Transcriptional enhancer association domain (TEAD) transcription factor inhibitors and uses thereof - Patents.com

Abstract

Provided herein are compounds of Formula (I'), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), and pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Also provided are methods and kits comprising the compounds or compositions of the invention for treating and / or preventing a disease in a subject, e.g., a proliferative disease (e.g., cancer, such as carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer, etc.). Methods of inhibiting TEAD transcription factors (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject are provided.

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. USSN 63 / 180,418, filed April 27, 2021, and U.S. Provisional Application No. USSN 63 / 291,845, filed December 20, 2021, each of which is incorporated herein by reference. [Background technology]

[0002] Transcription enhancer associated domain (TEAD) transcription factors bind to the coactivators YAP / TAZ and regulate the transcription of the Hippo pathway. The Hippo signaling pathway plays an important role in organ size control and tumor suppression. Signal transduction in the Hippo signaling pathway involves a core kinase cascade, resulting in YAP / TAZ phosphorylation. Physiological or pathological inactivation of the Hippo signaling pathway leads to its dephosphorylation and nuclear accumulation. Nuclear YAP / TAZ binds to transcription enhancer associated domain (TEAD) to mediate the expression of target genes. The TEAD-YAP complex regulates organ development and the amplification of oncogenic factors in many cancers (e.g., sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, and breast cancer). Several genes in the Hippo signaling pathway (e.g., YAP1) have been identified as tumor suppressors, and mutations in these genes are associated with various human cancers. Furthermore, elevated YAP levels are associated with certain human cancers.

[0003] Palmitoylation of TEADs is required for their stability and function in the hippo signaling pathway. Attachment of the fatty acid palmitate to cysteine ​​residues regulates protein trafficking, membrane localization, and signaling activity. TEAD transcription factors have been shown to possess intrinsic palmitoylase-like activity and undergo autopalmitoylation. Summary of the Invention

[0004] Several small molecule TEAD inhibitors were recently disclosed in International Application Publication WO 2020 / 081572, published April 23, 2020, which is incorporated herein by reference. Described herein are TEAD inhibitors of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Compounds of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof, can inhibit the activity of transcription factors (e.g., TEAD family transcription factors) in cells, biological samples, tissues, or subjects. Disclosed herein are compounds that bind to a cysteine ​​located in the central pocket of the YAP-binding domain (YBD) on transcription factors (e.g., TEAD transcription factors). Methods for studying the inhibition of transcription factors (e.g., TEAD1, TEAD2, TEAD3, TEAD4) using the disclosed compounds, as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof, are also described. The compounds described herein may be useful as therapeutic agents for the prevention and / or treatment of diseases associated with overexpression and / or aberrant (e.g., increased or unwanted) activity of a transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). The compounds described herein may be useful for treating and / or preventing a disease or condition, e.g., a proliferative disease (e.g., cancer), in a subject in need thereof. Uses, methods of use, pharmaceutical compositions, and kits comprising the compounds described herein are also provided.

[0005] In one aspect, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R and R 4 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; R 1 , R 2 , and R 3 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; Z 1 is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; R a each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R a When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; m is 1 or 2; q is 1 or 2; t is 0, 1, 2, 3, or 4; z is 0, 1, 2, or 3).

[0006] Exemplary compounds of formula (I') include, but are not limited to, the following: [ka]

[0007] In another aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)Ra , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; R 4 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; R a each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R a Instances of, when present, together with the heteroatom to which they are attached can form an optionally substituted heterocycle.

[0008] Exemplary compounds of formula (I) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0009] In another aspect, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 1 , R 2 , and R 3 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR b , -N(R b )2, -SR b , -C(=O)R b , -C(=O)OR b , -C(=O)N(R b )2, -OC(=O)R b , -N(R b )C(=O)R b , -CN, and -NO2; R 5 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR b , -N(R b )2, -SR b , -C(=O)R b , -C(=O)OR b , -C(=O)N(R b )2, -OC(=O)R b , -N(R b )C(=O)R b , -CN, and -NO2; R beach occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R b When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; However, this compound has the formula: [ka] provided that the information is not of the type specified in the contract.

[0010] Exemplary compounds of formula (II) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0011] In one aspect, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 6 is -CF3 or -C≡CH; R 7 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR c, -N(R c )2, -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)N(R c )2, -OC(=O)R c , -N(R c )C(=O)R c , -CN, or -NO2; R 8 each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR c , -N(R c )2, -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)N(R c )2, -OC(=O)R c , -N(R c )C(=O)R c , -CN, or -NO2; R c each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R c When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; X 1 and X 2 are each independently -N= or -C(H)=; n is 0, 1, or 2).

[0012] Exemplary compounds of formula (III) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0013] In one aspect, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 9 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR d , -N(R d )2, -SR d , -C(=O)R d , -C(=O)OR d , -C(=O)N(R d )2, -OC(=O)R d , -N(R d )C(=O)R d , -CN, or -NO2; R d each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R d Instances of, when present, together with the heteroatom to which they are attached can form an optionally substituted heterocycle.

[0014] Exemplary compounds of formula (IV) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0015] In one aspect, the present disclosure provides a compound of formula (V): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 10 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR e , -N(R e )2, -SR e , -C(=O)R e , -C(=O)OR e , -C(=O)N(R e )2, -OC(=O)R e , -N(R e )C(=O)R e , -CN, or -NO2; R e each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R eInstances of, when present, together with the heteroatom to which they are attached can form an optionally substituted heterocycle.

[0016] Exemplary compounds of formula (V) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0017] In one aspect, the present disclosure provides a compound of formula (VI): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 11 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR f , -N(R f )2, -SR f , -C(=O)R f , -C(=O)OR f , -C(=O)N(R f )2, -OC(=O)R f , -N(R f )C(=O)R f , -CN, or -NO2; R feach occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R f Instances of, when present, together with the heteroatom to which they are attached can form an optionally substituted heterocycle.

[0018] Exemplary compounds of formula (VI) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0019] In one aspect, the present disclosure provides a compound of formula (VII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0020] In one aspect, the present disclosure provides a compound of formula (VIII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 12is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR h , -N(R h )2, -SR h , -C(=O)R h , -C(=O)OR h , -C(=O)N(R h )2, -OC(=O)R h , -N(R h )C(=O)R h , -CN, or -NO2; R h each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R h Instances of, when present, together with the heteroatom to which they are attached can form an optionally substituted heterocycle.

[0021] Exemplary compounds of formula (VIII) include, but are not limited to, the following: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0022] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound described herein and, optionally, a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount or a prophylactically effective amount of a compound described herein. The pharmaceutical compositions may be useful for treating and / or preventing a disease (e.g., a proliferative disease) in a subject in need thereof. The pharmaceutical compositions may be useful for inhibiting the activity of a TEAD family transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) in a subject, biological sample, tissue, or cell. The compounds described herein may be useful for treating and / or preventing a disease or condition, e.g., a proliferative disease (e.g., cancer (e.g., sarcoma, carcinoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)).

[0023] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein and, optionally, a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a therapeutically effective amount or a prophylactically effective amount of a compound described herein. The pharmaceutical composition may be useful for treating a disease (e.g., a proliferative disease) in a subject in need thereof, or for inhibiting the activity of a TEAD family transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) in a subject, biological sample, tissue, or cell. In certain embodiments, the disease is a proliferative disease (e.g., cancer (e.g., carcinoma, sarcoma, carcinoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)).

[0024] In another aspect, described herein are methods of treating and / or preventing diseases (e.g., proliferative diseases). Exemplary proliferative diseases that can be treated include diseases associated with overexpression, unwanted activity, or increased activity of TEAD transcription factors, such as cancer (e.g., carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer).

[0025] Another aspect relates to a method of inhibiting the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a biological sample (e.g., a cell, a tissue) using a compound described herein. In another aspect, described herein is a method of inhibiting the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject using a compound described herein. In certain embodiments, the method includes inhibiting TEAD1, TEAD2, TEAD3, or TEAD4.

[0026] Described herein are methods for treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein or a pharmaceutical composition thereof. In certain embodiments, the methods described herein further comprise administering to the subject an additional pharmaceutical agent. Also described are methods for inhibiting cancer cells in a cell, comprising contacting the cell with an effective amount of a compound as described herein or a pharmaceutical composition thereof. In certain embodiments, the methods described herein further comprise contacting the cell with an additional pharmaceutical agent (e.g., an antiproliferative agent).

[0027] In yet another aspect, the disclosure provides compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), and Formula (VII), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof, for use in treating a disease (e.g., a proliferative disease, e.g., cancer) in a subject.

[0028] Another aspect of the present disclosure relates to a kit comprising a container containing a compound described herein or a pharmaceutical composition thereof. The kits described herein may contain a single dose or multiple doses of the compound or pharmaceutical composition. The kits may be useful in the methods of the present disclosure. In certain embodiments, the kits further comprise instructions for using the compound or pharmaceutical composition. The kits described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA), such as prescribing information.

[0029] The details of one or more embodiments of the invention are described herein. Other features, objects, and advantages of the invention will be apparent from the detailed description, examples, drawings, and claims.

[0030] definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are defined in the Handbook of Chemistry and Physics, 75 th The Periodic Table of Elements, CAS version, is identified on the endpaper of the Ed., and specific functional groups are generally defined as described therein. Further information on general principles of organic chemistry, as well as specific functional groups and reactivities, can be found in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0031] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0032] During the ceremony, [ka] is a single bond, and the stereochemistry of the moiety directly attached to it is not specified, [ka] is absent or a single bond, [ka] is a single or double bond.

[0033] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium. 19 F 18 Substitution by F, or 12 C 13 C or 14 Compounds having this structure except for substitution by C are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0034] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 The term "alkyl" is intended to encompass alkyls of the formula:

[0035] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0036] The term "alkyl" refers to the radical of a straight- or branched-chain saturated hydrocarbon group having from 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, e.g., F) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu) unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl (e.g., substituted C 1-6 alkyl, for example, -CF3, -Bn).

[0037] The term "haloalkyl" refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0038] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1-10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, heteroalkyl groups are saturated groups having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkyl groups are saturated groups having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, heteroalkyl groups are saturated groups having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkyl groups are saturated groups having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkyl groups are saturated groups having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0039] The term "alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 10 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 In alkenyl groups, a C=C double bond with no specified stereochemistry (e.g., -CH=CHCH3 or [ka] ) may be an (E)-double bond or a (Z)-double bond.

[0040] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur located within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, heteroalkenyl groups are groups having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl groups"). 2-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0041] The term "alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 10 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0042] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur located within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC"). 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0043] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3-14 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the aforementioned C 3-6Included are carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 As the carbocyclyl group, the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., including fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), may be saturated, and may contain one or more carbon-carbon double bonds or carbon-carbon triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups whose points of attachment are on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0044] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0045] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, where valence allows. Heterocyclyl groups can be monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system (a "bicyclic heterocyclyl") or a tricyclic system (a "tricyclic heterocyclyl")), can be saturated, and can contain one or more carbon-carbon double bonds or carbon-carbon triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups at the points of attachment on the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups at the points of attachment on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

[0046] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0047] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7 tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0048] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0049] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl portion.

[0050] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic arrangement) having carbon atoms and 1 to 4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be to a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups whose points of attachment are on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) allow the point of attachment to be in either ring, i.e., the heteroatom-bearing ring (e.g., 2-indolyl) or the heteroatom-free ring (e.g., 5-indolyl).

[0051] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is thiophene, benzothiophene, furan, isobenzofuran, pyrrole, imidazole, pyrazole, pyrazine, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, triazole, tetrazole, oxazole, isoxazole, thiazole, oxazole, and the like.

[0052] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0053] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0054] The term "unsaturated bond" refers to a double or triple bond.

[0055] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0056] The term "saturated" refers to a moiety that does not contain any double or triple bonds, i.e., that contains only single bonds.

[0057] The suffix "-ene" added to a group indicates that the group is a divalent moiety. For example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0058] Unless expressly specified otherwise, a group is optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom present on a group is replaced with an acceptable substituent, e.g., a substituent that results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include all permissible substituents of organic compounds, including substitution with any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. It is not intended that the present invention be limited in any way by the exemplary substituents described herein.

[0059] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa)3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C 1-10 アルキル、C 1-10 ペルハロアルキル、C 2-10 アルケニル、C 2-10Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd substituted with X groups - is the counterion; or two geminal hydrogens on a carbon atom are groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by; R aa Each instance of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Rbb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with X group; - is the counterion; R cc Each instance of independently represents hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(Rff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd The substituents may combine to form =O or =S; X - is the counterion; R ee Each instance of C 1-6 Alkyl, C 1-6 Perhaloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of independently represents hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups join to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2+ X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl), -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 Alkyl 2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 Alkyl 3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can combine to form =O or =S; X - is the counter ion.

[0060] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0061] The term "hydroxyl" or "hydroxy" refers to an -OH group. The term "substituted hydroxyl" or "substituted hydroxyl" refers, by extension, to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -OR aa , -ON(R bb )2, -OC(=O)SR aa, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb ))2, wherein X - , R aa , R bb , and R cc is as defined herein.

[0062] The term "amino" refers to the group -NH. The term "substituted amino" extends to mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0063] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc)2, and -NHP(=O)(N(R bb )2)2)2, wherein R aa , R bb , and R cc is as defined herein, and —NH(R bb ) group R bb is not hydrogen.

[0064] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2)2)2, wherein R aa , R bb , and R cc is as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0065] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein.

[0066] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2ORaa wherein R aa and R bb is as defined herein.

[0067] The term "sulfinyl" refers to -S(=O)R aa refers to a group, wherein R aa is as defined herein.

[0068] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1 )2, wherein R X1is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 The groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

[0069] The term "carbonyl" refers to the carbon directly attached to the parent molecule being sp 2 refers to a group that is hybridized and substituted with an oxygen, nitrogen, or sulfur atom, such as a ketone (-C(=O)R aa ), carboxylic acid (-CO2H), aldehyde (-CHO), ester (-CO2R aa , -C(=O)SR aa , -C(=S)SR aa ), amide (-C(=O)N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2), and imine (-C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb ) 2) wherein R aa and R bb is as defined herein.

[0070] The term "silyl" refers to -Si(R aa ) groups, where R aa is as defined herein.

[0071] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0072] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NRcc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups join to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined above.

[0073] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2Raa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined above. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0074] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0075] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc) ), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate.

[0076] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- These include, but are not limited to, dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0077] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacylate. Clopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorsalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,Examples of suitable amines include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0078] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc)2, and -P(=O)(N(R bb )2)2, in which X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0079] Examples of oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2-methyl- ... ,2,2-Trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methyl 4-chloroethoxypiperazinyl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethoxy , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl )methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylsilyl isopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate ester, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p -Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-( The alkyl esters include, but are not limited to, alkyl esters such as (methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). ,

[0080] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a "thiol protecting group"). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(Rbb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, including, but not limited to, wherein R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0081] A "counterion" or "anionic counterion" is a negatively charged group attached to a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3- 、 HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- 、 B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0082] As used herein, "leaving group" (LG) is an art-recognized term that refers to a molecular fragment (the molecular fragment is an anion or a neutral molecule) that leaves with an electron pair in a heterolytic bond cleavage. As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, e.g., Smith, March, Advanced Organic Chemistry 6 th ed. (501-502). Exemplary leaving groups include halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2, where R aa , R bb , and R cc are as defined herein).

[0083] As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4, or more instances, but also encompasses ranges such as 1-4, 1-3, 1-2, 2-4, 2-3, and 3-4 (inclusive).

[0084] The term "carbohydrate" or "saccharide" refers to an aldehyde or ketone derivative of a polyhydric alcohol. Carbohydrates include relatively small molecular compounds (e.g., sugars) as well as macromolecular or polymeric substances (e.g., starch, glycogen, and cellulose polysaccharides). The term "sugar" refers to a monosaccharide, disaccharide, or polysaccharide. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed into smaller carbohydrates. Most monosaccharides have the general formula C y H 2y O y (e.g., CH 12 O6 (a hexose such as glucose), where y is an integer greater than or equal to 3. Certain polyhydric alcohols not represented by the general formula above may also be considered monosaccharides. For example, deoxyribose has the formula CH 10O4 and are monosaccharides. Monosaccharides are usually composed of five or six carbon atoms and are called pentoses and hexoses, respectively. If a monosaccharide contains an aldehyde, it is called an aldose; if it contains a ketone, it is called a ketose. Monosaccharides can also be composed of three, four, or seven carbon atoms in the aldose or ketose form, called trioses, tetroses, and heptoses, respectively. Glyceraldehyde and dihydroxyacetone are considered aldotriose and ketotriose sugars, respectively. Examples of aldoterose sugars include erythrose and threose. Examples of ketotelose sugars include erythrulose. Aldopentose sugars include ribose, arabinose, xylose, and lyxose, while ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose. Examples of aldohexose sugars include glucose (e.g., dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose, while ketohexose sugars include fructose, psicose, sorbose, and tagatose. Ketoheptose sugars include sedoheptulose. Each carbon atom in a monosaccharide bearing a hydroxyl group (-OH) is asymmetric, except for the first and last carbons, which result in a stereogenic center with two possible configurations (R or S). Because of this asymmetry, a given monosaccharide formula can have multiple isomers. For example, the aldohexose D-glucose has the formula CH 12 O6, and all but two of its six carbon atoms are stereoisomeric, while D-glucose has 16 (i.e., 2 4) is one of the possible stereoisomers of the α-saccharide. The D or L assignment is made according to the orientation of the asymmetric carbon furthest from the carbonyl group. In a standard Fischer projection, if the hydroxyl group is on the right, the molecule is a D-sugar; otherwise, it is an L-sugar. The aldehyde or ketone group of a straight-chain monosaccharide can reversibly react with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between the two carbon atoms. Five- and six-atom rings, called furanose and pyranose forms, respectively, exist in equilibrium with the straight-chain form. During the conversion from the straight-chain form to the cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a stereocenter with two possible configurations: the oxygen atom can be located either above or below the plane of the ring. The resulting pair of possible stereoisomers is called anomers. In the α-anomer, the -OH substituent on the anomeric carbon is opposite (trans) to the -CHOH side branch of the ring. The alternative form, in which the -CHOH substituent and the anomeric hydroxyl are on the same side of the ring plane (cis), is called the β anomer. Carbohydrates containing two or more linked monosaccharide units are called disaccharides or polysaccharides (e.g., trisaccharides), respectively. Two or more monosaccharide units are linked together by a covalent bond known as a glycosidic bond, formed by a dehydration reaction, resulting in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from the other monosaccharide. Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, or rutinose. Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose. The term carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.

