a halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

[0077] Embodiment 1a of the present disclosure relates to a compound of formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y1 is NR 24 and Y2 is N; or Y1 is N and Y2 is NR 24 is; R 24 is H or C1-C3 alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl, cycloalkyl, or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is -O-, -NR 20 -, -CR 22 R 23 -, -CR 22 R 23 O- or -CR 22 R 23 NH-;R 20 is H or alkyl, and R 22is H, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, and R 23 is H, halogen or C1-C3 alkyl, or R 22 and R 23 together with the carbon atom to which they are attached to form a carbonyl; R 21 is C1-C6 alkyl optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with —O—C1-C6 alkyl; NH2, NH—C1-C6 alkyl, cycloalkyl; or C2-C6 alkenyl; Each G is a halogen, OH, CN, or one or more R 5 alkyl optionally substituted with, and one or more R 5 independently selected from alkoxy optionally substituted with Each R 2 are independently H, halogen, —C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1 to 3 halogens, provided that not more than one R 2 is —C(O)O-alkyl; R 3 is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with -C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R 4is H; alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-alkyl, -C(O)-alkenyl or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted with -C(O)-alkyl, -C(O)-CH2-OH or heteroaryl; R 5 is a halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

[0078] Embodiment 2 of the present disclosure relates to compounds of formula (Ia) or (Ib): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y1 is NR 24 and Y2 is N; or Y1 is N and Y2 is NR 24 is; R 24 is H or C1-C3 alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is -O-, -NR 20 -, -CR 22 R 23 -, -CR 22 R 23 O- or -CR 22 R 23 NH-;R 20 is H or alkyl, and R 22is H, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, and R 23 is H, halogen or C1-C3 alkyl, or R 22 and R 23 together with the carbon atom to which they are attached to form a carbonyl; R 21 is C1-C6 alkyl; Each G is a halogen, OH, CN, or one or more R 5 alkyl optionally substituted with, and one or more R 5 independently selected from alkoxy optionally substituted with Each R 2 are independently H, halogen, —C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1 to 3 halogens, provided that not more than one R 2 is —C(O)O-alkyl; R 3 is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with -C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R 4 is H; alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-alkyl, -C(O)-alkenyl or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted with -C(O)-alkyl, -C(O)-CH2-OH or heteroaryl; R 5 is a halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

[0079] Embodiment 2a of the present disclosure relates to compounds of formula (Ia), (Ib) or (Ic): [ka] [ka] [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y1 is NR 24 and Y2 is N; or Y1 is N and Y2 is NR 24 is; R 24 is H or C1-C3 alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl, cycloalkyl, or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is -O-, -NR 20 -, -CR 22 R 23 -, -CR 22 R 23 O- or -CR 22 R 23 NH-;R 20 is H or alkyl, and R 22 is H, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, and R 23 is H, halogen or C1-C3 alkyl, or R 22 and R 23 together with the carbon atom to which they are attached to form a carbonyl; R 21is C1-C6 alkyl optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with —O—C1-C6 alkyl; NH2, NH—C1-C6 alkyl, cycloalkyl; or C2-C6 alkenyl; Each G is a halogen, OH, CN, or one or more R 5 alkyl optionally substituted with, and one or more R 5 independently selected from alkoxy optionally substituted with Each R 2 are independently H, halogen, —C(O)O-alkyl, or C1-C3 alkyl optionally substituted with 1 to 3 halogens, provided that not more than one R 2 is —C(O)O-alkyl; R 3 is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with -C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R 4 is H; alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-alkyl, -C(O)-alkenyl or -C(O)-cycloalkyl; or heterocycloalkylalkyl optionally substituted with -C(O)-alkyl, -C(O)-CH2-OH or heteroaryl; R5 is halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

[0080] Embodiment 3 of the present disclosure relates to a compound of embodiment 1 or embodiment 2, wherein Q is -NH-, N(CH3)-, -O-, -CH2-, -C(O)-, -CH2-O-, -CF2-, -CHF-, -CH2-NH-, -CH(OH)-, -C(O)-NH-, or -CH(OCH3)-.

[0081] Embodiment 3a of the present disclosure relates to compounds according to embodiment 1a or embodiment 2a, wherein Q is -NH-, N(CH3)-, -O-, -CH2-, -C(O)-, -CH2-O-, -CF2-, -CHF-, -CH2-NH-, -CH(OH)-, -C(O)-NH-, or -CH(OCH3)-.

[0082] Embodiment 4 of the present disclosure relates to compounds according to embodiment 3, wherein Q is -NH-, N(CH3)-, or -O-.

[0083] Embodiment 4a of the present disclosure relates to compounds according to embodiment 3a, wherein Q is -NH-, N(CH3)-, or -O-.

[0084] Embodiment 5 of the present disclosure is v is 0, 1, 2 or 3; Each G is a halogen, CN, and 1 to 3 R 5 independently selected from C1-C3 alkyl optionally substituted with Each R 2 is H, halogen, or CH3; R 5 is halogen or OH; The compound according to embodiment 4.

[0085] Embodiment 5a of the present disclosure is v is 0, 1, 2 or 3; Each G is a halogen, CN, and 1 to 3 R 5 independently selected from C1-C3 alkyl optionally substituted with Each R 2 is H, halogen, or CH3; R 5is halogen or OH; This relates to compounds according to embodiment 4a.

[0086] Embodiment 6 of the present disclosure is v is 0, 1 or 2; Each G is Cl, F, CN, and 1-3 R 5 independently selected from C1-C3 alkyl substituted with Each R 2 is H, Cl, F, or CH3; and R 5 is a halogen, The present invention relates to compounds according to embodiment 5.

[0087] Embodiment 6a of the present disclosure is v is 0, 1 or 2; Each G is Cl, F, CN, and 1-3 R 5 independently selected from C1-C3 alkyl substituted with Each R 2 is H, Cl, F, or CH3; and R 5 is a halogen, This relates to compounds according to embodiment 5a.

[0088] Embodiment 7 of the present disclosure is R 5 is Cl or F.

[0089] Embodiment 7a of the present disclosure is R 5 is Cl or F.

[0090] Embodiment 8 of the present disclosure relates to a compound of the formula: [ka] The compound of any one of embodiments 1 to 4, having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), wherein: Each G is Cl, F, CN, and 1-3 R 5 C1-C3 alkyl substituted with R 5 is a halogen.

[0091] Embodiment 8a of the present disclosure is a compound of the formula: [ka] [ka] The compound of any one of embodiments 1a, 2a, 3a or 4a, having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), wherein: Each G is Cl, F, CN, and 1-3 R 5 C1-C3 alkyl substituted with R 5 is a halogen.

[0092] Embodiment 9 of the present disclosure relates to a compound of the formula: [ka] The compound of embodiment 8 having one of the following: or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf), wherein: G is Cl, F or CN.

[0093] Embodiment 9a of the present disclosure is a compound of the formula: [ka] [ka] Compounds according to embodiment 8a having one of the following: or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf), wherein: G is Cl, F or CN.

[0094] A tenth embodiment of the present disclosure is R 3 is H; halogen; C2-C4 alkenyl optionally substituted with cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted with C(O)-CH3; heterocycloalkenyl optionally substituted with C(O)-CH3; heterocycloalkylalkyl optionally substituted with C(O)-CH3; or 5-6 membered heteroaryl optionally substituted with haloalkyl, cyclopropyl, or cyclopropyl-CH2-.