[0085] The term "heteroatom" refers to an atom that is not hydrogen or carbon. In certain embodiments, a heteroatom is nitrogen. In certain embodiments, a heteroatom is oxygen. In certain embodiments, a heteroatom is sulfur.

[0086] The term "small molecule" refers to a molecule having a relatively low molecular weight, whether naturally occurring or artificially produced (e.g., by chemical synthesis). Typically, small molecules are organic compounds (i.e., contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocycles). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges are also possible (e.g., at least about 200 g / mol and up to about 500 g / mol). In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as an "organometallic small molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug has already been deemed safe and effective for human or animal use by the appropriate government or regulatory agency. For example, drugs approved for human use are listed by the FDA in 21 CFR §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference.Veterinary drugs are listed by the FDA at 21 CFR §§ 500-589, which are incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.

[0087] The "molecular weight" of the monovalent moiety -R is calculated by subtracting 1 from the molecular weight of the compound RH. The "molecular weight" of the divalent moiety -L- is calculated by subtracting 2 from the molecular weight of the compound HLH.

[0088] A "hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. The hydrocarbon chain includes (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain, (2) optionally one or more hydrogen atoms on the chain(s) of carbon atoms, and (3) optionally one or more substituents ("non-chain substituents" that are not hydrogen) on the chain(s) of carbon atoms. A chain of carbon atoms is made up of consecutively connected carbon atoms ("chain atoms") and does not include hydrogen atoms or heteroatoms. However, the non-chain substituents of a hydrocarbon chain can include any atom, including hydrogen atoms, carbon atoms, and heteroatoms. For example, a hydrocarbon chain -C A H(C B H2C C H3)- has one chain atom C A , C A one hydrogen atom on the chain, and a non-chain substituent -(C B H2C C H3) is included. x The term "hydrocarbon chain" refers to a hydrocarbon chain that contains x chain atoms (or atoms) between two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used to define the hydrocarbon chain. For example, -CH(C2H5)- is a C1 hydrocarbon chain; [ka] is a C hydrocarbon chain. When a range of values ​​is used, the meaning of the range is as described herein. For example, C 3-10A hydrocarbon chain refers to a hydrocarbon chain in which the number of chain atoms in the shortest carbon atom chain immediately between the two radicals of the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. The hydrocarbon chain may be saturated (e.g., -(CH2)4-). The hydrocarbon chain may be unsaturated and may contain one or more C=C and / or C≡C bonds anywhere in the hydrocarbon chain. For example, -CH=CH-(CH2)2-, -CH2-C≡C-CH2-, and -C≡C-CH=CH- are all examples of unsubstituted and unsaturated hydrocarbon chains. In certain embodiments, the hydrocarbon chain is unsubstituted (e.g., -C≡C- or -(CH2)4-). In certain embodiments, the hydrocarbon chain is substituted (e.g., -CH(C2H5)- and -CF2-). Any two substituents on the hydrocarbon chain can be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring. For example, [ka] are all examples of hydrocarbon chains. In contrast, in certain embodiments, [ka] is not within the scope of the hydrocarbon chains described herein. x When a chain atom of the hydrocarbon chain is replaced with a heteroatom, the resulting group is C x-1 In contrast to hydrocarbon chains, C chain atoms are replaced by heteroatoms x It is called a hydrocarbon chain. For example, [ka] is a C3 hydrocarbon chain in which one chain atom has been replaced with an oxygen atom.

[0089] The terms "crystalline" or "crystalline form" refer to a solid form that exhibits substantial three-dimensional order. In certain embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises one or more clearly defined peaks.

[0090] As used herein, the term "salt" refers to any salt, including pharmaceutically acceptable salts.

[0091] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations, formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0092] The term "solvate" refers to a form of a compound or its salt associated with a solvent, usually by solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, including both stoichiometric and non-stoichiometric solvates. In some cases, the solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include, but are not limited to, hydrates, ethanolates, and methanolates.

[0093] The term "hydrate" refers to a compound that is bound to water. Typically, the number of water molecules contained in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0094] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers varies depending on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0095] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." 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, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomer, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0096] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate). All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0097] The term "prodrug" refers to a compound having a cleavable group that, upon solvolysis or under physiological conditions, becomes a compound described herein that is pharmaceutically active in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, acid anhydride, or mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant to the compounds described herein are specific prodrugs. In some cases, it is desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The compounds described herein can be used in combination with C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C 12 Substituted aryl and C7-C 12 Aryl alkyl esters may be preferred.

[0098] The terms "composition" and "formulation" are used interchangeably.

[0099] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)), or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female, at any stage of development. The non-human animal may be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0100] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (such as Papanicolaou smears or blood smears) or samples of cells obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and separating their components, such as by centrifugation). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0101] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0102] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of disease have appeared or been observed. In other embodiments, treatment may be administered even in the absence of signs or symptoms of disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may also be continued after symptoms have subsided, e.g., to delay or prevent recurrence.

[0103] The terms "condition," "disease," and "disorder" are used interchangeably.

[0104] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the method of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple doses.

[0105] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic effect in treating a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms, signs, or pathogenesis of a condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit a TEAD transcription factor. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a proliferative disease.

[0106] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition or one or more symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient to inhibit a TEAD transcription factor. In certain embodiments, a prophylactically effective amount is an amount sufficient to treat a proliferative disease.

[0107] As used herein, in reference to a protein, e.g., a TEAD transcription factor, the term "inhibit" or "inhibition" refers to a reduction in the activity of the transcription factor. In some embodiments, the term refers to a reduction in the level of activity, e.g., TEAD1, TEAD2, TEAD3, or TEAD4 activity, to a level that is statistically significantly lower than an initial level, which may be, e.g., a baseline level of activity. In some embodiments, the term refers to a reduction in the level of enzymatic activity, e.g., TEAD1, TEAD2, TEAD3, or TEAD4 activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the initial level, which may be, e.g., a baseline level of activity of the transcription factor.

[0108] "Proliferative disease" refers to a disease caused by abnormal growth or expansion of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases may be associated with: 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0109] The term "angiogenesis" refers to the physiological process by which new blood vessels are formed from pre-existing vessels. Angiogenesis differs from vasculogenesis, which is the de novo formation of endothelial cells from mesodermal cell precursors. The first blood vessels in the developing embryo are formed by vasculogenesis, and angiogenesis subsequently accounts for most blood vessel growth during normal and abnormal development. Angiogenesis is an important process not only in growth and development, but also in wound healing and granulation tissue formation. However, angiogenesis is also a fundamental step in the transition of tumors from benign to malignant states, leading to the use of angiogenesis inhibitors in cancer treatment. Angiogenesis can be chemically stimulated by angiogenic proteins such as growth factors (e.g., VEGF). "Pathological angiogenesis" refers to abnormal (e.g., excessive or insufficient) angiogenesis that leads to and / or is associated with disease.

[0110] The terms "neoplasm" and "tumor" are used interchangeably herein to refer to an abnormal mass of tissue in which the growth of the mass exceeds and is uncoordinated with normal tissue. Neoplasms or tumors can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, characteristically grow slower than malignant neoplasms, and remain localized at the site of origin. Furthermore, benign neoplasms lack the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenoma, acrochordoma, senile hemangioma, seborrheic keratosis, lentigo, and sebaceous hyperplasia. In some cases, certain "benign" tumors can later give rise to malignant neoplasms. This may be due to additional genetic alterations in a subpopulation of the tumor's neoplastic cells; these tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and exhibit characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastatic" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, and are typically distinguishable by the presence of a "secondary tumor" or "secondary cell mass" of the histological type of the primary or original tumor, rather than the histological type of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to bone is referred to as metastatic prostate cancer, and includes cancerous prostate cancer cells growing in bone tissue.

[0111] The term "cancer" refers to a type of disease characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissue. See, e.g., Stedman's Medical Dictionary, 25 thed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, carcinoma of the breast, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; stomach cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL), and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, lymphoma, and anaplastic large cell lymphoma; leukemia / lymphoma combinations of one or more of the above; and multiple myeloma (MM)), heavy chain disorders (e.g., alpha chain disorders, gamma chain disorders, mu chain disorders); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic hypertension) Myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), aetiological myelodysplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer);Ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma) Cancer (BCC)); small intestine cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovium; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0112] A "transcription factor" is a type of protein involved in the process of transcribing DNA into RNA. Transcription factors function independently or with other proteins in complexes to induce or repress transcription. Transcription factors contain at least one DNA-binding domain that confers the ability to bind to specific sequences of DNA. Other proteins, such as coactivators, chromatin remodelers, histone acetyltransferases, histone deacetylases, kinases, and methylases, are also essential for gene regulation but are not transcription factors because they lack DNA-binding domains. These exemplary human transcription factors include AC008770.3, AC023509.3, AC092835.1, AC138696.1, ADNP, ADNP2, AEBP1, AEBP2, AHCTF1, AHDC1, AHR, AHRR, AIRE, AKAP8, AKAP8L, AKNA, ALX1, ALX3, ALX4, ANHX, ANKZF1, AR, ARGFX, ARHGAP35, ARID2, ARID 3A, ARID3B, ARID3C, ARID5A, ARID5B, ARNT, ARNT2, ARNTL, ARNTL2, ARX, ASCL1, ASCL2, ASCL3, ASCL4, ASCL5, ASH1 L, ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, ATF6B, ATF7, ATMIN, ATOH1, ATOH7, ATOH8, BACH1, BACH2, BARHL1, BARHL2, BARX1, BARX2, BATF, BATF2, BATF3, BAZ2A, BAZ2B, BBX, BCL11A, BCL11B, BCL6, BCL6B, BHLHA15, BHLHA9, BHLHE22, BHLHE23, BHLHE40, BHLHE41, BNC1, BNC2, BORCS-MEF2B, BPTF, BRF2, BSX, C11orf95, CAMTA1, CAMTA2, CARF, CASZ1 , CBX2, CC2D1A, CCDC169-SOHLH2, CCDC17, CDC5L, CDX1, CDX2, CDX4, CEBPA, CEBPB, CEBPD, CEBPE, CEBPG, CEBPZ, C ENPA, CENPB, CENPBD1, CENPS, CENPT, CENPX, CGGBP1, CHAMP1, CHCHD3, CIC, CLOCK, CPEB1, CPXCR1, CREB1, CREB3,CREB3L1、CREB3L2、CREB3L3、CREB3L4、CREB5、CREBL2、CREBZF、CREM、CRX、CSRNP1、CSRNP2、CSRNP3、CTCF、CTCFL、CUX1、CUX2、CXXC1、CXXC4、CXXC5、DACH1、DACH2、DBP、DBX1、DBX2、DDIT3、DEAF1、DLX1、DLX2、DLX3、DLX4、DLX5、DLX6、DMBX1、DMRT1、DMRT2、DMRT3、DMRTA1、DMRTA2、DMRTB1、DMRTC2、DMTF1、DNMT1、DNTTIP1、DOT1L、DPF1、DPF3、DPRX、DR1、DRAP1、DRGX、DUX1、DUX3、DUX4、DUXA、DZIP1、E2F1、E2F2、E2F3、E2F4、E2F5、E2F6、E2F7、E2F8、E4F1、EBF1、EBF2、EBF3、EBF4、EEA1、EGR1、EGR2、EGR3、EGR4、EHF、ELF1、ELF2、ELF3、ELF4、ELF5、ELK1、ELK3、ELK4、EMX1、EMX2、EN1、EN2、EOMES、EPAS1、ERF、ERG、ESR1、ESR2、ESRRA、ESRRB、ESRRG、ESX1、ETS1、ETS2、ETV1、ETV2、ETV3、ETV3L、ETV4、ETV5、ETV6、ETV7、EVX1、EVX2、FAM170A、FAM200B、FBXL19、FERD3L、FEV、FEZF1、FEZF2、FIGLA、FIZ1、FLI1、FLYWCH1、FOS、FOSB、FOSL1、FOSL2、FOXA1、FOXA2、FOXA3、FOXB1、FOXB2、FOXC1、FOXC2、FOXD1、FOXD2、FOXD3、FOXD4、FOXD4L1、FOXD4L3、FOXD4L4、FOXD4L5、FOXD4L6、FOXE1、FOXE3、FOXF1、FOXF2、FOXG1、FOXH1、FOXI1、FOXI2、FOXI3、FOXJ1、FOXJ2、FOXJ3、FOXK1、FOXK2、FOXL1、FOXL2、FOXM1、FOXN1、FOXN2、FOXN3、FOXN4、FOXO1、FOXO3、FOXO4、FOXO6、FOXP1、FOXP2、FOXP3、FOXP4、FOXQ1、FOXR1、FOXR2、FOXS1、GABPA、GATA1、GATA2, GATA3, GATA4, GATA5, GATA6, GATAD2A, GATAD2B, GBX1, GBX2, GCM1, G CM2、GFI1、GFI1B、GLI1、GLI2、GLI3、GLI4、GLIS1、GLIS2、GLIS3、GLMP、GLYR 1、GMEB1、GMEB2、GPBP1、GPBP1L1、GRHL1、GRHL2、GRHL3、GSC、GSC2、GSX1、GS X2、GTF2B、GTF2I、GTF2IRD1、GTF2IRD2、GTF2IRD2B、GTF3A、GZF1、HAND1、HAN D2、HBP1、HDX、HELT、HES1、HES2、HES3、HES4、HES5、HES6、HES7、HESX1、HEY1 HEY2、HEYL、HHEX、HIC1、HIC2、HIF1A、HIF3A、HINFP、HIVEP1、HIVEP2、HIVE P3、HKR1、HLF、HLX、HMBOX1、HMG20A、HMG20B、HMGA1、HMGA2、HMGN3、HMX1、HM X2、HMX3、HNF1A、HNF1B、HNF4A、HNF4G、HOMEZ、HOXA1、HOXA10、HOXA11、HOXA1 3、HOXA2、HOXA3、HOXA4、HOXA5、HOXA6、HOXA7、HOXA9、HOXB1、HOXB13、HOXB2 、HOXB3、HOXB4、HOXB5、HOXB6、HOXB7、HOXB8、HOXB9、HOXC10、HOXC11、HOXC1 2、HOXC13、HOXC4、HOXC5、HOXC6、HOXC8、HOXC9、HOXD1、HOXD10、HOXD11、HOX D12、HOXD13、HOXD3、HOXD4、HOXD8、HOXD9、HSF1、HSF2、HSF4、HSF5、HSFX1、HS FX2、HSFY1、HSFY2、IKZF1、IKZF2、IKZF3、IKZF4、IKZF5、INSM1、INSM2、IRF1 、IRF2、IRF3、IRF4、IRF5、IRF6、IRF7、IRF8、IRF9、IRX1、IRX2、IRX3、IRX4、IR X5、IRX6、ISL1、ISL2、ISX、JAZF1、JDP2、JRK、JRKL、JUN、JUNB、JUND、KAT7、K CMF1、KCNIP3、KDM2A、KDM2B、KDM5B、KIN、KLF1、KLF10、KLF11、KLF12、KLF13、KLF14、KLF15、KLF16、KLF17、KLF2、KLF3、KLF4、KLF5、KLF6、KLF7、KLF8、KLF 9、KMT2A、KMT2B、L3MBTL1、L3MBTL3、L3MBTL4、LBX1、LBX2、LCOR、LCORL、LEF 1、LEUTX、LHX1、LHX2、LHX3、LHX4、LHX5、LHX6、LHX8、LHX9、LIN28A、LIN28B、 LIN54、LMX1A、LMX1B、LTF、LYL1、MAF、MAFA、MAFB、MAFF、MAFG、MAFK、MAX、MAZ 、MBD1、MBD2、MBD3、MBD4、MBD6、MBNL2、MECOM、MECP2、MEF2A、MEF2B、MEF2C、 MEF2D、MEIS1、MEIS2、MEIS3、MEOX1、MEOX2、MESP1、MESP2、MGA、MITF、MIXL1、 MKX、MLX、MLXIP、MLXIPL、MNT、MNX1、MSANTD1、MSANTD3、MSANTD4、MSC、MSGN1、MSX1、MSX2、MTERF1、MTERF2、MTERF3、MTERF4、MTF1、MTF2、MXD1、MXD3、MXD 4、MXI1、MYB、MYBL1、MYBL2、MYC、MYCL、MYCN、MYF5、MYF6、MYNN、MYOD1、MYOG 、MYPOP、MYRF、MYRFL、MYSM1、MYT1、MYT1L、MZF1、NACC2、NAIF1、NANOG、NANOG NB、NANOGP8、NCOA1、NCOA2、NCOA3、NEUROD1、NEUROD2、NEUROD4、NEUROD6、N EUROG1、NEUROG2、NEUROG3、NFAT5、NFATC1、NFATC2、NFATC3、NFATC4、NFE2、N FE2L1、NFE2L2、NFE2L3、NFE4、NFIA、NFIB、NFIC、NFIL3、NFIX、NFKB1、NFKB2 、NFX1、NFXL1、NFYA、NFYB、NFYC、NHLH1、NHLH2、NKRF、NKX1-1、NKX1-2、NKX2- 1、NKX2-2、NKX2-3、NKX2-4、NKX2-5、NKX2-6、NKX2-8、NKX3-1、NKX3-2、NKX6 -1、NKX6-2、NKX6-3、NME2、NOBOX、NOTO、NPAS1、NPAS2、NPAS3、NPAS4、NR0B1、NR1D1、NR1D2、NR1H2、NR1H3、NR1H4、NR1I2、NR1I3、NR2C1、NR2C2、NR2E1、NR2E3、NR2F1、NR2F2、NR2F6、NR3C1、NR3C2、NR4A1、NR4A2、NR4A3、NR5A1、NR5A2、NR6A1、NRF1、NRL、OLIG1、OLIG2、OLIG3、ONECUT1、ONECUT2、ONECUT3、OSR1、OSR2、OTP、OTX1、OTX2、OVOL1、OVOL2、OVOL3、PA2G4、PATZ1、PAX1、PAX2、PAX3、PAX4、PAX5、PAX6、PAX7、PAX8、PAX9、PBX1、PBX2、PBX3、PBX4、PCGF2、PCGF6、PDX1、PEG3、PGR、PHF1、PHF19、PHF20、PHF21A、PHOX2A、PHOX2B、PIN1、PITX1、PITX2、PITX3、PKNOX1、PKNOX2、PLAG1、PLAGL1、PLAGL2、PLSCR1、POGK、POU1F1、POU2AF1、POU2F1、POU2F2、POU2F3、POU3F1、POU3F2、POU3F3、POU3F4、POU4F1、POU4F2、POU4F3、POU5F1、POU5F1B、POU5F2、POU6F1、POU6F2、PPARA、PPARD、PPARG、PRDM1、PRDM10、PRDM12、PRDM13、PRDM14、PRDM15、PRDM16、PRDM2、PRDM4、PRDM5、PRDM6、PRDM8、PRDM9、PREB、PRMT3、PROP1、PROX1、PROX2、PRR12、PRRX1、PRRX2、PTF1A、PURA、PURB、PURG、RAG1、RARA、RARB、RARG、RAX、RAX2、RBAK、RBCK1、RBPJ、RBPJL、RBSN、REL、RELA、RELB、REPIN1、REST、REXO4、RFX1、RFX2、RFX3、RFX4、RFX5、RFX6、RFX7、RFX8、RHOXF1、RHOXF2、RHOXF2B、RLF、RORA、RORB、RORC、RREB1、RUNX1、RUNX2、RUNX3、RXRA、RXRB、RXRG、SAFB、SAFB2、SALL1、SALL2、SALL3、SALL4、SATB1、SATB2、SCMH1、SCML4、SCRT1、SCRT2、SCX、SEBOX、SETBP1、SETDB1、SETDB2、SGSM2、SHOX、SHOX2、SIM1、SIM2、SIX1、SIX2、SIX3、SIX4、SIX5、SIX6、SKI、SKIL、SKOR1、SKOR2、SLC2A4RG、SMAD1、SMA、 D3、SMAD4、SMAD5、SMAD9、SMYD3、SNAI1、SNAI2、SNAI3、SNAPC2、SNAPC4、SNAPC5、SOHLH1、SOHLH2、SON、SOX1、SOX10、SOX11、SOX12、SOX13、SOX14、SOX15 、SOX17、SOX18、SOX2、SOX21、SOX3、SOX30、SOX4、SOX5、SOX6、SOX7、SOX8、SO X9, SP1, SP100, SP110, SP140, SP140L, SP2, SP3, SP4, SP5, SP6, SP7, SP8, SP9 、SPDEF、SPEN、SPI1、SPIB、SPIC、SPZ1、SRCAP、SREBF1、SREBF2、SRF、SRY、ST 18、STAT1、STAT2、STAT3、STAT4、STAT5A、STA5B、STT6、T、TAL1、TAL2、TBP、TB PL1、TBPL2、TBR1、TBX1、TBX10、TBX15、TBX18、TBX19、TBX2、TBX20、TBX21、T BX22、TBX3、TBX4、TBX5、TBX6、TCF12、TCF15、TCF20、TCF21、TCF23、TCF24、TC F3、TCF4、TCF7、TCF7L1、TCF7L2、TCFL5、TEAD1、TEAD2、TEAD3、TEAD4、TEF、T ERB1、TERF1、TERF2、TET1、TET2、TET3、TFAP2A、TFAP2B、TFAP2C、TFAP2D、TFA P2E、TFAP4、TFCP2、TFCP2L1、TFDP1、TFDP2、TFDP3、TFE3、TFEB、TFEC、TGIF1 、TGIF2、TGIF2LX、TGIF2LY、THAP1、THAP10、THAP11、THAP12、THAP2、THAP3、T HAP4、THAP5、THAP6、THAP7、THAP8、THAP9、THRA、THRB、THYN1、TIGD1、TIGD2 、TIGD3、TIGD4、TIGD5、TIGD6、TIGD7、TLX1、TLX2、TLX3、TMF1、TOPORS、TP53、 TP63、TP73、TPRX1、TRAFD1、TRERF1、TRPS1、TSC22D1、TSHZ1、TSHZ2、TSHZ3、 TTF1、TWIST1、TWIST、UBP1、UNCX、USF1、USF2、USF3、VAX1、VAX2、VDR、VENTX、VEZF1、VSX1、VSX2、WIZ、WT1、XBP1、XPA、YBX1、YBX2、YBX3、YY1、YY2、ZBED1、ZBED2、ZBED3、ZBED4、ZBED5、ZBED6、ZBED9、ZBTB1、ZBTB10、ZBTB11、ZBTB12、ZBTB14、ZBTB16、ZBTB17、ZBTB18、ZBTB2、ZBTB20、ZBTB21、ZBTB22、ZBTB24、ZBTB25、ZBTB26、ZBTB3、ZBTB32、ZBTB33、ZBTB34、ZBTB37、ZBTB38、ZBTB39、ZBTB4、ZBTB40、ZBTB41、ZBTB42、ZBTB43、ZBTB44、ZBTB45、ZBTB46、ZBTB47、ZBTB48、ZBTB49、ZBTB5、ZBTB6、ZBTB7A、ZBTB7B、ZBTB7C、ZBTB8A、ZBTB8B、ZBTB9、ZC3H8、ZEB1、ZEB2、ZFAT、ZFHX2、ZFHX3、ZFHX4、ZFP1、ZFP14、ZFP2、ZFP28、ZFP3、ZFP30、ZFP37、ZFP41、ZFP42、ZFP57、ZFP62、ZFP64、ZFP69、ZFP69B、ZFP82、ZFP90、ZFP91、ZFP92、ZFPM1、ZFPM2、ZFX、ZFY、ZGLP1、ZGPAT、ZHX1、ZHX2、ZHX3、ZIC1、ZIC2、ZIC3、ZIC4、ZIC5、ZIK1、ZIM2、ZIM3、ZKSCAN1、ZKSCAN2、ZKSCAN3、ZKSCAN4、ZKSCAN5、ZKSCAN7、ZKSCAN8、ZMAT1、ZMAT4、ZNF10、ZNF100、ZNF101、ZNF107、ZNF112、ZNF114、ZNF117、ZNF12、ZNF121、ZNF124、ZNF131、ZNF132、ZNF133、ZNF134、ZNF135、ZNF136、ZNF138、ZNF14、ZNF140、ZNF141、ZNF142、ZNF143、ZNF146、ZNF148、ZNF154、ZNF155、ZNF157、ZNF16、ZNF160、ZNF165、ZNF169、ZNF17、ZNF174、ZNF175、ZNF177、ZNF18、ZNF180、ZNF181、ZNF182、ZNF184、ZNF189、ZNF19、ZNF195、ZNF197、ZNF2、ZNF20、ZNF200、ZNF202、ZNF205、ZNF207、ZNF208、ZNF211、ZNF212、ZNF213、ZNF214、ZNF215、ZNF217、ZNF219、ZNF22、ZNF221、ZNF222、ZNF223、ZNF224、ZNF225、ZNF226、ZNF227、ZNF229、ZNF23、ZNF230、ZNF232、ZNF233、ZNF234、ZNF235、ZNF236、ZNF239、ZNF24、ZNF248、ZNF25、ZNF250、ZNF251、ZNF253、ZNF254、ZNF256、ZNF257、ZNF26、ZNF260、ZNF263、ZNF264、ZNF266、ZNF267、ZNF268、ZNF273、ZNF274、ZNF275、ZNF276、ZNF277、ZNF28、ZNF280A、ZNF280B、ZNF280C、ZNF280D、ZNF281、ZNF282、ZNF283、ZNF284、ZNF285、ZNF286A、ZNF286B、ZNF287、ZNF292、ZNF296、ZNF3、ZNF30、ZNF300、ZNF302、ZNF304、ZNF311、ZNF316、ZNF317、ZNF318、ZNF319、ZNF32、ZNF320、ZNF322、ZNF324、ZNF324B、ZNF326、ZNF329、ZNF331、ZNF333、ZNF334、ZNF335、ZNF337、ZNF33A、ZNF33B、ZNF34、ZNF341、ZNF343、ZNF345、ZNF346、ZNF347、ZNF35、ZNF350、ZNF354A、ZNF354B、ZNF354C、ZNF358、ZNF362、ZNF365、ZNF366、ZNF367、ZNF37A、ZNF382、ZNF383、ZNF384、ZNF385A、ZNF385B、ZNF385C、ZNF385D、ZNF391、ZNF394、ZNF395、ZNF396、ZNF397、ZNF398、ZNF404、ZNF407、ZNF408、ZNF41、ZNF410、ZNF414、ZNF415、ZNF416、ZNF417、ZNF418、ZNF419、ZNF420、ZNF423、ZNF425、ZNF426、ZNF428、ZNF429、ZNF43、ZNF430、ZNF431、ZNF432、ZNF433、ZNF436、ZNF438、ZNF439、ZNF44、ZNF440、ZNF441、ZNF442、ZNF443、ZNF444、ZNF445、ZNF446、ZNF449、ZNF45、ZNF451、ZNF454、ZNF460、ZNF461、ZNF462、ZNF467、ZNF468、ZNF469、ZNF470、ZNF471、ZNF473、ZNF474、ZNF479、ZNF48、ZNF480、ZNF483、ZNF484、ZNF485、ZNF486、ZNF487、ZNF488、ZNF490、ZNF491、ZNF492、ZNF493、ZNF496、ZNF497、ZNF500、ZNF501、ZNF502、ZNF503、ZNF506、ZNF507、ZNF510、ZNF511、ZNF512、ZNF512B、ZNF513、ZNF514、ZNF516、ZNF517、ZNF518A、ZNF518B、ZNF519、ZNF521、ZNF524、ZNF525、ZNF526、ZNF527、ZNF528、ZNF529、ZNF530、ZNF532、ZNF534、ZNF536、ZNF540、ZNF541、ZNF543、ZNF544、ZNF546、ZNF547、NF548、ZNF549、ZNF550、ZNF551、ZNF552、ZNF554、ZNF555、ZNF556、ZNF557、ZNF558、ZNF559、ZNF560、ZNF561、ZNF562、ZNF563、ZNF564、ZNF565、ZNF566、ZNF567、ZNF568、ZNF569、ZNF57、ZNF570、ZNF571、ZNF572、ZNF573、ZNF574、ZNF575、ZNF576、ZNF577、ZNF578、ZNF579、ZNF580、ZNF581、ZNF582、ZNF583、ZNF584、ZNF585A、ZNF585B、ZNF586、ZNF587、ZNF587B、ZNF589、ZNF592、ZNF594、ZNF595、ZNF596、ZNF597、ZNF598、ZNF599、ZNF600、ZNF605、ZNF606、ZNF607、ZNF608、ZNF609、ZNF610、ZNF611、ZNF613、ZNF614、ZNF615、ZNF616、ZNF618、ZNF619、ZNF620、ZNF621、ZNF623、ZNF624、ZNF625、ZNF626、ZNF627、ZNF628、ZNF629、ZNF630、ZNF639、ZNF641、ZNF644、ZNF645、ZNF646、ZNF648、ZNF649、ZNF652、ZNF653、ZNF654、ZNF655、ZNF658、ZNF66、ZNF660、ZNF662、ZNF664、ZNF665、ZNF667、ZNF668、ZNF669、ZNF670、ZNF671、ZNF672、ZNF674、ZNF675、ZNF676、ZNF677、ZNF678、ZNF679、ZNF680、ZNF681、ZNF682、ZNF683、ZNF684、ZNF687、ZNF688、ZNF689、ZNF69、ZNF691、ZNF692、ZNF695、ZNF696、ZNF697、ZNF699、ZNF7、ZNF70、ZNF700、ZNF701、ZNF703、ZNF704、ZNF705A、ZNF705B、ZNF705D、ZNF705E、ZNF705G、ZNF706、ZNF707、ZNF708、ZNF709、ZNF71、ZNF710、ZNF711、ZNF713、ZNF714、ZNF716、ZNF717、ZNF718、ZNF721、ZNF724、ZNF726、ZNF727、ZNF728、ZNF729、ZNF730、ZNF732、ZNF735、ZNF736、ZNF737、ZNF74、ZNF740、ZNF746、ZNF747、ZNF749、ZNF750、ZNF75A、ZNF75D、ZNF76、ZNF761、ZNF763、ZNF764、ZNF765、ZNF766、ZNF768、ZNF77、ZNF770、ZNF771、ZNF772、ZNF773、ZNF774、ZNF775、ZNF776、ZNF777、ZNF778、ZNF780A、ZNF780B、ZNF781、ZNF782、ZNF783、ZNF784、ZNF785、ZNF786、ZNF787、ZNF788、ZNF789、ZNF79、ZNF790、ZNF791、ZNF792、ZNF793、ZNF799、ZNF8、ZNF80、ZNF800、ZNF804A、ZNF804B、ZNF805、ZNF808、ZNF81、ZNF813、ZNF814、ZNF816、ZNF821、ZNF823、ZNF827、ZNF829、ZNF83、ZNF830、ZNF831、ZNF835、ZNF836、ZNF837, ZNF84, ZNF841, ZNF843, ZNF844, ZNF845, ZNF846, ZNF85, ZNF850, ZNF852, ZNF853, ZNF860, ZNF865, ZNF878, ZNF879, ZNF880, ZNF883, ZNF888, ZNF891, ZNF, 90, ZNF91, ZNF92, ZNF93, ZNF98, ZNF99, ZSCAN1, ZSCAN10, ZSCAN12, ZSCAN16, ZSCAN18, ZSCAN2, ZSCAN20, ZSCAN21, ZSCAN22, ZSCAN23, ZSCAN25, ZSCAN26, ZSCAN29, ZSCAN30, ZSCAN31, ZSCAN32, ZSCAN4, ZSCAN5A, ZSCAN5B, ZSCAN5C, ZSCAN9, ZUFSP, ZXDA, ZXDB, ZXDC, and ZZZ3.

[0113] The terms "inhibition," "inhibiting," "inhibit," or "inhibitor" refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a particular biological process (e.g., a transcription factor) in a cell relative to a vehicle.

[0114] Anti-cancer agents include biotherapeutic anti-cancer agents and chemotherapeutic agents.

[0115] Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon alpha, interferon gamma), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulatory and / or immunomodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF), and antibodies (e.g., Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexar (tositumomab)).

[0116] Exemplary chemotherapeutic agents include antiestrogens (e.g., tamoxifen, raloxifene, megestrol), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporphine (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxyhypocrelin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., For example, cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents such as nanoparticle albumin-bound paclitaxel, conjugated paclitaxel (DHA-paclitaxel, taxoplexin), polyglutamic acid-conjugated paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrugs (TAPs) (Angiopep-2 conjugated to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel conjugated to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, for example, 2'-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleoside reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, latitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (araC), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB1089, CB1093, and KH1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca; 2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (Tarceva®), gefitinib (Iressa®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TY) VERB®, lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (Tasigna®), semaxanib (semaxinib, SU5416), sunitinib (Sutent®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (Herceptin®), bevacizumab (Avastin®), rituximab (Rituxan®), cetuximab (Erbitux®), panitumumab (Vectibix®), ranibizumab (Lucentis®), nilotinib (Tasigna®), sorafenib (Nexavar®), everolimus (Afinitor®), alemtuzumab (Campus®), gemtuzumab ozogamicin (Mylotarg®), temsirolimus (Torisel®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW299 2 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)),mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi) Aventis), PF-4691502 (Pfizer), GDC0980 (Genentech), SF1126 (Semafoe), and OSI-027 (OSI), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbidine, prednisolone, dexamethasone, campatecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurocidin, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine.