[0095] Embodiment 10a of the present disclosure is R 3 is H; halogen; C2-C4 alkenyl optionally substituted with cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted with C(O)-CH3; heterocycloalkenyl optionally substituted with C(O)-CH3; heterocycloalkylalkyl optionally substituted with C(O)-CH3; or 5-6 membered heteroaryl optionally substituted with haloalkyl, cyclopropyl, or cyclopropyl-CH2-.

[0096] An eleventh embodiment of the present disclosure is R 4is H; C1-C3 alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-CH3, -C(O)-CH=CH2, or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted with -C(O)-CH3; -C(O)-CH2-OH; or 5-6 membered heteroaryl.

[0097] Embodiment 11a of the present disclosure is R 4 is H; C1-C3 alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-CH3, -C(O)-CH=CH2, or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted with -C(O)-CH3; -C(O)-CH2-OH; or 5-6 membered heteroaryl.

[0098] Embodiment 12 of the present disclosure relates to a compound of the formula: [ka] The compound of embodiments 1 to 4 having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein: G is Cl, F or CN; R 3 is H; halogen; C2-C4 alkenyl optionally substituted with cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted with C(O)-CH3; heterocycloalkenyl optionally substituted with C(O)-CH3; heterocycloalkylalkyl optionally substituted with C(O)-CH3; or 5-6 membered heteroaryl optionally substituted with haloalkyl, cyclopropyl, or cyclopropyl-CH2-; and R 4 is H; C1-C3 alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-CH3-C(O)-CH=CH2 or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted with -C(O)-CH3; -C(O)-CH2-OH; or 5- to 6-membered heteroaryl.

[0099] Embodiment 12a of the present disclosure is a compound of the formula: [ka] [ka] The compound of embodiment 1a, 2a, 3a or 4a having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein: G is Cl, F or CN; R 3 is H; halogen; C2-C4 alkenyl optionally substituted with cyclopropyl or heterocycloalkyl; heterocycloalkyl optionally substituted with C(O)-CH3; heterocycloalkenyl optionally substituted with C(O)-CH3; heterocycloalkylalkyl optionally substituted with C(O)-CH3; or 5-6 membered heteroaryl optionally substituted with haloalkyl, cyclopropyl, or cyclopropyl-CH2-; and R 4is H; C1-C3 alkyl; cycloalkyl optionally substituted with haloalkyl or -C(O)-alkenyl; heterocycloalkyl optionally substituted with -C(O)-CH3-C(O)-CH=CH2 or -C(O)-cyclopropyl; heterocycloalkylalkyl optionally substituted with -C(O)-CH3; -C(O)-CH2-OH; or 5- to 6-membered heteroaryl.

[0100] Embodiment 13 of the present disclosure is directed to a compound in which Y is NR 24 and Y2 is N.

[0101] Embodiment 13a of the present disclosure is directed to a compound in which Y is NR 24 and Y2 is N.

[0102] Embodiment 14 of the present disclosure is directed to a compound wherein Y1 is N and Y2 is NR 24 13. The compound of embodiment 12, wherein

[0103] Embodiment 14a of the present disclosure is directed to a compound in which Y1 is N and Y2 is NR 24 The compound of embodiment 12a is

[0104] A fifteenth embodiment of the present disclosure is R 24 is H or methyl.

[0105] Embodiment 15a of the present disclosure is R 24 is H or methyl.

[0106] A sixteenth embodiment of the present disclosure is R 21 is methyl or ethyl.

[0107] Embodiment 16a of the present disclosure is R 21is C1-C6 alkyl optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted with —O—C1-C6 alkyl. Embodiment 16b of the present disclosure is R 21 is C1-C6 alkyl.

[0108] Embodiment 16c of the present disclosure is R 21 is methyl or ethyl. 21 is methyl. Preferably, R 21 is ethyl.

[0109] Embodiment 16d of the present disclosure is R 21 is NH2 or NH-C1-C6 alkyl. Embodiment 16e of the present disclosure is R 21 is cycloalkyl.

[0110] A seventeenth embodiment of the present disclosure is R 3 is H; and R 4 is H, It relates to the compounds of embodiments 1 to 16.

[0111] Embodiment 17a of the present disclosure is R 3 is H; and R 4 is H, Concerning compounds of embodiment 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d or 16e.

[0112] An eighteenth embodiment of the present disclosure is a compound in which Q is NR 20 and R 20 is H or C1-C3 alkyl; The present invention relates to a compound according to one of the embodiments 1 to 17. Preferably, R 20 is H. Preferably, R 20 is C1 alkyl. Preferably, R 20 is a C2 alkyl. Preferably, R 20 is a C3 alkyl.

[0113] Embodiment 18a of the present disclosure is directed to a compound in which Q is NR 20 and R 20 is H or C1-C3 alkyl. 20 is H. Preferably, R 20 is C1 alkyl. Preferably, R 20 is a C2 alkyl. Preferably, R 20 is a C3 alkyl.

[0114] Embodiment 19 of the present disclosure is directed to a compound in which Q is -CR 22 R 23 -, -CR 22 R 23 O- or -CR 22 R 23 NH-;R 22 is H, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, and R 23 is H, halogen or C1-C3 alkyl, or R 22 and R 23 taken together with the carbon atom to which they are attached form a carbonyl.

[0115] Embodiment 19a of the present disclosure is directed to a compound in which Q is -CR 22 R 23 -, -CR 22 R 23O- or -CR 22 R 23 NH-;R 22 is H, halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy, and R 23 is H, halogen or C1-C3 alkyl, or R 22 and R 23 taken together with the carbon atom to which they are attached, form a carbonyl.

[0116] Embodiment 20 of the present disclosure relates to a compound of one of embodiments 1-17, wherein Q is —O—.

[0117] Embodiment 20a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, wherein Q is -O-.

[0118] Embodiment 21 of the present disclosure relates to a compound of any one of embodiments 1-20, wherein Ring A is phenyl and Ring B is phenyl. Ring A and / or Ring B can be further substituted as described herein.

[0119] Embodiment 21a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein Ring A is phenyl and Ring B is phenyl. Ring A and / or Ring B can be further substituted as described herein.

[0120] Embodiment 22 of the present disclosure relates to a compound of any one of embodiments 1 to 20, wherein ring A is phenyl and ring B is a 6-membered heteroaryl. Preferably, the 6-membered heteroaryl is pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is pyridine or pyrimidine. Ring A and / or ring B can be further substituted as described herein.

[0121] Embodiment 22a of the present disclosure relates to one compound of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, 17a, 18a, 19a, or 20a, wherein ring A is phenyl and ring B is a 6-membered heteroaryl. Preferably, the 6-membered heteroaryl is pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is pyridine or pyrimidine. Ring A and / or ring B can be further substituted as described herein.

[0122] Embodiment 23 of the present disclosure relates to a compound of any one of embodiments 1 to 20, wherein ring A is a 6-membered heteroaryl and ring B is phenyl. Preferably, the 6-membered heteroaryl is pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is pyridine or pyrimidine. Ring A and / or ring B can be further substituted as described herein.

[0123] Embodiment 23a of the present disclosure relates to one compound of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, 17a, 18a, 19a, or 20a, wherein ring A is a 6-membered heteroaryl and ring B is phenyl. Preferably, the 6-membered heteroaryl is pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is pyridine or pyrimidine. Ring A and / or ring B can be further substituted as described herein.

[0124] Embodiment 24 of the present disclosure relates to a compound of any one of embodiments 1-20, wherein Ring A is a 6-membered heteroaryl and Ring B is a 6-membered heteroaryl. Preferably, each instance of the 6-membered heteroaryl is independently selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, each instance of the 6-membered heteroaryl is independently selected from pyridine or pyrimidine. Ring A and / or Ring B can be further substituted as described herein.