[0117] The terms "prevent," "preventing," or "prevention" refer to the prophylactic treatment of a subject who does not have the disease, or who did not have the disease but is at risk of developing the disease, or who had the disease but does not have the disease and is at risk of regression of the disease. In certain embodiments, the subject is at higher risk of developing the disease or at higher risk of regression of the disease than the average healthy member of the population. [Brief explanation of the drawings]

[0118] [Figure 1] 1 shows a graph of percent inhibition versus log concentration of representative compounds of formula (I). [Figure 2] 1 shows a graph of percent inhibition versus log concentration of representative compounds of formula (II). [Figure 3] 1 shows a graph of percent inhibition versus log concentration of representative compounds of formula (IV). [Figure 4] 1 shows a graph of percent inhibition versus log concentration of representative compounds of formula (V). [Figure 5] 1 shows a graph of percent inhibition versus logarithm of concentration for representative compounds of formula (VII). [Figure 6] 1 shows an anti-proliferation assay in NCI-H226 cells (200 cells / well, 384 plates, 5 days treatment) for representative compounds of the present disclosure. [Figure 7] 1 shows an anti-proliferation assay in NCI-H226 cells (200 cells / well, 384 plates, 5 days treatment) for representative compounds of the present disclosure. [Figure 8] 1 shows the results of a gel-based antipalmitoylation assay for various compounds of the present disclosure. [Figure 9] 1 shows the results of a gel-based antipalmitoylation assay for various compounds of the present disclosure. [Figure 10] 1 shows the results of a gel-based antipalmitoylation assay for various compounds of the present disclosure. [Figure 11] 1 shows the results of a gel-based antipalmitoylation assay for various compounds of the present disclosure. [Figure 12] 1 shows the results of a gel-based antipalmitoylation assay for various compounds of the present disclosure. [Figure 13] 1 shows the results of a gel-based antipalmitoylation assay for various compounds of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0119] The present disclosure provides a compound of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, pharmaceutical compositions described herein comprise a compound of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compounds and compositions described herein may be useful for modulating (e.g., inhibiting or increasing) the activity (e.g., abnormal or undesirable activity, such as increased or decreased activity) of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject, biological sample, tissue, or cell. The compounds may also be useful in treating a wide range of diseases, such as diseases associated with abnormal activity (e.g., increased activity) of a transcription factor (e.g., TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)), e.g., proliferative diseases (e.g., cancer (e.g., carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)).

[0120] compound In certain embodiments, the compounds described herein have formula (I'): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R and R 4 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a, -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; R 1 , R 2 , and R 3 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; Z 1 is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; R a each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R aWhen present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; m is 1 or 2; q is 1 or 2; t is 0, 1, 2, 3, or 4; z is 0, 1, 2, or 3).

[0121] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0122] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0123] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0124] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0125] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0126] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0127] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0128] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0129] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0130] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0131] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0132] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0133] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0134] The compound of formula (I') may contain a substituent Z 1 In certain embodiments, Z 1 is an optionally substituted carbocyclylene. In certain embodiments, Z 1 is the expression: [ka] (In the formula, R 5a and R 6a are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , and -N(R a )C(=O)R a or optionally, R 5a and R 6a are joined together to form a carbocyclic or heterocyclic ring. 1 is an optionally substituted alkylene. In certain embodiments, Z 1 is an optionally substituted C1-C6 alkylene. In certain embodiments, Z 1 is the expression: [ka] (In the formula, R 5a and R 6aare each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , and -N(R a )C(=O)R a or optionally, R 5a and R 6a are joined together to form a carbocyclic or heterocyclic ring. 1 is the expression: [ka] In certain embodiments, Z 1 is the expression: [ka] In certain embodiments, Z 1 is the expression: [ka] In certain embodiments, Z 1 is the expression: [ka] It is of the type.

[0135] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0136] In certain embodiments, the compound of formula (I') has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0137] In certain embodiments, the substituent Z 1 is the substituent R 5a and R 6a In certain embodiments, R 5a and R 6a are each independently selected from hydrogen, halogen, and optionally substituted alkyl; or optionally R 5a and R 6a are joined together to form a carbocyclic or heterocyclic ring. In certain embodiments, R 5a is hydrogen. In certain embodiments, R 5a is halogen. In certain embodiments, R 5a is optionally substituted alkyl. In certain embodiments, R 5a is optionally substituted methyl. In certain embodiments, R 5a is an optionally substituted C1-C6 alkyl. In certain embodiments, R 5a is optionally substituted methyl. In certain embodiments, R is unsubstituted methyl. In certain embodiments, R 5a is optionally substituted alkenyl. In certain embodiments, R 5a is an optionally substituted alkynyl. In certain embodiments, R 5a is an optionally substituted carbocyclyl. In certain embodiments, R 5a is an optionally substituted heterocyclyl. In certain embodiments, R5a is optionally substituted aryl. In certain embodiments, R 5a is optionally substituted heteroaryl. In certain embodiments, R 5a HA-OR a In certain embodiments, R 5a -N(R a )2. In certain embodiments, R 5a Ha-SR a In certain embodiments, R 5a is -C(=O)R a In certain embodiments, R 5a is -C(=O)OR a In certain embodiments, R 5a is -C(=O)N(R a )2. In certain embodiments, R 5a is -OC(=O)R a In certain embodiments, R 5a -N(R a )C(=O)R a is.

[0138] In certain embodiments, R 6a is hydrogen. In certain embodiments, R 6a is halogen. In certain embodiments, R 6a is optionally substituted alkyl. In certain embodiments, R 6a is an optionally substituted C1-C6 alkyl. In certain embodiments, R 6a is optionally substituted methyl. In certain embodiments, R 6a is unsubstituted methyl. In certain embodiments, R 6a is optionally substituted alkenyl. In certain embodiments, R 6a is an optionally substituted alkynyl. In certain embodiments, R 6a is an optionally substituted carbocyclyl. In certain embodiments, R 6a is an optionally substituted heterocyclyl. In certain embodiments, R 6a is optionally substituted aryl. In certain embodiments, R6a is optionally substituted heteroaryl. In certain embodiments, R 6a HA-OR a In certain embodiments, R 6a -N(R a )2. In certain embodiments, R 6a Ha-SR a In certain embodiments, R 6a is -C(=O)R a In certain embodiments, R 6a is -C(=O)OR a In certain embodiments, R 6a is -C(=O)N(R a )2. In certain embodiments, R 6a is -OC(=O)R a In certain embodiments, R 6a -N(R a )C(=O)R a is.

[0139] In certain embodiments, R 5a is hydrogen and R 6a is hydrogen. In certain embodiments, R 5a is optionally substituted alkyl, and R 6a is optionally substituted alkyl. In certain embodiments, R 5a is methyl and R 6a is methyl. In certain embodiments, R 5a is a halogen and R 6a is halogen. In certain embodiments, R 5a is fluoro and R 6a is fluoro. In certain embodiments, R 5a is hydrogen and R 6a is fluoro. In certain embodiments, R 5a and R 6a are joined together to form an optionally substituted carbocyclic ring. In certain embodiments, R 5a and R 6a are joined together to form an optionally substituted cyclopropyl ring. In certain embodiments, R 5a and R6a are joined together to form an optionally substituted heterocycle.

[0140] In certain embodiments, the compounds described herein are compounds of formula (I): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , -CN, and -NO2; R a each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R a Instances of, when present, can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

[0141] In certain embodiments, the compound of formula (I) has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0142] In certain embodiments, the compound of formula (I) has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0143] In certain embodiments, the compound of formula (I) has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0144] In certain embodiments, the compound of formula (I) has the formula: [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0145] In certain embodiments, R 1 , R 2 , and R 3are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , —CN, and —NO2.

[0146] In certain embodiments, R 4 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR a , -N(R a )2, -SR a , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -OC(=O)R a , -N(R a )C(=O)R a , —CN, and —NO2.

[0147] In certain embodiments, R is hydrogen. In certain embodiments, R is halogen. In certain embodiments, R is fluoro. In certain embodiments, R is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R is haloalkyl. In certain embodiments, R is optionally substituted -CF3. In certain embodiments, R is optionally substituted alkenyl. In certain embodiments, R is optionally substituted alkynyl. In certain embodiments, R is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted aryl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R is -OR a In certain embodiments, R is —N(R a In certain embodiments, R is -SR. a In certain embodiments, R is —C(═O)R a In certain embodiments, R is —C(═O)OR a In certain embodiments, R is —C(═O)N(R a In certain embodiments, R is —OC(═O)R a In certain embodiments, R 1 -N(R a )C(=O)R a In certain embodiments, R is -CN. In certain embodiments, R is -NO.

[0148] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is fluoro. In certain embodiments, R 1 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 1 is haloalkyl. In certain embodiments, R 1 is optionally substituted -CF. In certain embodiments, R1 is optionally substituted alkenyl. In certain embodiments, R 1 is an optionally substituted alkynyl. In certain embodiments, R 1 is an optionally substituted carbocyclyl. In certain embodiments, R 1 is an optionally substituted heterocyclyl. In certain embodiments, R 1 is optionally substituted aryl. In certain embodiments, R 1 is optionally substituted heteroaryl. In certain embodiments, R 1 HA-OR a In certain embodiments, R 1 -N(R a )2. In certain embodiments, R 1 Ha-SR a In certain embodiments, R 1 is -C(=O)R a In certain embodiments, R 1 is -C(=O)OR a In certain embodiments, R 1 is -C(=O)N(R a )2. In certain embodiments, R 1 is -OC(=O)R a In certain embodiments, R 1 -N(R a )C(=O)R a In certain embodiments, R 1 is -CN. In certain embodiments, R 1 is -NO2.

[0149] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 2 is optionally substituted alkenyl. In certain embodiments, R 2 is an optionally substituted alkynyl. In certain embodiments, R2 is an optionally substituted carbocyclyl. In certain embodiments, R 2 is an optionally substituted heterocyclyl. In certain embodiments, R 2 is optionally substituted aryl. In certain embodiments, R 2 is optionally substituted heteroaryl. In certain embodiments, R 2 HA-OR a In certain embodiments, R 2 -N(R a )2. In certain embodiments, R 2 Ha-SR a In certain embodiments, R 2 is -C(=O)R a In certain embodiments, R 2 is -C(=O)OR a In certain embodiments, R 2 is -C(=O)N(R a )2. In certain embodiments, R 2 is -OC(=O)R a In certain embodiments, R 2 -N(R a )C(=O)R a In certain embodiments, R 2 is -CN. In certain embodiments, R 2 is —NO. In certain embodiments, R 2 is the expression: [ka] In certain embodiments, R 2 is the expression: [ka] In certain embodiments, R 2 is the expression: [ka] In certain embodiments, R 2 is the expression: [ka] It is of the type.

[0150] In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 3 is optionally substituted alkenyl. In certain embodiments, R 3 is an optionally substituted alkynyl. In certain embodiments, R 3 is an optionally substituted carbocyclyl. In certain embodiments, R 3 is an optionally substituted heterocyclyl. In certain embodiments, R 3 is optionally substituted aryl. In certain embodiments, R 3 is optionally substituted heteroaryl. In certain embodiments, R 3 HA-OR a In certain embodiments, R 3 -N(R a )2. In certain embodiments, R 3 Ha-SR a In certain embodiments, R 3 is -C(=O)R a In certain embodiments, R 3 is -C(=O)OR a In certain embodiments, R 3 is -C(=O)N(R a )2. In certain embodiments, R 3 is -OC(=O)R a In certain embodiments, R 3 -N(R a )C(=O)R a In certain embodiments, R 3 is -CN. In certain embodiments, R 3 is -NO2.

[0151] In certain embodiments, R 1 is H and R 2 is H and R 3 is H. In certain embodiments, R 1 is a halogen and R 2 is H and R 3 is H. In certain embodiments, R 1 is fluoro and R 2 is H and R 3 is H. In certain embodiments, R 1 is H and R 2 is the expression: [ka] R 3 is H. In certain embodiments, R 1 is H and R 2 is the expression: [ka] R 3 is H. In certain embodiments, R 1 is H and R 2 is the expression: [ka] R 3 is H. In certain embodiments, R 1 is H and R 2 is the expression: [ka] R 3 is H.

[0152] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 is halogen. In certain embodiments, R 4is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 4 is optionally substituted alkenyl. In certain embodiments, R 4 is an optionally substituted alkynyl. In certain embodiments, R 4 is an optionally substituted carbocyclyl. In certain embodiments, R 4 is an optionally substituted heterocyclyl. In certain embodiments, R 4 teeth [ka] In certain embodiments, R 4 teeth [ka] In certain embodiments, R 4 teeth [ka] In certain embodiments, R 4 is optionally substituted aryl. In certain embodiments, R 4 is optionally substituted heteroaryl. In certain embodiments, R 4 is an optionally substituted pyrrolidine. In certain embodiments, R 4 is optionally replaced [ka] In certain embodiments, R 4 HA-OR a In certain embodiments, R 4 is -OMe. In certain embodiments, R 4 teeth [ka] In certain embodiments, R 4 -N(R a )2. In certain embodiments, R4 Ha-SR a In certain embodiments, R 4 is -C(=O)R a In certain embodiments, R 4 is -C(=O)OR a In certain embodiments, R 4 is -C(=O)N(R a )2. In certain embodiments, R 4 is -OC(=O)R a In certain embodiments, R 4 -N(R a )C(=O)R a In certain embodiments, R 4 is -CN. In certain embodiments, R 4 is -NO2.

[0153] Substituent R 1 , R 2 , R 3 , and R 4 is the substituent R a In certain embodiments, R a is hydrogen. In certain embodiments, R a is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R a is -Me. In certain embodiments, R a is optionally substituted alkenyl. In certain embodiments, R a is an optionally substituted alkynyl. In certain embodiments, R a is an optionally substituted carbocyclyl. In certain embodiments, R a is an optionally substituted heterocyclyl. In certain embodiments, R a is optionally substituted aryl. In certain embodiments, R a is optionally substituted heteroaryl. In certain embodiments, R a is a nitrogen protecting group. In certain embodiments, two R aWhen present, instances of together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle.

[0154] In certain embodiments, m is 1. In certain embodiments, m is 2.

[0155] In certain embodiments, q is 1. In certain embodiments, q is 2.

[0156] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4.

[0157] In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3.

[0158] In certain embodiments, the compound of formula (I) is one of the formulas in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0159] In certain embodiments, the compound of formula (I') is one of the formulas in Table 1A below. [Table 2-1] [Table 2-2] [Table 2-3] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0160] In certain embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof. In certain embodiments, the compound of formula (I) has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0161] In certain embodiments, the compounds described herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, or mixtures thereof. In certain embodiments, the compounds described herein are compounds of formula (I), or pharmaceutically acceptable salts thereof.

[0162] In certain embodiments, the compounds described herein have formula (II): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 1 , R 2 , and R 3are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR b , -N(R b )2, -SR b , -C(=O)R b , -C(=O)OR b , -C(=O)N(R b )2, -OC(=O)R b , -N(R b )C(=O)R b , -CN, and -NO2; R 5 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR b , -N(R b )2, -SR b , -C(=O)R b , -C(=O)OR b , -C(=O)N(R b )2, -OC(=O)R b , -N(R b )C(=O)R b , -CN, and -NO2; R b each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R b When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; However, this compound has the formula: [ka] (The condition is that the

[0163] In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is halogen. In certain embodiments, R 5 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 5 is an optionally substituted C1-C6 alkyl. In certain embodiments, R 5 is -CH2N(R b )2. In certain embodiments, R 5 is optionally substituted alkenyl. In certain embodiments, R 5 is an optionally substituted alkynyl. In certain embodiments, R 5 is an optionally substituted carbocyclyl. In certain embodiments, R 5 is an optionally substituted heterocyclyl. In certain embodiments, R 5 is optionally substituted aryl. In certain embodiments, R 5 is optionally substituted phenyl. In certain embodiments, R 5 is monosubstituted phenyl. In certain embodiments, R 5 is the expression: [ka] In certain embodiments, R 5 is the expression: [ka] In certain embodiments, R 5 is a disubstituted phenyl. In certain embodiments, R 5 is optionally substituted heteroaryl. In certain embodiments, R 5 is an optionally substituted pyridine. In certain embodiments, R 5is an optionally substituted pyrimidine. In certain embodiments, R 5 is an optionally substituted pyridazine. In certain embodiments, R 5 is an optionally substituted pyrazine. In certain embodiments, R 5 teeth [ka] In certain embodiments, R 5 teeth [ka] In certain embodiments, R 5 teeth [ka] In certain embodiments, R 5 teeth [ka] In certain embodiments, R 5 teeth [ka] In certain embodiments, R 5 teeth [ka] In certain embodiments, R 5 HA-OR b In certain embodiments, R 5 -N(R b )2. In certain embodiments, R 5 Ha-SR b In certain embodiments, R 5 is -C(=O)R b In certain embodiments, R 5 is -C(=O)OR b In certain embodiments, R 5 is -C(=O)N(R b )2. In certain embodiments, R5 is —C(═O)N(H). In certain embodiments, R 5 is —C(═O)N(H)Me. In certain embodiments, R 5 is —C(═O)N(Me) 2 . In certain embodiments, R 5 is -OC(=O)R b In certain embodiments, R 5 -N(R b )C(=O)R b In certain embodiments, R 5 is -CN. In certain embodiments, R 5 is -NO2.

[0164] In certain embodiments, R b At least one instance of R is hydrogen. b is hydrogen. In certain embodiments, one instance of R b The instance of is hydrogen and one R b An instance of R is methyl. In certain embodiments, two R b An instance of R is methyl. b is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R b is -Me. In certain embodiments, R b is optionally substituted alkenyl. In certain embodiments, R b is an optionally substituted alkynyl. In certain embodiments, R b is an optionally substituted carbocyclyl. In certain embodiments, R b is an optionally substituted heterocyclyl. In certain embodiments, R b is optionally substituted aryl. In certain embodiments, R b is optionally substituted heteroaryl. In certain embodiments, R b is a nitrogen protecting group. In certain embodiments, two R bWhen present, instances of together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle.

[0165] In certain embodiments, the compound of formula (II) has the formula: [ka] It is not one of.

[0166] In certain embodiments, the compound of formula (II) has the formula: [ka] It is of the type.

[0167] In certain embodiments, the compound of formula (II) has the formula: [ka] It is of the type.

[0168] In certain embodiments, the compound of formula (II) is one of the formulas in Table 2 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0169] In certain embodiments, the compounds described herein have formula (III): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 6 is -CF3 or -C≡CH; R 7 and R 8 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR c , -N(R c )2, -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)N(R c )2, -OC(=O)R c , -N(R c )C(=O)R c , -CN, or -NO2; R 7 and R 8 are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR c , -N(R c )2, -SR c , -C(=O)R c , -C(=O)OR c , -C(=O)N(R c )2, -OC(=O)R c , -N(R c )C(=O)R c , -CN, or -NO2; R ceach occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R c When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; X 1 and X 2 are each independently -N= or -C(H)=; and n is 0, 1, or 2.

[0170] In certain embodiments, R 6 is —CF or —C≡CH. In certain embodiments, R 6 is —CF. In certain embodiments, R 6 is -C≡CH.

[0171] In certain embodiments, R 7 or R 8 are independently hydrogen. In certain embodiments, R 7 or R 8 is independently halogen. In certain embodiments, R 7 or R 8 is independently an optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 7 or R 8 is independently an optionally substituted alkenyl. In certain embodiments, R 7 or R 8 is independently an optionally substituted alkynyl. In certain embodiments, R 7 or R 8 is independently an optionally substituted carbocyclyl. In certain embodiments, R 7 or R 8 is independently an optionally substituted heterocyclyl. In certain embodiments, R 7or R 8 is independently an optionally substituted aryl. In certain embodiments, R 7 or R 8 is independently an optionally substituted heteroaryl. In certain embodiments, R 7 or R 8 are independently -OR c In certain embodiments, R 7 or R 8 are independently -N(R c )2. In certain embodiments, R 7 or R 8 independently, -SR c In certain embodiments, R 7 or R 8 are independently -C(=O)R c In certain embodiments, R 7 or R 8 are independently -C(=O)OR c In certain embodiments, R 7 or R 8 are independently -C(=O)N(R c )2. In certain embodiments, R 7 or R 8 are independently -OC(=O)R c In certain embodiments, R 7 or R 8 are independently -N(R c )C(=O)R c In certain embodiments, R 7 or R 8 is independently -CN. In certain embodiments, R 7 or R 8 is independently —NO. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is optionally substituted heteroaryl. In certain embodiments, R 7 is an optionally substituted pyridine. In certain embodiments, R 7 is the expression: [ka] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is halo. In certain embodiments, R 8 is chloro.

[0172] In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0173] In certain embodiments, the compound of formula (III) has the formula (III-a): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0174] In certain embodiments, X 1 and X 2 are each independently -N= or -C(H)=. In certain embodiments, X 1 is -N=. In certain embodiments, X 1 is -C(H)=. In certain embodiments, X 2 is -C(H)=. In certain embodiments, X 2 is -N=. In certain embodiments, X 1 is -N = X 2 is -C(H)=. In certain embodiments, X 2 is -N = X 1 is -C(H)=.

[0175] In certain embodiments, the compound of formula (III) has formula (III-b): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0176] In certain embodiments, the compound of formula (III-b) has the formula (III-b-1): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0177] In certain embodiments, the compound of formula (III-b) has the formula (III-b-2): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0178] In some embodiments, the substituent R 7 and R 8 is the substituent R c In certain embodiments, R c is hydrogen. In certain embodiments, R c is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R c is -Me. In certain embodiments, R c is optionally substituted alkenyl. In certain embodiments, R c is an optionally substituted alkynyl. In certain embodiments, R c is an optionally substituted carbocyclyl. In certain embodiments, R c is an optionally substituted heterocyclyl. In certain embodiments, R cis optionally substituted aryl. In certain embodiments, R c is optionally substituted heteroaryl. In certain embodiments, R c is a nitrogen protecting group. In certain embodiments, two R c When present, instances of together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle.

[0179] In certain embodiments, the compound of formula (III) is one of the formulas in Table 3 below. [Table 4-1] [Table 4-2] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0180] In certain embodiments, the compounds described herein have formula (IV): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 9 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR d , -N(R d )2, -SR d , -C(=O)R d , -C(=O)OR d , -C(=O)N(R d )2, -OC(=O)R d, -N(R d )C(=O)R d , -CN, or -NO2; R d each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R d Instances of, when present, can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

[0181] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-a): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0182] In certain embodiments, the compound of formula (IV) or (IV-a) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0183] In certain embodiments, the compound of formula (IV) or (IV-a) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0184] In certain embodiments, the compound of formula (IV) is a compound of formula (IV-b): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0185] In certain embodiments, the compound of formula (IV) or (IV-b) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0186] In certain embodiments, the compound of formula (IV) or (IV-b) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0187] In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is halogen. In certain embodiments, R 9 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 9 is optionally substituted alkenyl. In certain embodiments, R 9 is an optionally substituted alkynyl. In certain embodiments, R 9 is an optionally substituted carbocyclyl. In certain embodiments, R 9is an optionally substituted heterocyclyl. In certain embodiments, R 9 is optionally substituted aryl. In certain embodiments, R 9 is optionally substituted heteroaryl. In certain embodiments, R 9 HA-OR d In certain embodiments, R 9 -N(R d )2. In certain embodiments, R 9 Ha-SR d In certain embodiments, R 9 is -C(=O)R d In certain embodiments, R 9 is -C(=O)OR d In certain embodiments, R 9 is -C(=O)N(R d )2. In certain embodiments, R 9 is —C(═O)N(H)Me. In certain embodiments, R 9 is -OC(=O)R d In certain embodiments, R 9 -N(R d )C(=O)R d In certain embodiments, R 9 is -CN. In certain embodiments, R 9 is -NO2.

[0188] In certain embodiments, R d is hydrogen. In certain embodiments, R d is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R d At least one instance of is -Me. In certain embodiments, R d is optionally substituted alkenyl. In certain embodiments, R d is an optionally substituted alkynyl. In certain embodiments, R d is an optionally substituted carbocyclyl. In certain embodiments, R d is an optionally substituted heterocyclyl. In certain embodiments, Rd is optionally substituted aryl. In certain embodiments, R d is optionally substituted heteroaryl. In certain embodiments, R d is a nitrogen protecting group. In certain embodiments, two R d When present, instances of R together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle. In certain embodiments, one R d The instance of is methyl, and one R d An instance of is hydrogen.

[0189] In certain embodiments, the compound of formula (IV) is one of the formulas in Table 4 below. [Table 5] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0190] In certain embodiments, the compounds described herein have formula (V): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 10 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR e , -N(R e )2, -SR e , -C(=O)R e , -C(=O)OR e , -C(=O)N(R e)2, -OC(=O)R e , -N(R e )C(=O)R e , -CN, or -NO2; R e each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R e Instances of, when present, can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

[0191] In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is halogen. In certain embodiments, R 10 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 10 is optionally substituted alkenyl. In certain embodiments, R 10 is an optionally substituted alkynyl. In certain embodiments, R 10 is an optionally substituted carbocyclyl. In certain embodiments, R 10 is an optionally substituted heterocyclyl. In certain embodiments, R 10 is optionally substituted aryl. In certain embodiments, R 10 is optionally substituted phenyl. In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 is optionally substituted heteroaryl. In certain embodiments, R 10 is an optionally substituted pyridine. In certain embodiments, R 10is an optionally substituted pyrimidine. In certain embodiments, R 10 is an optionally substituted pyridazine. In certain embodiments, R 10 is an optionally substituted pyrazine. In certain embodiments, R 10 is an optionally substituted pyrazole. In certain embodiments, R 10 is an optionally substituted imidazole. In certain embodiments, R 10 is an optionally substituted oxazole. In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 is the expression: [ka] In certain embodiments, R 10 HA-OR e In certain embodiments, R 10 -N(R e )2. In certain embodiments, R 10 Ha-SR eIn certain embodiments, R 10 is -C(=O)R e In certain embodiments, R 10 is -C(=O)OR e In certain embodiments, R 10 is -C(=O)N(R e )2. In certain embodiments, R 10 is -OC(=O)R e In certain embodiments, R 10 -N(R e )C(=O)R e In certain embodiments, R 10 is -CN. In certain embodiments, R 10 is -NO2.

[0192] In some embodiments, the substituent R 10 is the substituent R e In certain embodiments, R e is hydrogen. In certain embodiments, R e is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R e is -Me. In certain embodiments, R e is optionally substituted alkenyl. In certain embodiments, R e is an optionally substituted alkynyl. In certain embodiments, R e is an optionally substituted carbocyclyl. In certain embodiments, R e is an optionally substituted heterocyclyl. In certain embodiments, R e is optionally substituted aryl. In certain embodiments, R e is optionally substituted heteroaryl. In certain embodiments, R e is a nitrogen protecting group. In certain embodiments, two R e When present, instances of together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle.

[0193] In certain embodiments, the compound of formula (V) is one of the formulas in Table 5 below. [Table 6-1] [Table 6-2] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0194] In certain embodiments, the compounds described herein have formula (VI): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 11 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR f , -N(R f )2, -SR f , -C(=O)R f , -C(=O)OR f , -C(=O)N(R f )2, -OC(=O)R f , -N(R f )C(=O)R f , -CN, or -NO2; R f each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two Rf Instances of, when present, can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

[0195] In certain embodiments, the compound of formula (VI) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0196] In certain embodiments, the compound of formula (VI) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0197] In certain embodiments, R 11 is hydrogen. In certain embodiments, R 11 is halogen. In certain embodiments, R 11 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 11 is optionally substituted alkenyl. In certain embodiments, R 11 is an optionally substituted alkynyl. In certain embodiments, R 11 is an optionally substituted carbocyclyl. In certain embodiments, R 11 is an optionally substituted heterocyclyl. In certain embodiments, R 11 is optionally substituted aryl. In certain embodiments, R 11 is optionally substituted heteroaryl. In certain embodiments, R 11is an optionally substituted imidazole. In certain embodiments, R 11 is the expression: [ka] In certain embodiments, R 11 HA-OR f In certain embodiments, R 11 -N(R f )2. In certain embodiments, R 11 Ha-SR f In certain embodiments, R 11 is -C(=O)R f In certain embodiments, R 11 is -C(=O)OR f In certain embodiments, R 11 is -C(=O)N(R f )2. In certain embodiments, R 11 is -OC(=O)R f In certain embodiments, R 11 -N(R f )C(=O)R f In certain embodiments, R 11 is -CN. In certain embodiments, R 11 is -NO2.

[0198] In some embodiments, the substituent R 11 is the substituent R f In certain embodiments, R f is hydrogen. In certain embodiments, R f is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R f is -Me. In certain embodiments, R f is optionally substituted alkenyl. In certain embodiments, R f is an optionally substituted alkynyl. In certain embodiments, R f is an optionally substituted carbocyclyl. In certain embodiments, R fis an optionally substituted heterocyclyl. In certain embodiments, R f is optionally substituted aryl. In certain embodiments, R f is optionally substituted heteroaryl. In certain embodiments, R f is a nitrogen protecting group. In certain embodiments, two R f When present, instances of together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle.

[0199] In certain embodiments, the compound of formula (VI) is one of the formulas in Table 6 below. [Table 7] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0200] In certain embodiments, the compound of formula (VII) described herein is one of the formulas in Table 7 below. [Table 8-1] [Table 8-2] [Table 8-3] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof.

[0201] In certain embodiments, the compounds described herein are compounds of formula (VIII): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R 12 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR h , -N(R h )2, -SR h , -C(=O)R h , -C(=O)OR h , -C(=O)N(R h )2, -OC(=O)R h , -N(R h )C(=O)R h , -CN, or -NO2; R h each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R h Instances of, when present, can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

[0202] In certain embodiments, the compound of formula (VIII) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0203] In certain embodiments, the compound of formula (VIII) is a compound of the following formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0204] In certain embodiments, R 12 is hydrogen. In certain embodiments, R 12 is halogen. In certain embodiments, R 12 is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R 12 is optionally substituted alkenyl. In certain embodiments, R 12 is an optionally substituted alkynyl. In certain embodiments, R 12 is an optionally substituted carbocyclyl. In certain embodiments, R 12 is an optionally substituted heterocyclyl. In certain embodiments, R 12 is optionally substituted aryl. In certain embodiments, R 12 is optionally substituted heteroaryl. In certain embodiments, R 12 is an optionally substituted imidazole. In certain embodiments, R 12 is the expression: [ka] In certain embodiments, R 12 HA-OR h In certain embodiments, R 12 -N(R h )2. In certain embodiments, R 12 Ha-SR h In certain embodiments, R 12 is -C(=O)R h In certain embodiments, R 12 is -C(=O)OR h In certain embodiments, R 12 is -C(=O)N(Rh )2. In certain embodiments, R 12 is -OC(=O)R h In certain embodiments, R 12 -N(R h )C(=O)R h In certain embodiments, R 12 is -CN. In certain embodiments, R 12 is -NO2.

[0205] In some embodiments, the substituent R 12 is the substituent R h In certain embodiments, R h is hydrogen. In certain embodiments, R h is optionally substituted alkyl (e.g., -Me, -Et, -i-Pr). In certain embodiments, R h is -Me. In certain embodiments, R h is optionally substituted alkenyl. In certain embodiments, R h is an optionally substituted alkynyl. In certain embodiments, R h is an optionally substituted carbocyclyl. In certain embodiments, R h is an optionally substituted heterocyclyl. In certain embodiments, R h is optionally substituted aryl. In certain embodiments, R h is optionally substituted heteroaryl. In certain embodiments, R h is a nitrogen protecting group. In certain embodiments, two R h When present, instances of together with the heteroatom to which they are attached can be joined to form an optionally substituted heterocycle.

[0206] In certain embodiments, the compound of formula (VIII) has the formula (VIII-1): [ka] Things, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof.

[0207] In certain embodiments, the compound described herein is provided in an effective amount in a pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to treat a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to reduce the risk of developing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to inhibit activity (e.g., aberrant activity, such as increased activity or undesirable activity) of a transcription factor (e.g., TEAD) in a subject or cell. In certain embodiments, the effective amount is an amount effective to modulate activity of the hippo signaling pathway in a subject or cell.

[0208] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, e.g., a dog or cat. In certain embodiments, the subject is a livestock animal, e.g., a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, e.g., a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or a reptile.

[0209] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo.

[0210] In certain embodiments, an effective amount is an amount effective to inhibit the activity of a transcription factor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of a TEAD family transcription factor by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of a TEAD family transcription factor by a percentage recited in this paragraph and another percentage recited in this paragraph, inclusive.

[0211] In certain embodiments, the transcription factor is a TEAD family transcription factor. In certain embodiments, the TEAD is TEAD1. In certain embodiments, the TEAD is TEAD2. In certain embodiments, the TEAD is TEAD3. In certain embodiments, the TEAD is TEAD4. In certain embodiments, the disclosure provides inhibitors of the TEAD family of transcription factors (e.g., TEAD1, TEAD2, TEAD3, TEAD4). In certain embodiments, the compounds of the invention inhibit the activity of TEAD. In certain embodiments, the inhibitors are selective for the TEAD family of transcription factors.

[0212] The present disclosure provides methods of using the compounds described herein, e.g., as biological probes for studying inhibition of the activity of the hippo signaling pathway or a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4)), and as therapeutic agents in the treatment and / or prevention of diseases associated with overexpression and / or aberrant activity of the hippo signaling pathway or a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4)). In certain embodiments, the compound covalently binds to a TEAD (e.g., TEAD1). In certain embodiments, the disease to be treated and / or prevented includes, but is not limited to, a proliferative disease. Proliferative diseases include, but are not limited to, cancer (e.g., carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer). In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is Kaposi's sarcoma. In certain embodiments, the cancer is associated with overexpression and / or aberrant activity of a transcription factor (e.g., TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4). The present disclosure also provides mixtures, compositions, pharmaceutical compositions, kits, methods, and uses of compounds of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII) described herein.

[0213] The compounds described herein can be useful for treating and / or preventing a disease in a subject (e.g., a proliferative disease (e.g., cancer)) or a disease associated with the activity of a transcription factor (e.g., TEAD1, TEAD2, TEAD3, TEAD4), or for inhibiting the activity of a transcription factor (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or biological sample. In certain embodiments, the compounds described herein are compounds of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the compounds described herein are compounds of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or pharmaceutically acceptable salts thereof. In certain embodiments, the compounds described herein are compounds of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or compositions thereof.