[0125] Embodiment 24a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein ring A is a 6-membered heteroaryl and ring B is a 6-membered heteroaryl. Preferably, each 6-membered heteroaryl is independently selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, each 6-membered heteroaryl is independently selected from pyridine or pyrimidine. Ring A and / or ring B can be further substituted as described herein.

[0126] Embodiment 25 of the present disclosure relates to a compound of any one of embodiments 1-20, wherein Ring A is phenyl and Ring B is a 5-membered heteroaryl. Preferably, the 5-membered heteroaryl is pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or Ring B can be further substituted as described herein.

[0127] Embodiment 25a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein Ring A is phenyl and Ring B is a 5-membered heteroaryl. Preferably, the 5-membered heteroaryl is pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or Ring B can be further substituted as described herein.

[0128] Embodiment 26 of the present disclosure relates to a compound of any one of embodiments 1-20, wherein Ring A is a 5-membered heteroaryl and Ring B is phenyl. Preferably, the 5-membered heteroaryl is pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or Ring B can be further substituted as described herein.

[0129] Embodiment 26a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein ring A is a 5-membered heteroaryl and ring B is phenyl. Preferably, the 5-membered heteroaryl is pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or ring B can be further substituted as described herein.

[0130] Embodiment 27 of the present disclosure relates to a compound of any one of embodiments 1-20, wherein Ring A is a 5-membered heteroaryl and Ring B is a 5-membered heteroaryl. Preferably, the 5-membered heteroaryl in each instance is independently selected from pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or Ring B can be further substituted as described herein.

[0131] Embodiment 27a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein Ring A is a 5-membered heteroaryl and Ring B is a 5-membered heteroaryl. Preferably, the 5-membered heteroaryl in each instance is independently selected from pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or Ring B can be further substituted as described herein.

[0132] Embodiment 28 of the present disclosure relates to a compound of any one of embodiments 1 to 20, wherein ring A is a 5-membered heteroaryl and ring B is a 6-membered heteroaryl. Preferably, the 6-membered heteroaryl is selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is selected from pyridine or pyrimidine. Preferably, the 5-membered heteroaryl is selected from pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or ring B can be further substituted as described herein.

[0133] Embodiment 28a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein ring A is a 5-membered heteroaryl and ring B is a 6-membered heteroaryl. Preferably, the 6-membered heteroaryl is selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is selected from pyridine or pyrimidine. Preferably, the 5-membered heteroaryl is selected from pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or ring B can be further substituted as described herein.

[0134] Embodiment 29 of the present disclosure relates to a compound of any one of embodiments 1 to 20, wherein Ring A is a 6-membered heteroaryl and Ring B is a 5-membered heteroaryl. Preferably, the 6-membered heteroaryl is selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is selected from pyridine or pyrimidine. Preferably, the 5-membered heteroaryl is selected from pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or Ring B can be further substituted as described herein.

[0135] Embodiment 29a of the present disclosure relates to a compound of one of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, or 17a, 18a, 19a, or 20a, wherein ring A is a 6-membered heteroaryl and ring B is a 5-membered heteroaryl. Preferably, the 6-membered heteroaryl is selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is selected from pyridine or pyrimidine. Preferably, the 5-membered heteroaryl is selected from pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, or isoxazole. Ring A and / or ring B can be further substituted as described herein.

[0136] Embodiment 30 of the present disclosure is a compound of the formula: [ka] Compounds having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein: Y1 is NR 24 and Y2 is N; or Y1 is N and Y2 is NR 24 is; Ring A is phenyl; Ring B is phenyl or a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is -NH- or -O-; R 24 is H or C1-C3 alkyl; R 21 is C1-C3 alkyl; G is Cl, F or CN; R 3 is H; R 4 is H.

[0137] Embodiment 30a of the present disclosure is a compound of the formula: [ka] [ka] Compounds having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein: Y1 is NR 24 and Y2 is N; or Y1 is N and Y2 is NR 24 is Ring A is phenyl; Ring B is phenyl or a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is -NH- or -O-; R 24 is H or C1-C3 alkyl; R 21 is C1-C6 alkyl optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with —O—C1-C6 alkyl; NH2, NH—C1-C6 alkyl, cycloalkyl; or C2-C6 alkenyl; G is Cl, F or CN; R 3 is H; R 4 is H.

[0138] Embodiment 31 of the present disclosure is directed to a compound in which Y is NR 24 and Y2 is N.

[0139] Embodiment 31a of the present disclosure is directed to a compound in which Y1 is NR 24 and Y2 is N.

[0140] Embodiment 32 of the present disclosure is directed to an embodiment wherein Y1 is N and Y2 is NR 24 31. The compound of embodiment 30, wherein

[0141] Embodiment 32a of the present disclosure is directed to a compound in which Y1 is N and Y2 is NR 24 The compound of embodiment 30a, wherein

[0142] Embodiment 33 of the present disclosure is R 24 is H or methyl. Preferably, R 24 is H. Preferably, R 24 is methyl.

[0143] Embodiment 33a of the present disclosure is R 24 is H or methyl. Preferably, R 24 is H. Preferably, R 24 is methyl.

[0144] Embodiment 34 of the present disclosure is R 21 is methyl or ethyl. 21 is methyl. Preferably, R 21 is ethyl.

[0145] Embodiment 34a of the present disclosure is R 21 is C1-C6 alkyl optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocycloalkyl is optionally substituted with —O—C1-C6 alkyl. Embodiment 34b of the present disclosure is R 21 is C1-C6 alkyl.

[0146] Embodiment 34c of the present disclosure is R 21 is methyl or ethyl. 21 is methyl. Preferably, R 21 is ethyl.

[0147] Embodiment 34d of the present disclosure is R 21 is NH2 or NH-C1-C6 alkyl. Embodiment 34e of the present disclosure is R 21 is cycloalkyl.

[0148] Embodiment 35 of the present disclosure relates to compounds of embodiments 30-34, wherein G is F.

[0149] Embodiment 35a of the present disclosure relates to compounds of embodiments 30a, 31a, 32a, 33a, 34a, 34b, 34c, 34d, or 34e, wherein G is F.

[0150] Embodiment 36 of the present disclosure relates to a compound of one of embodiments 30-35, wherein Ring B is phenyl.

[0151] Embodiment 36a of the present disclosure relates to a compound of one of embodiments 30a, 31a, 32a, 33a, 34a, 34b, 34c, 34d, 34e, or 35a, wherein Ring B is phenyl.

[0152] Embodiment 37 of the present disclosure relates to a compound of any one of embodiments 30-35, wherein Ring B is a 6-membered heteroaryl. Preferably, each instance of the 6-membered heteroaryl is independently selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is pyridine or pyrimidine.

[0153] Embodiment 37a of the present disclosure relates to a compound of one of embodiments 30a, 31a, 32a, 33a, 34a, 34b, 34c, 34d, 34e, or 35a, wherein ring B is a 6-membered heteroaryl. Preferably, the 6-membered heteroaryl in each instance is independently selected from pyridine, pyridazine, pyrimidine, or pyrazine. Preferably, the 6-membered heteroaryl is pyridine or pyrimidine.

[0154] Embodiment 38 of the present disclosure relates to a compound of any of embodiments 1-37, which is a formate salt.

[0155] Embodiment 38 of the present disclosure relates to a compound of any of Embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, 17a, 18a, 19a, or 20a, 21a, 22a, 23a, 24a, 25a, 26a, 27a, 28a, 29a, 30a, 31a, 32a, 33a, 34a, 34b, 34c, 34d, 34e, 35a, 36a, or 37a, which is a formate salt.