[0214] Certain compounds described herein bind to, covalently modify, and / or inhibit transcription factors. In certain embodiments, compounds described herein irreversibly inhibit transcription factors. In certain embodiments, compounds described herein reversibly inhibit transcription factors. In certain embodiments, the transcription factor is a transcription enhancer factor. In certain embodiments, the transcription factor is a TEAD family transcription factor. In certain embodiments, the transcription factor is TEAD1. In certain embodiments, the transcription factor is TEAD2. In certain embodiments, the transcription factor is TEAD3. In certain embodiments, the transcription factor is TEAD4. In certain embodiments, compounds described herein covalently bind to a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, compounds described herein reversibly bind to a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds described herein irreversibly bind to a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds described herein modulate the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds described herein inhibit the activity of a transcription factor (e.g., a TEAD family transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds described herein reversibly inhibit the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds described herein irreversibly inhibit the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds described herein covalently inhibit the activity of a transcription factor (eg, a TEAD (eg, TEAD1, TEAD2, TEAD3, or TEAD4)).

[0215] The binding affinity of the compounds described herein for a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) can be determined by measuring the dissociation constant (K) of the adduct between the compound and the transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) using methods known in the art (e.g., isothermal titration calorimetry (ITC)). d In certain embodiments, the K d The value is about 100 μM or less, about 10 μM or less, about 1 μM or less, about 100 nM or less, about 10 nM or less, or about 1 nM or less.

[0216] In certain embodiments, the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) is inhibited by a compound described herein. Inhibition of the activity of a transcription factor (e.g., a TEAD family transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4))) by a compound described herein is measured by measuring the median maximum inhibitory concentration (IC) of the compound when the compound, or a pharmaceutical composition thereof, is contacted with the transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). 50 It can be measured by determining the IC 50 The IC values ​​can be obtained using methods known in the art (e.g., by competitive binding assays). In certain embodiments, the IC values ​​of the compounds described herein are 50 The value is about 1 mM or less, about 100 μM or less, about 10 μM or less, about 1 μM or less, about 100 nM or less, about 10 nM or less, or about 1 nM or less.

[0217] The compounds described herein can selectively modulate the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds selectively increase the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds selectively inhibit the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the compounds inhibit the activity of two or more protein transcription factors (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) to the same extent. In certain embodiments, the compounds increase the activity of two or more transcription factors (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) to the same extent.

[0218] The selectivity of the compounds described herein in inhibiting the activity of a first transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) over a second transcription factor can be measured by the IC of the compound that inhibits the activity of the second transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). 50 The value is expressed as the IC value of the compound that inhibits the activity of the first transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). 50 The selectivity of a compound described herein in modulating the activity of a first transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) over a second transcription factor can be measured by dividing the K value of the adduct of the compound and the second transcription factor by the K value. d The value is the K of the adduct between the compound and the first transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). dIn certain embodiments, the selectivity is at least about 1-fold, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, at least about 1,000-fold, at least about 3,000-fold, at least about 10,000-fold, at least about 30,000-fold, or at least about 100,000-fold.

[0219] Pharmaceutical Compositions, Kits, and Administration The present disclosure also provides a pharmaceutical composition comprising a compound described herein and, optionally, a pharmaceutically acceptable excipient. In certain embodiments, the compound described herein is a compound of Formula (I'), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0220] In certain embodiments, the compound described herein is provided in an effective amount in a pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the therapeutically effective amount is an amount effective to inhibit the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, the therapeutically effective amount is an amount effective to treat a disease (e.g., a disease associated with abnormal activity of a TEAD (e.g., a proliferative disease)). In certain embodiments, the therapeutically effective amount is an amount effective to inhibit the activity of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) and treat a disease (e.g., a disease associated with abnormal activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4) (e.g., a proliferative disease)). In certain embodiments, the therapeutically effective amount is an amount effective to induce apoptosis in a cell (e.g., a cell in vivo or in vitro). In certain embodiments, a prophylactically effective amount is an amount effective to inhibit the activity of a protein (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). In certain embodiments, a prophylactically effective amount is an amount effective to prevent a disease (e.g., a disease associated with TEAD activity (e.g., a proliferative disease such as cancer)) or keep a subject in need thereof in remission of the disease. In certain embodiments, a prophylactically effective amount is an amount effective to inhibit the activity of a TEAD and to prevent a disease (e.g., a disease associated with TEAD activity (e.g., a proliferative disease such as cancer)) or keep a subject in need thereof in remission of the disease.

[0221] In certain embodiments, an effective amount is an amount effective to inhibit the activity of a transcription factor (e.g., a TEAD, (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, an effective amount is an amount effective to inhibit the activity of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) by no more than 10%, no more than 20%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, no more than 95%, or no more than 98%.

[0222] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, e.g., a dog or cat. In certain embodiments, the subject is a livestock animal, e.g., a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, e.g., a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or a reptile.

[0223] In certain embodiments, the cell contacted with a compound or composition described herein is in vitro. In certain embodiments, the cell contacted with a compound or composition described herein is in vivo.

[0224] Additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, analgesics, and combinations thereof. In certain embodiments, the additional pharmaceutical agent is an antiproliferative agent (e.g., an anticancer agent). In certain embodiments, the additional pharmaceutical agent is an anti-leukemia agent. In certain embodiments, the additional pharmaceutical agent is avitrexate (methotrexate), ADE, adriamycin RDF (doxorubicin hydrochloride), ambochlorin (chlorambucil), Alanon (nelarabine), Arzera (ofatumumab), Bosulif (bosutinib), Busulfex (busulfan), Cambus (alemtuzumab), Cerbidine (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), Chloral (clofarabine), CVP, Cytosar-U (cytarabine), Cytoxan (cyclophosphamide), Erwinase (asparaginase), Erwinia Chrysanthemi), Fludara (fludarabine phosphate), Folex (methotrexate), Folex PFS (methotrexate), Gazyva (obinutuzumab), Gleevec (imatinib mesylate), Hyper-CVAD, Iclusig (ponatinib hydrochloride), Imbruvica (ibrutinib), Leukeran (chlorambucil), LINFOLIZIN (chlorambucil), Markivo (vincristine sulfate liposome), methotrexate LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), methotrexate hydrochloride Xantrone, Mastergen (mechlorethamine hydrochloride), Myleran (busulfan), NEOSAR (cyclophosphamide), Oncaspar (peguaspargase), Purinesol (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicin hydrochloride), Sprycel (dasatinib), Synribo (omacetaxine mepeccate), Tarabine PFS (cytarabine), Tasigna (nilotinib), Treanda (bendamustine hydrochloride), Trisenox (arsenic trioxide), Vincasar PFS (vincristine sulfate), Zydelig (idelalisib),or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is avitrexate (methotrexate), ABVD, ABVE, ABVE-PC, Adcetris (brentuximab vedotin), Adriamycin PFS (doxorubicin hydrochloride), Adriamycin RDF (doxorubicin hydrochloride), ambochlorin (chlorambucil), ambochlorin (chlorambucil), Alanon (nelarabine), BEACOPP, Besenam (carmustine), Beleodac (belinostat), Bexar (tositumomab and iodine I 131 tositumomab), BICNU (carmustine), Blenoxan (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, Cytoxan (cyclophosphamide), Depocyt (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, Folex (methotrexate), Folex PFS (methotrexate), Folotin (pralatrexate), HYPER-CVAD, ICE, Imbruvica (ibrutinib), Intron A (recombinant interferon alpha-2b), Istodax (romidepsin), Leukeran (chlorambucil), LINFOLIZIN (chlorambucil), lomustine, Matulan (procarbazine hydrochloride), methotrexate These include: Rexate LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, Mozovir (plelixafor), Mastergen (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP, Revlimid (lenalidomide), Rituxan (rituximab), Stanford V, Trenda (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), Vincasar PFS (vincristine sulfate), Zevalin (ibritumomab tiuxetan), Zolinza (vorinostat), Zydelig (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is Revlimid (lenalidomide),Dacogen (decitabine), Vidaza (azacitidine), Cytosar-U (cytarabine), Idamycin (idarubicin), Cervizin (daunorubicin), Leukeran (chlorambucil), Neosar (cyclophosphamide), Fludara (fludarabine), Leustatin (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is Abitrexate (methotrexate), Abraxane (paclitaxel albumin-stabilized nanoparticle formulation), AC, AC-T, ADE, Adriamycin PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), Afinitor (everolimus), Afinitor dispersible tablets (everolimus), Aldara (imiquimod), Alimta (pemetrexed disodium), Aredia (pamidronate disodium), Alimin Dex (anastrozole), Aromasin (exemestane), Avastin (bevacizumab), Besenam (carmustine), BEP, BICNU (carmustine), Blenoxane (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, Caprelsa (vandetanib), carboplatin-taxol, CARMUBRIS (carmustine), Casodex (bicalutamide), Seenu (lomustine), Cervidine (daunorubicin hydrochloride), Cervarix (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), Cosmegen (dactinomycin), CYFOS (ifosfamide), Cyramza (ramucirumab), Cytosar-U (cytarabine), Cytoxan (cyclophosphamide), Dacogen (decitabine), Degarelix, Doxil (doxorubicin hydrochloride liposomal), doxorubicin hydrochloride, DOX-SL (doxorubicin doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), Efudex (fluorouracil), ELLENCE (epirubicin hydrochloride), Eloxatin (oxaliplatin), Erbitux (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), Fairston (toremifene), Faslodex (fulvestrant), FEC, Femara (letrozole),Fluoroplex (fluorouracil), Folex (methotrexate), Folex PFS (methotrexate), Forfiri, Forfiri-bevacizumab, Forfiri-cetuximab, Forfirinox, Folfox, FU-LV, Gardasil (recombinant human papillomavirus (HPV) quadrivalent vaccine), gemcitabine-cisplatin, gemcitabine-oxaliplatin, Gemzar (gemcitabine hydrochloride), Gilotrif (afatinib dimaleate), Glivec (imatinib mesylate), Gliadel (Calmus) tin implant), Gliadel wafer (carmustine implant), Herceptin (trastuzumab), Hycamtin (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), Inlyta (axitinib), Intron A (recombinant interferon alpha-2b), Iressa (gefitinib), Ixempra (ixabepilone), Jakafi (ruxolitinib phosphate), Jevtana (cabazitaxel), Kadcyla (ado-trastuzumab emtansine), Keytruda (pembrolizumab), Kypro Lis (Carfilzomib), Lipodox (Doxorubicin Hydrochloride Liposomal), Lupron (Leuprolin Acetate), Lupron Depot (Leuprolide Acetate), Lupron Depot-3 Month (Leuprolide Acetate), Lupron Depot-4 Month (Leuprolide Acetate), Lupron Depot-PED (Leuprolide Acetate), MEGACE (Megestrol Acetate), Mekinist (Trametinib), Metazolastone (Temozolomide), Methotrexate LPF (Methotrexate), MEXATE (Methotrexate), MEXATE-AQ (Methotrexate) ate), mitoxantrone hydrochloride, Mitozytrex (mitomycin c), Mozobil (plelixafor), Mastergen (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacytidine), Navelbine (vinorelbine tartrate), NEOSAR (cyclophosphamide), Nexavar (sorafenib tosylate), Nolvadex (tamoxifen citrate), Novaldex (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), Paraplatin (carboplatin),PEG-Intron (peginterferon alpha-2b), pemetrexed disodium, Perjeta (pertuzumab), PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), Pomalyst (pomalidomide), prednisone, Proleukin (aldesleukin), Pralia (denosumab), Provenge (sipuleucel-t), Revlimid (lenalidomide), rubidomycin (daunorubicin hydrochloride), Sprycel (dasatinib), Stivarga (regorafenib), Sutent (sunitinib malate), SYLATRON (peginterferon alpha-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, Tafi Nlar (dabrafenib), Tarabin PFS (cytarabine), Tarceva (erlotinib hydrochloride), Tasigna (nilotinib), Taxol (paclitaxel), Taxotere (docetaxel), Temodar (temozolomide), Thalomid (thalidomide), Toposar (etoposide), Torisel (temsirolimus), TPF, Trisenox (arsenic trioxide), Tykerb (lapatinib ditosylate), Vectibix (panitumumab), VEIP, VELBAN (vinblastine sulfate), Velcade (bortezomib), VELSAR (vinblastine sulfate), Bepcid (etoposide), VIADUR (leuprolide acetate), Vidaza (azacitidine), VINCASAR PFS (vincristine sulfate), Votrient (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), Xalkori (crizotinib), Xeloda (capecitabine), Xerox, Zygeva (denosumab), Xofigo (radium-223 dichloride), Xtandi (enzalutamide), Yervoy (ipilimumab), Zaltrap (diflufenat), Zelboraf (vemurafenib), Zoladek (goserelin acetate), Zometa (zoledronic acid), Zykadia (ceritinib), Zytiga (abiraterone acetate), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470,BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (, CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi In certain embodiments, the additional pharmaceutical agent is ibrutinib. ... In certain embodiments, the additional pharmaceutical agent is a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is a TEAD binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is a TEAD1 binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is a TEAD2 binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is a TEAD3 binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is a TEAD4 binder or inhibitor.In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional regulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic agents (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., transcription factor inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with anti-cancer therapies, including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplant, bone marrow transplant), immunotherapy, and chemotherapy.

[0225] Thus, in one aspect, a kit is provided that includes a first container containing a compound or pharmaceutical composition described herein. In certain embodiments, the kit is useful for treating a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kit is useful for preventing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kit is useful for inhibiting the activity (e.g., abnormal or undesirable activity, such as increased activity) of a transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) in a subject, biological sample, tissue, or cell. In certain embodiments, the kit is useful for inducing apoptosis in a cell (e.g., a cell in vivo or in vitro).

[0226] In certain embodiments, the kits described herein further include instructions for using the compound or pharmaceutical composition included in the kit. The kits described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., a proliferative disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for modulating (e.g., inhibiting) the activity (e.g., abnormal activity, such as increased activity) of a transcription factor (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject, biological sample, tissue, or cell. In certain embodiments, the kits and instructions provide for inducing apoptosis in a cell. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

[0227] Treatment Methods and Uses The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant or undesirable activity, such as increased or decreased activity) of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)). The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) in a subject, biological sample, tissue, or cell. The present disclosure also provides methods of treating a wide range of disorders associated with aberrant activity (e.g., increased activity) of a transcription factor, such as proliferative disorders, in a subject in need thereof. The present disclosure provides methods of treating and / or preventing proliferative disorders (e.g., cancer (e.g., carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)).

[0228] The present disclosure also provides a compound of Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), Formula (F), or Formula (F), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, for use in treating a disease, such as a proliferative disease, in a subject in need of such treatment.

[0229] The present disclosure also provides the use of a compound of Formula (F), Formula (F), Formula (F), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, in the manufacture of a medicament for treating a disease, such as a proliferative disease, in a subject in need thereof.

[0230] In another aspect, the disclosure provides methods of modulating the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject, biological sample, tissue, or cell. In certain embodiments, methods are provided for inhibiting the activity of a transcription factor in a subject. In certain embodiments, methods are provided for inhibiting the activity of a transcription factor in a cell. In certain embodiments, methods are provided for increasing the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject. The compounds described herein can exhibit transcription factor inhibitory activity; the ability to inhibit transcription enhancer factors; the ability to inhibit TEAD family transcription factors; the ability to inhibit TEAD; the ability to inhibit TEAD1 without inhibiting other transcription factors (e.g., TEAD2, TEAD3, or TEAD4); the ability to inhibit TEAD2 without inhibiting other transcription factors (e.g., TEAD1, TEAD3, or TEAD4); the ability to inhibit TEAD3 without inhibiting other transcription factors (e.g., TEAD1, TEAD2, or TEAD4); therapeutic and / or prophylactic effects in the treatment of cancer; therapeutic and / or prophylactic effects in the treatment of proliferative diseases; and / or a therapeutic profile (e.g., optimal safety and therapeutic efficacy) superior to existing chemotherapeutic agents.

[0231] In certain embodiments, the methods described herein provide a way to reduce the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject or biological sample (e.g., a cell, a tissue) by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) in a subject or cell is reduced by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% by the methods described herein. In some embodiments, the activity of a transcription factor (e.g., a TEAD1 (e.g., a TEAD2, TEAD3, or TEAD4)) in a subject or cell is selectively inhibited by the methods. In some embodiments, the activity of a transcription factor (e.g., a TEAD (e.g., a TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject or cell is selectively reduced by the methods.

[0232] Without wishing to be bound by any particular theory, the compounds described herein are capable of binding to (e.g., covalently modifying) the transcription factor to be inhibited. In certain embodiments, the compounds described herein are capable of binding to (e.g., covalently modifying) the transcription factor. In certain embodiments, the compounds described herein are capable of covalently binding to a cysteine ​​residue of the transcription factor. In certain embodiments, the compounds are capable of covalently binding to the central pocket of the YAP / TAZ domain of a TEAD family transcription factor. In certain embodiments, the compounds are capable of covalently binding to TEAD1, TEAD2, TEAD3, or TEAD4. In certain embodiments, the compounds are capable of covalently modifying TEAD1, TEAD2, TEAD3, or TEAD4. In certain embodiments, the compounds are capable of covalently modifying the YAP-binding domain of a TEAD family transcription factor. In certain embodiments, the compounds are capable of covalently modifying TEAD1. In certain embodiments, the compounds are capable of covalently modifying TEAD2. In certain embodiments, the compounds are capable of covalently modifying TEAD3. In certain embodiments, the compounds are capable of covalently modifying TEAD4.

[0233] In another aspect, the disclosure provides a method of inhibiting the activity of a transcription factor in a subject by administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound described herein, or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of inhibiting the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a biological sample by contacting the biological sample with an effective amount of a compound described herein, or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of inhibiting the activity of a transcription factor in a tissue or cell, the method comprising contacting the tissue or cell with an effective amount of a compound described herein, or a pharmaceutical composition thereof.

[0234] In another aspect, the disclosure provides a method of inhibiting the activity of a transcription factor (e.g., a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a cell by contacting the cell with an effective amount of a compound described herein, or a pharmaceutical composition thereof.

[0235] In certain embodiments, the biological sample contacted with the compound or composition is breast tissue, bone marrow, lymph node, lymphatic tissue, spleen, or blood. In certain embodiments, the biological sample contacted with the compound or composition is tumor or cancer tissue. In certain embodiments, the biological sample contacted with the compound or composition is serum, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swab (such as cheek swab), or any material containing biomolecules derived from the initial biological sample.

[0236] In certain embodiments, the cell or tissue contacted with the compound or composition is present in vitro. In certain embodiments, the cell or tissue contacted with the compound or composition is present in vivo. In certain embodiments, the cell or tissue contacted with the compound or composition is present ex vivo. In certain embodiments, the cell or tissue contacted with the compound or composition is a malignant cell.

[0237] The diseases (e.g., proliferative diseases) treated or prevented using the compounds described herein may be associated with increased activity of a transcription factor such as a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). The diseases (e.g., proliferative diseases) treated or prevented using the compounds described herein may be associated with overexpression of a transcription factor such as a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4).

[0238] In certain embodiments, the disease (e.g., a proliferative disease) treated or prevented using the compounds described herein may be associated with overexpression of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). The disease (e.g., a proliferative disease) may be associated with abnormal activity of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). The abnormal activity of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) may be elevated activity and / or inappropriate or undesirable activity of a TEAD. The compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, may inhibit the activity of a TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) and may be useful for treating and / or preventing diseases (e.g., a proliferative disease). The compounds described herein, and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs, may inhibit the activity of TEAD and may be useful for treating and / or preventing diseases (e.g., proliferative diseases). The compounds described herein, and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs, may inhibit the activity of TEAD and may be useful for treating and / or preventing diseases (e.g., proliferative diseases).

[0239] All types of biological samples described herein or known in the art are considered to be within the scope of the present invention. In certain embodiments, the disease (e.g., a proliferative disease) treated or prevented using the compounds described herein is cancer. All types of cancer disclosed herein or known in the art are considered to be within the scope of the present invention. In certain embodiments, the proliferative disease is a carcinoma. In certain embodiments, the proliferative disease is fallopian tube cancer. In certain embodiments, the proliferative disease is a carcinoma. In certain embodiments, the proliferative disease is Kaposi's carcinoma. In certain embodiments, the proliferative disease is colorectal cancer. In certain embodiments, the proliferative disease is colon cancer. In certain embodiments, the proliferative disease is breast cancer. In certain embodiments, the proliferative disease is recurrent breast cancer. In certain embodiments, the proliferative disease is mutant breast cancer. In certain embodiments, the proliferative disease is HER2 + In certain embodiments, the proliferative disease is breast cancer. - In certain embodiments, the proliferative disease is breast cancer. In certain embodiments, the proliferative disease is triple-negative breast cancer (TNBC). In certain embodiments, the proliferative disease is lung cancer. In certain embodiments, the proliferative disease is thyroid cancer. In certain embodiments, the proliferative disease is skin cancer. In certain embodiments, the proliferative disease is ovarian cancer. In certain embodiments, the proliferative disease is prostate cancer. In certain embodiments, the proliferative disease is pancreatic cancer. In certain embodiments, the proliferative disease is esophageal cancer. In certain embodiments, the proliferative disease is liver cancer. In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are considered to be within the scope of the present invention. In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are considered to be within the scope of the present invention.

[0240] In certain embodiments, the methods described herein include administering to a subject or contacting with a biological sample an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the methods described herein include administering to a subject or contacting with a biological sample an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the compound is contacted with a biological sample. In certain embodiments, the compound is administered to a subject. In certain embodiments, the compound is administered in combination with one or more additional pharmaceutical agents described herein.

[0241] The compounds or compositions of the present invention can synergistically enhance the inhibition of TEAD induced by additional agent(s) in a biological sample or subject. Thus, the combination of the compounds or compositions of the present invention with additional pharmaceutical agents(s) can be useful for treating proliferative diseases that are resistant to treatment using the additional pharmaceutical agents(s) without the compounds or compositions of the present invention.

[0242] In certain embodiments, the kits described herein comprise a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits described herein are useful for treating and / or preventing a disease, such as a proliferative disease (e.g., cancer (e.g., sarcoma, carcinoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)) in a subject in need thereof, inhibiting the activity of a transcription factor (e.g., TEAD (e.g., TEAD1, TEAD2, TEAD3, or TEAD4)) in a subject, biological sample, tissue, or cell, and / or inducing apoptosis in a cell. [Example]

[0243] In order that this disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0244] Example 1. Antiproliferative assay in NCI-H226 cells (200 cells / well, 384 plates, 5 days treatment) Compounds of the present disclosure were tested for their potency in an antiproliferative assay using NCI-H226 cells (FIGS. 6 and 7). The following table summarizes the IC50 values ​​calculated from a graph of percent inhibition versus logarithm of concentration for representative compounds of the present disclosure. Compound (II-8) also showed an IC50 of 142 nM using H2052 cells. 50 (Figure 2).

[0245] For 2D adherent cell viability experiments, cells were seeded at a density of 200 cells / well in 384-well plates (Corning, no. 3570) (Figures 1-7). The following day, compounds were added using a Janus workstation (PerkinElmer). After 5 days of treatment, cell viability was measured using the CellTiter-Glo kit (Promega, no. G7570) according to the manufacturer's recommendations. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0246] Example 2. Gel-based antipalmitoylation assay 1 μM His-tagged TEAD-YBD recombinant protein was incubated with the indicated concentrations of inhibitors at 37°C for 2 h, followed by the addition of palmitoyl alkyne-coenzyme A (Cayman Chemical, no. 15968) in a total volume of 50 μL (see Figures 8–13). After 30 min of incubation, 5 μL of 10% SDS was added, followed by 5 μL of click reagent to initiate the click reaction. After an additional 1 h, 4x loading buffer was added to the reaction mixture, and the samples were subjected to Western blot analysis. IRDye 800CW streptavidin (LI-COR, no. 92632230) and His-tag mouse mAb (Cell Signaling, no. 2366S) were used for biotin and His-tag detection. Blots were imaged on an Odyssey CLx Imager (LI-COR).

[0247] Example 3. Synthesis of compounds Compounds IV-2, IV-3, IV-4, IV-5, VI-1, VI-2, VI-3, VII-1, VII-2, and VIII-1 were synthesized according to general synthetic route I shown in Scheme 1, using specific reagents detailed in Table 9. Scheme 2 shows the synthesis of compound IV-1. Scheme 1. General synthetic route I [ka] [Table 10-1] [Table 10-2] [Table 10-3]

[0248] Scheme 2. Synthesis of Compound IV-1 [ka] Step 1: Synthesis of tert-butyl trans-3-(4-cyano-1H-pyrazol-1-yl)-4-hydroxypyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 1.08 mmol), 1H-pyrazole-4-carbonitrile (100 mg, 1.08 mmol), and CsCO (351 mg, 1.08 mmol) in DMF (10 mL) was stirred overnight at 80 °C under N. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organics were washed with HO (50 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 20% v / v) to give compound 3 as a yellow oil (200 mg, 66% yield). LC-MS (ESI) m / z: 179 [M+H-100] + .

[0249] Step 2: Synthesis of tert-butyl trans-3-(4-cyano-1H-pyrazol-1-yl)-4-(3-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) A mixture of tert-butyl trans-3-(4-cyano-1H-pyrazol-1-yl)-4-hydroxypyrrolidine-1-carboxylate (20 mg, 0.07 mmol), 1-(bromomethyl)-3-(trifluoromethyl)benzene (17 mg, 0.07 mmol), and NaH (3 mg, 0.07 mmol) in DMF (5 mL) was stirred at room temperature under N for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organics were washed with HO (50 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 40% v / v) to give crude compound 5 as a yellow oil (36 mg, 98% yield). LC-MS (ESI) m / z: 437 [M+H-100]. + .

[0250] Step 3: Synthesis of 1-((trans-4-(3-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-4-carbonitrile (compound 6) A mixture of compound 5 (36 mg, 0.08 mmol) and TFA (1 mL) in DCM (3 mL) was stirred under N at room temperature for 2 hours. The mixture was concentrated to give crude compound 6 as a yellow oil (26 mg, 96% yield), which was used directly in the next step. LC-MS (ESI) m / z: 337 [M+H] + .

[0251] Step 4: Synthesis of 1-(trans-1-acryloyl-4-(3-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-4-carbonitrile (IV-1) To a mixture of compound 6 (30 mg, 0.089 mmol) and TEA (18 mg, 0.178 mmol) in DCM (5 mL) was added acryloyl chloride (8 mg, 0.089 mmol), and the mixture was stirred at room temperature under N for 2 h. The mixture was concentrated and purified by preparative HPLC (MeCN / HO / TFA) to give the desired product as a yellow oil (6 mg, 18% yield). LC-MS (ESI) m / z: 391 [M+H] + . 1 H-NMR (400 MHz, CD3OD) δ (ppm): 8.48 (d, J = 6.5 Hz, 1H), 8.00 (s, 1H), 7.75 - 7.56 (m, 4H), 6.69 (ddd, J = 16.8, 10.4, 8.4 Hz, 1H), 6.47 - 6.31 (m, 1H), 5.86 (ddd, J = 10.4, 5.8, 1.9 Hz, 1H), 5.36 - 5.18 (m, 1H), 4.78 (t, J = 3.5 Hz, 2H), 4.58 (dd, J = 18.5, 5.7 Hz, 1H), 4.40 - 3.65 (m, 4H).

[0252] Scheme 3. Synthesis of Compound IV-3 [ka] Step 1: Synthesis of ethyl 1-(trans-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)-1H-pyrazole-4-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (647 mg, 3.5 mmol), ethyl 1H-pyrazole-4-carboxylate (500 mg, 3.5 mmol), and CsCO (1160 mg, 3.5 mmol) in DMF (10 mL) was stirred at room temperature overnight at 80 °C under N. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL), and the organics were washed with water (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give compound 3 as a white oil (900 mg, 79% yield). LC-MS (ESI) m / z: 348 [M+23] + .

[0253] Step 2: Synthesis of ethyl 1-(trans-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-4-carboxylate (compound 5) A mixture of compound 3 (370 mg, 1.1 mmol), 1-(bromomethyl)-4-(trifluoromethyl)benzene (272 mg, 1.1 mmol), and NaH (44 mg, 1.1 mmol) in DMF (10 mL) was stirred at room temperature under N for 2 hours. The reaction mixture was monitored by LCMS. The mixture was extracted with ethyl acetate (100 mL), washed with water (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 5 as a yellow oil (500 mg, 94% yield). LC-MS (ESI) m / z: 428 [M+H-56] + .

[0254] Step 3: Synthesis of 1-(trans-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-4-carboxylic acid (compound 6) A mixture of compound 5 (200 mg, 0.41 mmol) and LiOH (50 mg, 2 mmol) in HO (4 mL) and EtOH (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to give crude compound 6 as a yellow oil (150 mg, 80% yield). LC-MS (ESI) m / z: 400 [M+H-56] + .

[0255] Step 4: Synthesis of tert-butyl-trans-3-(4-(methylcarbamoyl)-1H-pyrazol-1-yl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (compound 8) A mixture of compound 6 (150 mg, 0.32 mmol), methylamine (10 mg, 0.32 mmol), HATU (182 mg, 0.48 mmol), and TEA (97 mg, 0.64 mmol) in DMF (4 mL) was stirred overnight at room temperature. The mixture was directly purified by preparative HPLC to give compound 8 as an oil (65 mg, 43% yield). LC-MS (ESI) m / z: 413 [M+H-56] + .

[0256] Synthesis of N-methyl-1-(trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (Compound 9) A mixture of compound 8 (65 mg, 0.13 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature under N for 2 hours. The mixture was concentrated to give crude compound 9 as a yellow oil (45 mg, 93% yield). LC-MS (ESI) m / z: 369 [M+H] + .

[0257] Step 4: Synthesis of 1-(trans-1-acryloyl-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-N-methyl-1H-pyrazole-4-carboxamide (IV-3) A mixture of compound 9 (50 mg, 0.13 mmol), acryloyl chloride (12 mg, 0.13 mmol), and TEA (26 mg, 0.26 mmol) in DCM (5 mL) was stirred at room temperature under N for 2 hours. The mixture was concentrated and purified by preparative HPLC to give the desired compound IV-3 as a white solid (16 mg, 29% yield). LC-MS (ESI) m / z: 423 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 8.28 (d, J = 7.3 Hz, 1H), 8.09 (d, J = 3.0 Hz, 1H), 7.89 (d, J = 3.5 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 6.62 (ddd, J = 16.7, 10.3, 4.0 Hz, 1H), 6.18 (dt, J = 16.8, 2.3 Hz, 1H), 5.71 (ddd, J = 10.2, 5.9, 2.3 Hz, 1H), 5.31 - 5.04 (m, 1H), 4.69 (d, J = 4.9 Hz, 2H), 4.39 (dd, J = 23.0, 5.3 Hz, 1H), 4.25 - 3.49 (m, 4H), 2.71 (d, J = 4.5 Hz, 3H).

[0258] Scheme 4. Synthesis of Compound IV-2 [ka] Step 1: Synthesis of tert-butyl trans-3-(3-cyano-1H-pyrazol-1-yl)-4-hydroxypyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (397 mg, 2.15 mmol), 1H-pyrazole-5-carbonitrile (200 mg, 2.15 mmol), and CsCO (698 mg, 2.15 mmol) in DMF (5 mL) was stirred overnight at 80 °C under N. The reaction mixture was monitored by LCMS. The mixture was diluted with ethyl acetate (50 mL), washed with HO (50 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give compound 3 as a clear oil (145 mg, 38% yield). LC-MS (ESI) m / z: 179 [M+H-100] + .

[0259] Step 2: Synthesis of tert-butyl trans-3-(3-cyano-1H-pyrazol-1-yl)-4-(3-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) To a mixture of compound 3 (200 mg, 0.71 mmol) in DMF (10 mL) was added NaH (29 mg, 0.71 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, 1-(bromomethyl)-3-(trifluoromethyl)benzene (170 mg, 0.71 mmol) was added, and the mixture was stirred at room temperature under N for 2 hours. The reaction mixture was monitored by LCMS. The mixture was diluted with ethyl acetate (100 mL), washed with H2O (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude compound 5 as a yellow oil (260 mg, 85% yield). LC-MS (ESI) m / z: 437 [M+H-100] + .

[0260] Step 3: Synthesis of 1-(trans-4-(3-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carbonitrile (compound 6)

[0261] A mixture of compound 5 (100 mg, 0.23 mmol) and TFA (3 mL) in DCM (10 mL) was stirred at room temperature under N for 2 hours. The mixture was concentrated to give crude compound 6 as a yellow oil (70 mg, 90% yield). LC-MS (ESI) m / z: 337 [M+H] + .

[0262] Step 4: Synthesis of 1-(trans-1-acryloyl-4-(3-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carbonitrile (IV-2) A mixture of compound 6 (80 mg, 0.24 mmol), acryloyl chloride (21 mg, 0.24 mmol), and TEA (48 mg, 0.24 mmol) in DCM (5 mL) was stirred at room temperature under N for 2 h. The mixture was concentrated and purified by preparative HPLC (MeCN / HO / TFA) to give IV-2 as a yellow oil (35 mg, 37% yield). LC-MS (ESI) m / z: 391 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ (ppm) 7.96 (dd, J = 4.9, 2.5 Hz, 1H), 7.69 - 7.47 (m, 4H), 6.84 (t, J = 2.5 Hz, 1H), 6.64 (ddd, J = 16.8, 10.4, 8.9 Hz, 1H), 6.34 (d, J = 16.7 Hz, 1H), 5.81 (ddd, J = 10.4, 6.0, 1.9 Hz, 1H), 5.34 - 5.11 (m, 1H), 4.71 (t, J = 3.9 Hz, 2H), 4.52 (dd, J = 19.2, 5.7 Hz, 1H), 4.34 - 3.65 (m, 4H).

[0263] Scheme 5. Synthesis of Compound VII-2 [ka] Step 1: Synthesis of tert-butyl trans-3-hydroxy-4-(3-(methylthio)phenyl)pyrrolidine-1-carboxylate (compound 4) A mixture of (3-bromophenyl)(methyl)sulfane (1085 mg, 5.4 mmol) and Mg (129 mg, 5.4 mmol) in THF (10 mL) was stirred at reflux under N for 2 h. The mixture was then cooled to 0 °C, and tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1000 mg, 5.4 mmol) and CuI (102 mg, 0.54 mmol) in THF (5 mL) were added, and the resulting mixture was stirred at 50 °C overnight. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give product 4 as a white solid (850 mg, 51% yield). LC-MS (ESI) m / z: 254 [M+H-56] + .

[0264] Step 2: Synthesis of tert-butyl trans-3-(3-(methylthio)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 6) To a mixture of tert-butyl trans-3-hydroxy-4-(3-(methylthio)phenyl)pyrrolidine-1-carboxylate (200 mg, 0.64 mmol) and NaH (26 mg, 0.64 mmol) in DMF (5 mL) was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (154 mg, 0.54 mmol), and the mixture was stirred at room temperature under N for 2 h, diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give crude product 6 as a yellow oil (250 mg, 83% yield), which was used directly in the next step. LC-MS (ESI) m / z: 368 [M+H-100] + .