[0156] Embodiment 39 of the present disclosure relates to a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0157] Embodiment 40 of the present disclosure relates to a compound according to any of embodiments 1 to 39 that is a non-covalent inhibitor of TEAD.

[0158] Embodiment 40a of the present disclosure relates to a compound of any of embodiments 1a, 2a, 3a, 4a, 5a, 6a, 7a, 8, 9a, 10a, 11a, 12a, 13a, 14a, 15a, 16a, 16b, 16c, 16d, 16e, 17a, 18a, 19a, or 20a, 21a, 22a, 23a, 24a, 25a, 26a, 27a, 28a, 29a, 30a, 31a, 32a, 33a, 34a, 34b, 34c, 34d, 34e, 35a, 36a, 37a, 38a, or 39a, wherein the compound is a non-covalent inhibitor of TEAD.

[0159] The compounds contemplated herein are described with reference to both general formulas and specific compounds. In addition, any compound 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.

[0160] It is understood that some compounds may exhibit 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 formula drawing.

[0161] Similarly, 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.

[0162] In some embodiments, 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 of skill in the art, an optically pure compound having one chiral center is a compound that consists essentially of one of 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, a compound exists in optically pure form.

[0163] 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.

[0164] In addition to the formulas and compounds described herein, the present disclosure also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof.

[0165] Unless otherwise specified, the specification of a compound herein includes pharmaceutically acceptable salts of such compound.

[0166] 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 mechanochemical methods such as spray drying, roller compaction, or microwave irradiation of the parent compound mixed with acid or base. Such methods may also include the addition of ionic and / or nonionic 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. Additionally, amorphous complexes are more easily friable, which improves compaction for filling the solid into capsule or tablet form.

[0167] III. Formulation and Administration Embodiment 41 of the present disclosure relates to a pharmaceutical composition comprising a compound of any one of embodiments 1 to 40 and a pharmaceutically acceptable carrier.

[0168] Embodiment 41a of the present disclosure relates to a pharmaceutical composition comprising a compound of any one of embodiments 1a-40a and a pharmaceutically acceptable carrier.

[0169] Embodiment 42 of the present disclosure relates to the pharmaceutical composition of embodiment 41, further comprising a second pharmaceutical agent.

[0170] Embodiment 42a of the present disclosure relates to the pharmaceutical composition of embodiment 41a, further comprising a second pharmaceutical agent.

[0171] Suitable dosage forms depend in part on the use or route of administration, for example, oral, transdermal, transmucosal, inhalant or injection (parenteral).Such dosage forms should allow compound to reach target cells.Other factors are well known in the art, and include considerations such as toxicity and dosage forms that delay compound or composition from exerting its effect.Techniques and formulations can generally be found in Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (incorporated herein by reference).

[0172] The compounds of the present disclosure (ie, any of the compounds described in embodiments 1-40, including any of the subembodiments thereof) can be formulated as pharmaceutically acceptable salts.

[0173] The compounds of the present disclosure (ie, any of the compounds described in embodiments 1a through 40a, including any of the subembodiments thereof) can be formulated as pharmaceutically acceptable salts.

[0174] Carrier or excipient can be used to produce compositions.Carrier or excipient can be selected to facilitate the 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 physiologically compatible solvents.Examples of physiologically compatible solvents include sterile water for injection (WFI), physiological saline and dextrose.

[0175] Compound can be administered by different routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal or inhalant.In some embodiments, compound can be administered by oral administration.For oral administration, for example, compound can be formulated into conventional oral dosage forms, such as capsules, tablets, and liquid preparations, such as syrups, elixirs and concentrated drops.

[0176] For inhalants, the compounds of the present disclosure can be formulated as dry powder or suitable solution, suspension or aerosol.Powder and solution can be formulated with suitable additives known in the art.For example, powder can contain suitable powder base such as lactose or starch, and solution can contain 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 etc. The compounds of the present disclosure may also be used in combination with other inhaled therapies, such as corticosteroids, e.g., fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists, e.g., albuterol, salmeterol, and formoterol; anticholinergics, e.g., ipratropium bromide or tiotropium; vasodilators, e.g., treprostinal and iloprost; enzymes, e.g., DNAase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides, e.g., single- or double-stranded DNA or RNA, siRNA; antibiotics, e.g., tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocril sodium; and sodium cromoglycate.

[0177] Oral pharmaceutical preparations can be obtained, for example, by combining active compound with solid excipient, optionally grinding the resulting mixture, and if desired, adding suitable excipients, and then processing the granular mixture 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 salt, such as sodium alginate, can be added.

[0178] Sugar-coated tablet core is provided with suitable coating.For this purpose, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and concentrated sugar solution, which can optionally contain suitable organic solvent or solvent mixture.For identification or to characterize different combinations of active compound dosage, dyes or pigments can be added to tablet or sugar-coated tablet coating.

[0179] Pharmaceutical preparations that can be used orally include push-fit capsules ("gelcaps") made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. 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). In addition, stabilizers may be added.

[0180] Alternatively, injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal and / or subcutaneous, can 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 can be formulated in solid form and redissolved or suspended immediately before use.Lyophilized form can also be produced.

[0181] Administration can also be by transmucosal, topical, transdermal or inhalant means. For transmucosal, topical or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to promote penetration. Transmucosal administration can be, for example, by nasal spray or suppository (rectal or vaginal).

[0182] 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, humectants, and antioxidants, as well as agents imparting 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, into which the active ingredient dissolved in a small amount of solvent (e.g., oil) is mixed. Furthermore, transdermal administration may include transdermal patches or dressings, such as adhesive bandages, impregnated with the active ingredient and, optionally, one or more carriers or diluents known in the art. Needless to say, for administration in the form of a transdermal delivery system, dosage administration is continuous rather than intermittent throughout the entire administration regimen.

[0183] The amount of various compounds administered is determined based on the IC 50The dosage can be determined by standard procedures, taking into account factors such as the biological half-life of the compound, the age, size, and weight of the subject, and the indication being treated. The importance of these and other factors is well known to those skilled in the art. Generally, the dosage is about 0.01 to 50 mg, or 0.1 to 20 mg per kg of subject being treated. Multiple doses may be used.

[0184] The compound of the present disclosure may be used in combination with other therapies for treating the same disease.Such combinations include administering the compound and one or more other therapeutic agents at different times, or administering the compound and one or more other therapeutic agents simultaneously.In some embodiments, the dosage of one or more of the compounds of the present disclosure or other therapeutic agents used in combination can be modified by methods well known to those skilled in the art, for example, to reduce the dosage of the compound or therapy used alone.

[0185] Combinations include use with other therapies, drugs, medical procedures, etc., and it is understood that the other therapy or procedure may be administered at a different time from the compounds of the present disclosure (e.g., within a short time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours), or within a longer time, such as 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 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 compounds of the present disclosure and one or more other pharmaceutical therapeutic agents delivered by different or the same route of administration. Combinations for any route of administration include the delivery of compounds of the present disclosure and one or more other pharmaceutical therapeutic agents delivered together by the same route of administration in any formulation, e.g., a formulation in which the two compounds are chemically linked so as to maintain their therapeutic activity when administered. In one embodiment, other drug therapies may be co-administered with one or more compounds of the present disclosure. Co-administration includes co-formulations or chemically linked compound formulations administered by the same or different routes, or administration of two or more compounds in separate formulations within a short time (e.g., within 1 hour, 2 hours, 3 hours, or up to 24 hours) of each other. Co-administration of separate formulations includes simultaneous administration via delivery through a single device, such as the same inhalant device, the same syringe, or administration from separate devices within a short time. Co-formulation of a compound of the present disclosure with one or more additional drug therapies delivered by the same route includes preparing materials together so that they can be administered by a single device, including separate compounds combined in a single formulation, or compounds that are chemically linked but modified to still maintain their biological activity. Such chemically linked compounds may have a bond that is substantially maintained in vivo, or the bond may degrade in vivo to separate the two active ingredients.

[0186] IV.How to use Disease indications and regulation of YAP / TEAD Representative 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 has also been 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. TAZ knockout, which results in PKD, has also been observed to downregulate other genes required for proper cilia development and function, implicating YAP as a potential therapeutic target for PKD (Steven W Plouffe et al.; Disease Implications of the Hippo / YAP Pathway; Trends Mol Med. 2015 Apr;21(4):212-222).

[0187] 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 thought 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).

[0188] 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 leads to 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).

[0189] 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 also mediate 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 mimetic that activates the constitutive androstane receptor, increasing YAP protein levels and inducing HCC. Furthermore, in a liver-specific transgenic model, induction of YAP overexpression led to abnormal hepatocyte proliferation, suppressed apoptosis, increased liver size, and increased HCC, implicating YAP as a potential therapeutic target for HCC (Steven W Plouffe et al., 2015).

[0190] epithelioid hemangioendothelioma Epithelioid hemangioendothelioma (EHE) is a vascular tumor commonly found in the lungs, bone, and skin. YAP / TAZ chromosomal translocations have been observed to occur in virtually all EHE cases, strongly suggesting that dysregulated YAP / TAZ fusion proteins may act as cancer drivers in EHE, implicating YAP as a potential therapeutic target for EHE (Steven W Plouffe et al., 2015).

[0191] breast cancer In various human breast cancer subtypes, YAP / TAZ activity correlates with increased risk of metastasis and decreased survival. TAZ is highly expressed in invasive breast cancer cell lines and primary breast tumors. Furthermore, 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 an oncogene-induced breast cancer model, implicating YAP as a potential therapeutic target for breast cancer (Steven W Plouffe et al., 2015).

[0192] lung cancer Both YAP and TAZ are highly expressed in human non-small cell lung cancer (NSCLC). 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 for NSCLC (Steven W Plouffe et al., 2015).

[0193] Malignant mesothelioma It was observed that knockdown of YAP in malignant mesothelioma cells was sufficient to inhibit cell proliferation and anchorage-independent growth, implicating the dysregulation of the Hippo pathway in malignant mesothelioma and YAP as a potential therapeutic target for malignant mesothelioma ( Steven W Plouffe et al., 2015 ).

[0194] Pancreatic cancer In pancreatic ductal adenocarcinoma (PDAC), YAP expression is often elevated, and increased YAP expression correlates with poor prognosis. Furthermore, YAP knockdown has been observed to result in decreased proliferation and anchorage-independent growth in pancreatic cancer cells, suggesting that YAP may play an important role in PDAC progression. It has also been reported that deletion of YAP is sufficient to prevent PDAC in a mouse model expressing mutated KRAS (Steven W Plouffe et al., 2015).

[0195] 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 when YAP / TAZ is depleted, cells overexpressing vGPCRs are unable to grow in a xenograft mouse model, indicating that YAP / TAZ is required for KSHV-induced tumorigenesis (Steven W Plouffe et al., 2015).

[0196] Uveal melanoma Eighty percent 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).

[0197] renal cell carcinoma YAP is involved in renal cell carcinoma (RCC). A recent report found that YAP activity is increased in RCC, that RCC tissues exhibit elevated YAP levels, and that knocking down YAP in RCC cell lines inhibited cell proliferation and increased apoptosis ( Steven W Plouffe et al., 2015 ).

[0198] colorectal cancer YAP is often overexpressed in colorectal cancer (CRC), and YAP / TAZ activity has been observed to correlate with decreased survival. In mice, induction of YAP overexpression in the intestine leads to metaplasia after 2 days, but cessation of induction results in intestinal regeneration. Furthermore, in knockout mice that developed adenomas after 13 weeks and polyps after 13 months, these phenotypes were prevented by YAP deletion, indicating that these pathologies are YAP-dependent. Additionally, increased YAP protein levels were observed in human CRC liver metastases and correlated with CRC recurrence (Steven W Plouffe et al., 2015).

[0199] 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).

[0200] Nervous system tumors The Hippo pathway is involved in several nervous system tumors. Loss-of-function mutations in NF2 cause neurofibromatosis type 2, a genetic disorder characterized by increased YAP expression and NF2-dependent mitochondrial dysfunction. 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 reduced 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).

[0201] 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.

[0202] 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 for and / or unlikely to benefit from cancer therapy.

[0203] In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10 mg 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 2500 mg per day. In other 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, 2500, 3000, 3500, 4000, 4500, or 5000 mg per day or more. In certain embodiments, the compound is administered continuously.

[0204] In certain embodiments, provided herein is a method for treating a disease or condition mediated by YAP or TEAD by administering to a mammal having the disease or condition at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg per day of any of the compounds described in one of embodiments 1-40, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, wherein the compound is administered on an empty stomach.

[0205] In certain embodiments, provided herein is a method for treating a disease or condition mediated by YAP or TEAD by administering to a mammal having the disease or condition at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, or 5000 mg per day of any of the compounds described in one of Embodiments 1a-40a, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, wherein the compound is administered on an empty stomach.

[0206] Embodiment 43 of the present disclosure relates to 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 any one of embodiments 1-40, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 41-42.

[0207] Embodiment 43a of the present disclosure relates to 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 any one of embodiments 1a-40a, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition of any one of embodiments 41a or 42a.

[0208] Embodiment 44 of the present disclosure relates to the method of embodiment 43, wherein the disease or condition is cancer, a neurodegenerative disease, a heart-related disorder, or a kidney-related disorder.

[0209] Embodiment 44a of the present disclosure relates to the method of embodiment 43a, wherein the disease or condition is cancer, a neurodegenerative disease, a heart-related disorder, or a kidney-related disorder.

[0210] Embodiment 45 of the present disclosure relates to the method of embodiment 43, 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.

[0211] Embodiment 45a of the present disclosure relates to the method of embodiment 43a, 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.

[0212] 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, a composition comprises any one or more compounds described herein together with one or more compounds therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect for the disease indication. In one embodiment, a 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, wherein the compounds are synergistically effective in treating cancer.

[0213] Embodiment 46 of the present disclosure relates to a method according to any one of embodiments 43-45, further comprising administering one or more additional therapeutic agents.

[0214] Embodiment 46a of the present disclosure relates to a method according to any one of embodiments 43a-45a, further comprising administering one or more additional therapeutic agents.

[0215] Embodiment 47 of the present disclosure is directed to a method for treating rheumatoid arthritis in which the one or more additional therapeutic agents are selected from the group consisting of i) 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 alkylating agent selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antibiotic selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, antimetabolites selected from methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immune checkpoint agents selected from PD-1 inhibitors, PD-L1 inhibitors, and anti-CTLA4 inhibitors; v) enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, and raloxifene. vi) a hormone or hormone antagonist selected from phenanthrene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI287, 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, flavopiridol, mesylate xii) kinase inhibitors selected from imatinib, 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), alto Rasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors and aromatase inhibitors (anastrozole, letrozole, extreamly octadecyl benzoate, benzodiazepine ... 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.

[0216] Embodiment 47a of the present disclosure is directed to a method for treating rheumatoid arthritis in which the one or more additional therapeutic agents are selected from the group consisting of i) 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 alkylating agent selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antibiotic selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, and 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) enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, and raloxifene. vi) a hormone or hormone antagonist selected from fen, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI287, 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, flavopiridol, mesylate xii) kinase inhibitors selected from imatinib, 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), alto Rasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors and aromatase inhibitors (anastrozole, letrozole, extreamly octadecyl benzoate, benzodiazepine ... 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.

[0217] In another embodiment, the present disclosure provides a method of 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, including 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 a chemotherapeutic agent (e.g., a chemotherapy drug), radiation therapy (e.g., X-ray, gamma ray, or electron, proton, neutron, or alpha particle beam), 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.

[0218] VI. Kit In another aspect, the present disclosure provides kits comprising one or more compounds described in any one of Embodiments 1-40, or pharmaceutically acceptable salts, deuterated analogs, tautomers, or stereoisomers thereof, or the pharmaceutical composition of one of Embodiments 41-42. In some embodiments, the compound or composition is packaged, for example, in a vial, bottle, or flask, which may be further packaged, for example, in a box, envelope, or bag. The compound or composition may be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal, for example, a human. The compound or composition may be approved for administration to a mammal, for example, a human, for a disease or condition mediated by YAP / TEAD. The kits described herein may include instructions for use and / or other indication that the compound or composition is suitable for 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.

[0219] In another aspect, the present disclosure provides kits comprising one or more compounds described in any one of Embodiments 1a-40a, or pharmaceutically acceptable salts, deuterated analogs, tautomers, or stereoisomers thereof, or the pharmaceutical composition of one of Embodiments 41a or 42a. In some embodiments, the compound or composition is packaged, for example, in a vial, bottle, or flask, which may be further packaged, for example, in a box, envelope, or bag. The compound or composition may be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal, for example, a human. The compound or composition may be approved for administration to a mammal, for example, a human, for a disease or condition mediated by YAP / TEAD. The kits described herein may include instructions for use and / or other indication that the compound or composition is suitable for 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.

[0220] 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 statistically significant, with a confidence level of at least 90%, or at least 95, 97, 98, 99%, or higher, that the assay signal represents binding to the target molecule, i.e., is distinguishable 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.

[0221] Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, a "low activity" compound is one that exhibits an inhibitory concentration (IC) of greater than 1 μM under standard conditions. 50 ) or effective concentration (EC 50 "Very low activity" means an IC50 activity greater than 100 μM under standard conditions.50 or EC 50 "Very low activity" means an IC 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 means 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., enzyme or other protein) activity 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 produced by the occurrence of an enzymatic reaction or other activity by the protein being measured.

[0222] "Background signal," in the context of binding assays, 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.

[0223] "Standard deviation" means the square root of the variance. Variance is a measure of how spread out a distribution is. It is calculated as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is: σ 2 = (1-2) 2 +(2-2) 2 +(3-2) 2 =0.667. 3

[0224] 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。.

[0225] 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 opposite side of the sensor chip surface is reflected, also inducing an evanescent wave in the gold film, which causes 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., due to binding of a ligand to a binding protein) causes a shift in the resonance angle. This angle shift can be measured, and 1000 RU corresponds 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, which indicates the association and dissociation of any biological reaction.

[0226] 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 discover new drugs by screening chemicals that act on specific enzymes or molecules. For example, if a chemical inactivates an enzyme, it may prove effective in preventing a disease-causing process within the cell. High-throughput methods allow researchers to very rapidly assay thousands of different chemicals against each target molecule using robotic handling systems and automated analysis of the results.

[0227] As used herein, "high throughput screening" or "HTS" refers to the rapid in vitro screening of large numbers of compounds (libraries), generally 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.

[0228] 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 responses of multiple candidate compounds. Multi-well microplates may also be used as carriers. Such multi-well microplates and methods for using them in multiple assays are known in the art and commercially available.

[0229] Screening assays may include controls for calibration and confirmation of proper operation of the assay components. Blank wells containing all the reactants but no members of the chemical library are typically included. As another example, a known inhibitor (or activator) of the enzyme for which a modulator is sought can be incubated with one sample in the assay, and the resulting decrease (or increase) in enzyme activity can be used as a comparative control or control. It will be 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.

[0230] 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.

[0231] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxides, as described in Gordon, A. J. and Ford, R. A., (1972) The Chemist's Companion: A Handbook of Practical Data, Techniques, and References, John Wiley and Sons, NY, Page 437.

[0232] 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 general 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.

[0233] In spectrofluorometric analysis, an enzyme is exposed to a substrate that changes its intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is non-fluorescent and is converted to a fluorophore through 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 spectrofluorometric analysis.

[0234] Fluorescence polarization (FP) is based on the slowing of the molecular rotation 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 empirically determined by measuring the vertical and horizontal components of fluorophore emission after excitation with plane-polarized light. As the molecular rotation of the fluorophore decreases, polarized emission increases. When a fluorophore is bound to a larger molecule (i.e., a receptor), the molecular rotation of the fluorophore slows, and the fluorophore generates a larger polarized signal. The magnitude of the polarized signal is quantitatively related to the degree of fluorescent ligand binding. Therefore, the polarization of the "bound" signal depends on the maintenance of high-affinity binding.

[0235] FP is a homogeneous technique, and the reaction is extremely rapid, taking seconds to minutes to reach equilibrium. The reagents are stable, large batches may be prepared, and high reproducibility is achieved. 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.

[0236] FP is particularly desirable because its readout is independent of luminescence intensity (Checovich, WJ, et al., (1995) Nature 375:254-256; Dandliker, WB, et al., (1981) Methods in Enzymology 74:3-28) and therefore is insensitive to the presence of colored compounds that quench 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.

[0237] 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.

[0238] Exemplary normal and polarized fluorescence readers include the POLARION® Fluorescence Polarization System (Tecan AG, Hombrechtikon, Switzerland). General multiwell plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multiwell plate spectrophotometer (both from Molecular Devices).

[0239] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interactions and has been described. 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 closely spaced fluorescent substances 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. This results in a shift in the emission spectrum of the sample, which can be measured using a fluorometer such as an fMAX multiwell fluorometer (Molecular Devices, Sunnyvale, Calif.).

[0240] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interaction with target molecules.SPA has been 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 plate (NEN Life Science Products, Boston, MA).

[0241] Target molecules can be bound to scintillator plates by various well-known means. Derivatized scintillant plates are available that can bind to fusion proteins, such as GST, His6, or Flag fusion proteins. When the target molecule is a protein complex or multimer, 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 a bound complex.

[0242] In a typical SPA assay, gene products in the expression pool are radioactively labeled and added to wells, where they interact with the immobilized target molecules and the solid phase, which is the scintillant coating. The assay can be measured immediately or allowed to reach equilibrium. In either case, once the radioactive label is sufficiently close to the scintillant coating, a signal is generated that can be detected by an instrument such as the TOPCOUNT NXT® Microplate Scintillation Counter (Packard BioScience Co., Meriden Conn.). 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.

[0243] In contrast, labeled proteins that do not bind to target molecules or only bind for a short time do not remain near the scintillant long enough to generate a signal above background. The 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 radioactive labels used during the expression process, but they do not generate a significant signal because they are in solution rather than interacting with the target molecule. Therefore, 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 achieved (Nichols et al., (1998) Anal. Biochem. 257:112-119).

[0244] General Synthesis The 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 also be used. The synthesis of typical compounds described herein may be achieved as described in the following examples. When available, reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0245] 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. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0246] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting 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.

[0247] The compounds of the present disclosure may contain one or more asymmetric or chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolving agents, etc.

[0248] 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-Chem 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.

[0249] 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 an enantiomerically pure or enriched compound is desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be used, as conventionally used in the art or as described in the examples.

[0250] Preparation of TEAD inhibitors containing imidazole sulfone-linked headpieces A. [ka]

[0251] B. Synthesis scheme of nitrogen-linked base amine hydrochloride intermediates. [ka]

[0252] C. Synthetic scheme for the ether-linked base amine hydrochloride intermediate [ka]

[0253] General scheme for the synthesis of 6-amine linked intermediates: [ka]

[0254] General procedure for the synthesis of 6-ether linked intermediates: [ka]

[0255] All compounds in Table 1 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 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38]

[0256] 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 1 The human mesothelioma cell line MSTO-211H was stably transfected with the pGL4.21 plasmid, which contains 12 copies of a synthetic promoter with a TEAD-responsive element driving expression of GTIIC. Puromycin was used to select transfected cells, and single-cell clones expressing this construct (termed MSTO-211H+12XGTIIC) were generated by limiting dilution. MSTO-211H cells express the Hippo pathway, leading to upregulation of YAP / TEAD-mediated transcription. 2Genetic alterations in key components of the TEAD pathway were characterized. 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 per well in a 96-well plate. 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 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 luminescence signal. The luminescence signal was normalized to the fluorescence signal to correct for any loss of cell viability over the 24-hour compound incubation period. The percentage of inhibition of the normalized luminescence signal, representing compound-mediated inhibition of TEAD-dependent transcription, was calculated at each compound concentration compared to the high and low controls. Data were analyzed using nonlinear regression to determine the IC of each compound. 50 Generated a value.

[0257] References 1. Dupont, S. et al. Role of YAP / TAZ in mechanotransduction. Nature474, 179-184 (2011). 2. Miyanaga, A. et al. Hippo pathway gene mutations in malignant mesothelioma: Revealed by RNA and targeted exon sequencing. Journal of Thoracic Oncology 10, 844-851 (2015). 3. Kaneda, A. et al. The novel potent TEAD inhibitor, K-975, inhibits YAP1 / TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma. Am J Cancer Res vol. 10 (2020).

[0258] Table 2 below provides data demonstrating 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. Absence of data in Table 2 indicates that the data is not available and is not indicative of activity. [Table 2-1] [Table 2-2]

[0259] All patents and other references cited herein 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 were individually incorporated by reference in its entirety.

[0260] 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.

[0261] 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. Accordingly, such additional embodiments are within the scope of the present disclosure and the appended claims.

[0262] The present disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, or limitation or limitations, not specifically described herein. The terms and expressions used are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude the features shown and described or equivalents thereof, but it is recognized that various modifications are possible within the scope of the present disclosure as claimed. Thus, while the present disclosure has been specifically described by embodiments and optional features, it should be understood that modifications and variations of the concepts described herein may be employed by those skilled in the art, and that such modifications and variations are considered to be within the scope of the present disclosure as defined by the appended claims.

[0263] Additionally, where features or aspects of the disclosure are 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 member or subgroup of members of the group thereby described herein.

[0264] Also, unless indicated to the contrary, when various numerical values ​​are provided for embodiments, 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 this disclosure.

[0265] Accordingly, additional embodiments are within the scope of this disclosure and the following claims.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y １ is NR ２４ and Y ２ is N; or Y １ is N, and Y ２ is NR ２４ is; R ２４ is H or C １ ~C ３ is alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl, cycloalkyl, or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is —O—, —NR ２０ -, -CR ２２ R ２３ -, -CR ２２ R ２３ O- or -CR ２２ R ２３ NH—; R ２０ is H or alkyl, and R ２２ is H, halogen, hydroxy, C １ ~C ３ Alkyl or C １ ~C ３ is alkoxy, and R ２３ is H, halogen or C １ ~C ３ alkyl, or R ２２ and R ２３ together with the carbon atom to which they are attached to form a carbonyl; R ２１ is a C optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; １ ~C ６ alkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are —O—C １ ~C ６ optionally substituted with alkyl, C １ ~C ６ Alkyl; NH ２ , NH-C １ ~C ６ alkyl, cycloalkyl; or C ２ ~C ６ alkenyl; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted with, and one or more R ５ alkoxy optionally substituted with Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted with 1 to 3 halogens. １ ~C ３ alkyl, provided that there is not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with —C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted with haloalkyl or —C(O)-alkenyl; heterocycloalkyl optionally substituted with —C(O)-alkyl, —C(O)-alkenyl or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ heterocycloalkylalkyl optionally substituted with —OH or heteroaryl; R ５ is halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

2. Formula (Ia), (Ib) or (Ic): 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog thereof, wherein: Y １ is NR ２４ and Y ２ is N; or Y １ is N, and Y ２ is NR ２４ is; R ２４ is H or C １ ~C ３ is alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl, cycloalkyl, or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is —O—, —NR ２０ -, -CR ２２ R ２３ -, -CR ２２ R ２３ O- or -CR ２２ R ２３ NH—; R ２０ is H or alkyl, and R ２２ is H, halogen, hydroxy, C １ ~C ３ Alkyl or C １ ~C ３ is alkoxy, and R ２３ is H, halogen or C １ ~C ３ alkyl, or R ２２ and R ２３ together with the carbon atom to which they are attached to form a carbonyl; R ２１ is a C optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; １ ~C ６ alkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are —O—C １ ~C ６ optionally substituted with alkyl, C １ ~C ６ Alkyl; NH ２ , NH-C １ ~C ６ alkyl, cycloalkyl; or C ２ ~C ６ alkenyl; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted with, and one or more R ５ alkoxy optionally substituted with Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted with 1 to 3 halogens. １ ~C ３ alkyl, provided that there is not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with —C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted with haloalkyl or —C(O)-alkenyl; heterocycloalkyl optionally substituted with —C(O)-alkyl, —C(O)-alkenyl or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ heterocycloalkylalkyl optionally substituted with —OH or heteroaryl; R5 is halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

3. Formula (I): 【Transformation 5】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein: Y １ is NR ２４ and Y ２ is N; or Y １ is N, and Y ２ is NR ２４ is; R ２４ is H or C １ ~C ３ is alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is —O—, —NR ２０ -, -CR ２２ R ２３ -, -CR ２２ R ２３ O- or -CR ２２ R ２３ NH—; R ２０ is H or alkyl, and R ２２ is H, halogen, hydroxy, C １ ~C ３ Alkyl or C １ ~C ３ is alkoxy, and R ２３ is H, halogen or C １ ~C ３ alkyl, or R ２２ and R ２３ together with the carbon atom to which they are attached to form a carbonyl; R ２１ is C １ ~C ６ is alkyl; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted with, and one or more R ５ alkoxy optionally substituted with Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted with 1 to 3 halogens. １ ~C ３ alkyl, provided that there is not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with —C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted with haloalkyl or —C(O)-alkenyl; heterocycloalkyl optionally substituted with —C(O)-alkyl, —C(O)-alkenyl or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ heterocycloalkylalkyl optionally substituted with —OH or heteroaryl; R ５ is halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

4. Formula (Ia) or (Ib): 【Transformation 6】 or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue thereof, wherein: Y １ is NR ２４ and Y ２ is N; or Y １ is N, and Y ２ is NR ２４ is; R ２４ is H or C １ ~C ３ is alkyl; Ring A is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Ring B is phenyl or a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is —O—, —NR ２０ -, -CR ２２ R ２３ -, -CR ２２ R ２３ O- or -CR ２２ R ２３ NH—; R ２０ is H or alkyl, and R ２２ is H, halogen, hydroxy, C １ ~C ３ Alkyl or C １ ~C ３ is alkoxy, and R ２３ is H, halogen or C １ ~C ３ alkyl, or R ２２ and R ２３ together with the carbon atom to which they are attached to form a carbonyl; R ２１ is C １ ~C ６ is alkyl; Each G is a halogen, OH, CN, one or more R ５ alkyl optionally substituted with, and one or more R ５ alkoxy optionally substituted with Each R ２ are independently H, halogen, —C(O)O-alkyl, or C optionally substituted with 1 to 3 halogens. １ ~C ３ alkyl, provided that there is not more than one R ２ is —C(O)O-alkyl; R ３ is H; halogen; alkenyl optionally substituted with cycloalkyl or heterocycloalkyl; heterocycloalkyl optionally substituted with —C(O)-alkyl; heterocycloalkenyl optionally substituted with C(O)-alkyl; heterocycloalkylalkyl optionally substituted with C(O)-alkyl; or heteroaryl optionally substituted with haloalkyl, cycloalkyl or cycloalkylalkyl; R ４ is H; alkyl; cycloalkyl optionally substituted with haloalkyl or —C(O)-alkenyl; heterocycloalkyl optionally substituted with —C(O)-alkyl, —C(O)-alkenyl or —C(O)-cycloalkyl; or —C(O)-alkyl, —C(O)—CH ２ heterocycloalkylalkyl optionally substituted with —OH or heteroaryl; R ５ is halogen or OH; v is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and q is 0, 1 or 2.

5. Q is -NH-, N(CH ３ )-, -O-, -CH ２ -, -C(O)-, -CH ２ —O—, —CF ２ -, -CHF-, -CH ２ -NH-, -CH(OH)-, -C(O)-NH- or -CH(OCH ３ 5. The compound according to claim 3 or claim 4, wherein:

6. The compound according to any one of claims 3 to 5, wherein Q is -NH- or -O-.

7. v is 0, 1, 2 or 3; Each G is selected from halogen, CN, and 1 to 3 R ５ C optionally substituted with １ ~C ３ independently selected from alkyl; Each R ２ is H, halogen, or CH ３ and R ５ is halogen or OH; The compound according to any one of claims 3 to 6.

8. v is 0, 1 or 2; Each G is selected from Cl, F, CN, and 1 to 3 R ５ C substituted with 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 7.

9. R ５ The compound of claim 8 , wherein is Cl or F.

10. The following formula: 【Transformation 7】 The compound according to any one of claims 3 to 5, having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf), wherein: Each G is selected from Cl, F, CN, and 1 to 3 R ５ C substituted with １ ~C ３ alkyl; and R ５ is a halogen.

11. The following formula: 【Transformation 8】 The compound of claim 10 having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein G is Cl, F or CN.

12. R ３ is optionally substituted with H; halogen; cyclopropyl or heterocycloalkyl; ２ ~C ４ Alkenyl; C(O)-CH ３ heterocycloalkyl optionally substituted with C(O)—CH ３ heterocycloalkenyl optionally substituted by C(O)—CH ３ heterocycloalkylalkyl optionally substituted with; or haloalkyl, cyclopropyl or cyclopropyl-CH ２ The compound according to claim 10 or 11, which is a 5- to 6-membered heteroaryl optionally substituted with -.

13. R ４ But H;C １ ~C ３ Alkyl; cycloalkyl optionally substituted with haloalkyl or -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 The compound of any one of claims 10 to 12, wherein the aryl is -OH; or 5- to 6-membered heteroaryl.

14. The following formula: 【Chemistry 9】 The compound according to any one of claims 3 to 5, having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein G is Cl, F or CN; R ３ is H; halogen; C optionally substituted with cyclopropyl or heterocycloalkyl ２ ~C ４ Alkenyl; C(O)-CH ３ heterocycloalkyl optionally substituted with C(O)—CH ３ heterocycloalkenyl optionally substituted by C(O)—CH ３ heterocycloalkylalkyl optionally substituted with; or haloalkyl, cyclopropyl or cyclopropyl-CH ２ - is a 5- to 6-membered heteroaryl optionally substituted with -; R ４ is H;C １ ~C ３ Alkyl; cycloalkyl optionally substituted with haloalkyl or -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.

15. R ３ is H; and R ４ The compound of claim 14, wherein is H.

16. R ３ is H; R ４ is H; and Y １ NR ２４ and Y ２ The compound of claim 14, wherein is N.

17. R ３ is H; R ４ is H; and Y １ is N, and Y ２ NR ２４ 15. The compound of claim 14, wherein:

18. R ２４ 18. The compound of claim 16 or 17, wherein is H or methyl.

19. R ２１ The compound according to any one of claims 14 to 18, wherein is methyl or ethyl.

20. The following formula: 【Chemistry 10-1】 【Chemistry 10-2】 A compound having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein Y １ is NR ２４ and Y ２ is N; or Y １ is N, and Y ２ is NR ２４ is Ring A is phenyl; Ring B is phenyl or a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is —NH— or —O—; R ２４ is H or C １ ~C ３ is alkyl; R ２１ is a C optionally substituted with halogen, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; １ ~C ６ alkyl, and the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each —O—C １ ~C ６ Optionally substituted with alkyl; NH ２ , NH-C １ ~C ６ alkyl, cycloalkyl; or C ２ ~C ６ alkenyl; G is Cl, F or CN; R ３ is H; R ４ is H.

21. The following formula: 【Chemistry 11】 A compound having one of or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analogue of any of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf); wherein Y １ is NR ２４ and Y ２ is N; Y １ is N, and Y ２ is NR ２４ is; Ring A is phenyl; Ring B is a 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; Q is —NH— or —O—; R ２４ is H or C １ ~C ３ is alkyl; R ２１ is C １ ~C ３ is alkyl; G is Cl, F or CN; R ３ is H; R ４ is H.

22. Y １ NR ２４ and Y ２ 22. The compound of claim 21, wherein is N.

23. Y １ is N, and Y ２ NR ２４ 22. The compound of claim 21, wherein:

24. R ２４ The compound of any one of claims 21 to 23, wherein is H or methyl.

25. R ２１ 25. The compound of claim 24, wherein is methyl or ethyl.

26. A formate salt of a compound according to any one of claims 1 to 25.

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

28. 28. The compound of any one of claims 1 to 27, which is a non-covalent inhibitor of a TEAD.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier.

30. 30. The pharmaceutical composition of claim 29, further comprising a second pharmaceutical agent.

31. 31. 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 any one of claims 1-28, or a pharmaceutically acceptable salt, deuterated analogue, tautomer or stereoisomer thereof, or a pharmaceutical composition of any one of claims 29-30.

32. 32. The method of claim 31, wherein the disease or condition is cancer, a neurodegenerative disease, a heart-related disorder, or a kidney-related disorder.

33. 32. The method of claim 31, 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.

34. 34. The method of any one of claims 31 to 33, further comprising administering one or more additional therapeutic agents.

35. 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) bleomycin, iii) antibiotics selected from 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 trimethoprim-4000; iv) an immune checkpoint agent selected from a PD-1 inhibitor, a PD-L1 inhibitor, and an anti-CTLA4 inhibitor; v) a hormone or hormone antagonist selected from enzalutamide, abiraterone, anastrozole, an androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) DJ-927, docetaxel, vii) a taxane selected from TPI287, 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) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) an anticancer drug 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) chemotherapy selected from 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, and aromatase inhibitors (anastrozole, letrozole, exemestane). xvi) a BRAF inhibitor; xvii) a Mek inhibitor; xviii) a c-Kit mutant inhibitor, xix) an EGFR inhibitor, xx) an epigenetic modulator; xxi) another adenosine axis blocker selected from CD39, CD38, A2AR, and A2BR; or xxii) an agonist of a TNFA superfamily member; and xxiii) an anti-ErbB2 mAb.

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