[0265] Step 3: Synthesis of tert-butyl trans-3-(3-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 7) A mixture of tert-butyl trans-3-(3-(methylthio)phenyl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (260 mg, 0.55 mmol) and mCPBA (239 mg, 1.4 mmol) in DCM (10 mL) was stirred overnight at room temperature under N. The mixture was concentrated and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give product 7 as a yellow oil (30 mg, 11% yield). LC-MS (ESI) m / z: 522 [M+23] + .

[0266] Step 4: Synthesis of trans-3-(3-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine (compound 8) A mixture of tert-butyl trans-3-(3-(methylsulfonyl)phenyl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (30 mg, 0.06 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give crude product 8 as a yellow oil (23 mg, 100% yield). LC-MS (ESI) m / z: 400 [M+H] + .

[0267] Step 5: Synthesis of trans-3-(3-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (VII-2) A mixture of trans-3-(3-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine (25 mg, 0.06 mmol), acryloyl chloride (6 mg, 0.06 mmol), and TEA (12 mg, 0.12 mmol) in DCM (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated and purified by preparative HPLC (MeCN / HO / TFA) to give the desired VII-2 as a white solid (7 mg, 26% yield). LC-MS (ESI) m / z: 454 [M+H] + .1 H-NMR (400 MHz, CD3OD) δ (ppm) 7.98 - 7.88 (m, 2H), 7.71 - 7.59 (m, 4H), 7.47 (d, J = 8.0 Hz, 2H), 6.67 (td, J = 16.3, 10.5 Hz, 1H), 6.35 (dd, J = 16.8, 1.8 Hz, 1H), 5.81 (dd, J = 10.4, 2.2 Hz, 1H), 4.68 (q, J = 12.7 Hz, 2H), 4.42 - 3.95 (m, 3H), 3.94 - 3.53 (m, 3H), 3.14 (s, 3H).

[0268] Scheme 6. Synthesis of Compound VII-1 [ka] Step 1: Synthesis of tert-butyl trans-3-hydroxy-4-(4-(methylthio)phenyl)pyrrolidine-1-carboxylate (Compound 3) A mixture of (4-bromophenyl)(methyl)sulfane (2190 mg, 10.8 mmol) and Mg (259 mg, 10.8 mmol) in THF (200 mL) was stirred at reflux under N for 2 h. The reaction mixture was then cooled to 0 °C, and a mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2000 mg, 10.8 mmol) and CuI (205 mg, 1.08 mmol) in THF (10 mL) was added, and the resulting mixture was stirred at 50 °C overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organics were washed with water (100 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give the desired compound 3 as a white solid (3 g, 90% yield). LC-MS (ESI) m / z: 254[M+H-56] + .

[0269] Step 2: Synthesis of tert-butyl trans-3-(4-(methylthio)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) To a solution of compound 3 (500 mg, 1.6 mmol) in DMF (10 mL) was added NaH (64 mg, 1.6 mmol), the mixture was stirred at 0 °C for 10 min, then 1-(bromomethyl)-4-(trifluoromethyl)benzene (386 mg, 1.6 mmol) was added, the reaction mixture was stirred at room temperature under N for 2 h, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), the combined organics were washed with water (100 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 40% v / v) to give compound 5 as a yellow oil (660 mg, 88% yield). LC-MS (ESI) m / z: 412 [M+H-56] + .

[0270] Step 3: Synthesis of tert-butyl trans-3-(4-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 6) A mixture of compound 5 (300 mg, 0.64 mmol) and mCPBA (276 mg, 1.6 mmol) in DCM (10 mL) was stirred overnight at room temperature under N. The mixture was concentrated and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 40% v / v) to give compound 6 as a yellow oil (260 mg, 81% yield). LC-MS (ESI) m / z: 522 [M+23] + .

[0271] Step 4: Synthesis of trans-3-(4-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine (Compound 7) A mixture of compound 6 (100 mg, 0.2 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature under N for 2 hours. The mixture was concentrated to give crude compound 7 as a yellow oil (80 mg, 100% yield). LC-MS (ESI) m / z: 400 [M+H] + .

[0272] Step 5: Synthesis of 1-(trans-3-(4-(methylsulfonyl)phenyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (VII-1) To a mixture of compound 7 (90 mg, 0.2 mmol) and TEA (44 mg, 0.4 mmol) in DCM (5 mL) was added acryloyl chloride (19 mg, 0.2 mmol), and the mixture was stirred at room temperature under N for 2 h. The mixture was concentrated and purified by preparative HPLC (MeCN / HO / TFA) to give the desired compound VII-1 as a white solid (20 mg, 18% yield). LC-MS (ESI) m / z: 454 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.90 (dd, J = 8.3, 2.6 Hz, 2H), 7.69 (d, J = 8.3, 2.6 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 6.69 - 6.58 (m, 1H), 6.22-6.15 (m, 1H), 5.75 - 5.67 (m, 1H), 4.66 (d, J = 3.4 Hz, 2H), 4.33 -4.22 (m, 1H), 4.13-3.99 (m, 1H), 3.95-3.40 (m, 4H), 3.21 (s, 3 H).

[0273] Scheme 7. Synthesis of Compound VII-10 [ka] Step 1: Synthesis of tert-butyl trans-3-cyano-4-hydroxypyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1200 mg, 6.48 mmol), KCN (840 mg, 12.96 mmol), and LiClO (1032 mg, 9.72 mmol) in CHCN (20 mL) was stirred at 70 °C under N for 2 days. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 2), and the combined organics were washed with HO (50 mL), dried over anhydrous NaSO, concentrated, and purified by preparative HPLC to give compound 3 as a clear oil (1 g, 72% yield). LC-MS (ESI) m / z: 235 [M+23] + .

[0274] Step 2: Synthesis of tert-butyl trans-3-cyano-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) A mixture of compound 3 (300 mg, 1.41 mmol), 1-(bromomethyl)-4-(trifluoromethyl)benzene (360 mg, 1.41 mmol), and AgO (1620 mg, 9.2 mmol) in THF (25 mL) was stirred overnight at 90 °C under N. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (60 mL), and the organics were washed with water (40 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 40% v / v) to give crude compound 5 (300 mg) as a yellow oil. LC-MS (ESI) m / z: 315 [M+H-56] + .

[0275] Step 3: Synthesis of tert-butyl trans-3-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 6) A mixture of compound 5 (300 mg, 0.81 mmol), NaN (90 mg, 1.2 mmol), and NH Cl (72 mg, 4.02 mmol) in DMF (5 mL) was stirred overnight at 130 °C under N. The mixture was monitored by LCMS. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL), and the organics were washed with water (40 mL), dried over anhydrous Na SO , concentrated, and purified by preparative HPLC to give compound 6 as a yellow solid (60 mg, 24% yield). LC-MS (ESI) m / z: 314 [M+H-100] + .

[0276] Step 4: Synthesis of 5-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-2H-tetrazole (compound 7) A mixture of compound 6 (50 mg, 0.1 mmol) and TFA (1 mL) in DCM (3 mL) was stirred under N at room temperature for 2 hours. The mixture was concentrated to give crude compound 7 as a yellow oil (34 mg, 100% yield). LC-MS (ESI) m / z: 314 [M+H] + .

[0277] Step 5: Synthesis of 1-(trans-3-(2H-tetrazol-5-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (VII-10) A mixture of compound 7 (50 mg, 0.16 mmol), acryloyl chloride (20 mg, 0.16 mmol), and TEA (40 mg, 0.32 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC to give compound VII-10 as a white solid (15 mg, 25% yield). LC-MS (ESI) m / z: 368 [M+H] + . 1H NMR (400 MHz, CD3OD) δ (ppm) 7.66 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 6.8 Hz, 2H), 6.69-6.57 (m, 1H), 6.36-6.28 (m, 1H), 5.83-5.75 (m, 1H), 4.75 (s, 2H), 4.57-4.44 (m, 1H), 4.29-3.93 (m, 4H), 3.90-3.69 (m, 2H).

[0278] Scheme 8. Synthesis of Compound IV-5 [ka] Step 1: Synthesis of ethyl 1-(trans-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)-1H-pyrazole-3-carboxylate (compound 3) To a solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1320 mg, 7.13 mmol) in dry DMF (20 mL) was added ethyl 1H-pyrazole-3-carboxylate (1000 mg, 7.13 mmol). The mixture was stirred at 50 °C overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organics were washed with brine (200 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate) to give the desired compound 3 as an oil (800 mg, 34.5% yield). LC-MS (ESI) m / z: 348 [M+Na] + .

[0279] Step 2: Synthesis of ethyl 1-(trans-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carboxylate (compound 5) To a solution of ethyl 1-(trans-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)-1H-pyrazole-3-carboxylate (700 mg, 2.15 mmol) in DMF (20 mL) was added NaH (60%, 103 mg, 2.58 mmol), and the mixture was stirred at 0 °C under N for 0.5 h. Then, 1-(bromomethyl)-4-(trifluoromethyl)benzene (512 mg, 2.15 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organics were washed with brine (200 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate) to give the desired compound 5 as an oil (700 mg, 67.4% yield). LC-MS (ESI) m / z: 506[M+Na] + .

[0280] Step 3: Synthesis of 1-(trans-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carboxylic acid (compound 6) To a solution of ethyl 1-(trans-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carboxylate (400 mg, 0.83 mmol) in EtOH (15 mL) was added a solution of NaOH (132 mg, 3.31 mmol) in HO (15 mL). The mixture was stirred at 80° C. for 2 h. The mixture was poured into aqueous HCl solution (1N, 40 mL) and extracted with EtOAc (100 mL×3), and the combined organics were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 6 as an oil (400 mg, crude). LC-MS (ESI) m / z: 400 [M-55] + .

[0281] Step 4: Synthesis of tert-butyl trans-3-(3-(methylcarbamoyl)-1H-pyrazol-1-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 8) To a solution of 1-(trans-1-(tert-butoxycarbonyl)-4-(4-(trifluoromethyl)benzyloxy)-pyrrolidin-3-yl)-1H-pyrazole-3-carboxylic acid (400 mg, 0.88 mmol) in DMF (15 mL) was added a solution of methanamine in THF (0.4 mL, 2 M, 0.88 mmol), HATU (400 mg, 1.04 mmol), and EtN (177.6 mg, 3.12 mmol). The mixture was stirred at room temperature for 3 h, diluted with water (100 mL), extracted with EtOAc (50 mL × 3), and the combined organics were washed with brine (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (eluted with DCM / MeOH) to give the desired compound 8 as an oil (340 mg, 82.7% yield). LC-MS (ESI) m / z: 491[M+Na] + .

[0282] Step 5: Synthesis of N-methyl-1-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carboxamide (Compound 9) To a solution of compound 8 (290 mg, 0.62 mmol) in DCM (10 mL) was added TFA (2 mL), and the mixture was stirred at 0° C. for 1 h and then concentrated to give crude compound 9 as an oil (300 mg, crude). LC-MS (ESI) m / z: 369 [M+H] + .

[0283] Step 6: Synthesis of 1-(trans-1-acryloyl-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-N-methyl-1H-pyrazole-3-carboxamide (compound IV-5) To a solution of compound 9 (250 mg, 0.74 mmol) in DCM (15 mL) was added acryloyl chloride (61 mg, 0.74 mmol) and EtN (137 mg, 1.47 mmol). The mixture was stirred at 0 °C for 1 h, then diluted with water (100 mL) and extracted with EtOAc (50 mL × 2). The combined organics were washed with brine (100 mL), dried over anhydrous NaSO, concentrated, and purified by preparative HPLC to give the desired compound IV-5 as a solid (50 mg, 16% yield). LC-MS (ESI) m / z: 423 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ (ppm) 7.87 - 7.78 (m, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 2.4 Hz, 1H), 6.64 (ddd, J = 17.4, 10.4, 7.4 Hz, 1H), 6.34 (dd, J = 16.8, 1.6 Hz, 1H), 5.85 - 5.77 (m, 1H), 5.20 - 5.08 (m, 1H), 4.72 - 4.67 (m, 2H), 4.60 - 4.49 (m, 1H), 4.33 - 4.19 (m, 1H), 4.17 - 3.96 (m, 2H), 3.85 - 3.65 (m, 1H), 2.90 (s, 3H).

[0284] Scheme 9. Synthesis of Compound IV-4 [ka] Step 1: Synthesis of tert-butyl trans-3-(3-cyano-1H-pyrazol-1-yl)-4-hydroxypyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (397 mg, 2.15 mmol), 1H-pyrazole-5-carbonitrile (200 mg, 2.15 mmol), and CsCO (698 mg, 2.15 mmol) in DMF (5 mL) was stirred at 80 °C overnight. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL), and the organics were washed with HO (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give compound 3 as a white oil (200 mg, 33% yield). LC-MS (ESI) m / z: 279 [M+H] + .

[0285] Step 2: Synthesis of tert-butyl trans-3-(3-cyano-1H-pyrazol-1-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) To a solution of compound 3 (200 mg, 0.71 mmol) in DMF (10 mL) was added NaH (28 mg, 0.71 mmol), and the mixture was stirred at room temperature for 10 min. Then, 1-(bromomethyl)-4-(trifluoromethyl)benzene (172 mg, 0.71 mmol) was added. The resulting mixture was stirred at room temperature under N for 2 h, diluted with water (100 mL), extracted with ethyl acetate (100 mL), and the organics were washed with HO (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 5 (300 mg, 96% yield) as a yellow oil, which was used directly in the next step. LC-MS (ESI) m / z: 337 [M+H-100] + .

[0286] Step 3: Synthesis of 1-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carbonitrile (compound 6) A mixture of compound 5 (200 mg, 0.46 mmol) and TFA (3 mL) in DCM (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give crude compound 6 as a yellow oil (100 mg, 64% yield), which was used directly in the next step. LC-MS (ESI) m / z: 337 [M+H] + .

[0287] Step 4: Synthesis of 1-(trans-1-acryloyl-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-1H-pyrazole-3-carbonitrile (IV-4) A mixture of compound 6 (100 mg, 0.29 mmol), acryloyl chloride (26 mg, 0.29 mmol), and TEA (58 mg, 0.58 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC to give the desired compound IV-4 as a yellow oil (16 mg, 14% yield). LC-MS (ESI) m / z: 391 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ (ppm) 7.96 (dd, J = 5.1, 2.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 6.85 (t, J = 2.7 Hz, 1H), 6.69 - 6.55 (m, 1H), 6.34 (dd, J = 16.8, 1.9 Hz, 1H), 5.81 (ddd, J = 10.4, 4.5, 1.9 Hz, 1H), 5.34 - 5.11 (m, 1H), 4.72 (d, J = 4.8 Hz, 2H), 4.58 - 3.68 (m, 5H).

[0288] Scheme 10. Synthesis of Compound VI-1 [ka] Step 1: Synthesis of tert-butyl trans-3-(6-oxopyridazin-1(6H)-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (compound 3) To a solution of tert-butyl trans-3-hydroxy-4-(6-oxopyridazin-1(6H)-yl)pyrrolidine-1-carboxylate (200 mg, 0.71 mmol) in DMF (10 mL) was added NaH (60%, 32.74 mg, 0.85 mmol), and the mixture was stirred at 0 °C under N for 0.5 h. Then 1-(bromomethyl)-4-(trifluoromethyl)benzene (169.4 mg, 0.71 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h, diluted with water (100 mL), extracted with EtOAc (500 mL × 2), and the combined organics were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated to give crude compound 3 as an oil (300 mg, crude). LC-MS (ESI) m / z: 439 [M+H] + .

[0289] Step 2: Synthesis of 2-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)pyridazin-3(2H)-one (compound 4) A mixture of tert-butyl trans-3-(6-oxopyridazin-1(6H)-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol) and TFA (3 mL) in DCM (10 mL) was stirred at 0° C. for 1 h and then concentrated to give crude compound 4 as an oil (240 mg, crude). LC-MS (ESI) m / z: 339 [M+H] + .

[0290] Step 3: Synthesis of 2-(trans-1-acryloyl-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)pyridazin-3(2H)-one (Compound VI-1) To a solution of 2-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)pyridazin-3(2H)-one (240 mg, 0.71 mmol) in DCM (10 mL) was added acryloyl chloride (64 mg, 0.71 mmol) and EtN (143 mg, 1.42 mmol). The mixture was stirred at 0 °C for 1 h, then concentrated and purified by preparative HPLC to give the desired compound VI-1 as a solid (61 mg, 22% yield). LC-MS (ESI) m / z: 394 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ (ppm) 7.94 (dd, J = 3.8, 1.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.50 - 7.40 (m, 1H), 7.02 (dt, J = 9.5, 1.6 Hz, 1H), 6.64 (ddd, J = 16.8, 12.6, 10.5 Hz, 1H), 6.32 (dd, J = 16.8, 1.5 Hz, 1H), 5.84 - 5.76 (m, 1H), 5.69 - 5.59 (m, 1H), 4.82 (dd, J = 19.8, 7.6 Hz, 2H), 4.42 - 4.29 (m, 1H), 4.24 - 4.09 (m, 1H), 4.05 - 3.99 (m, 1H), 3.99 - 3.83 (m, 1H), 3.77 (d, J = 3.7 Hz, 1H).

[0291] Scheme 11. Synthesis of Compound VII-6 [ka] Step 1: Synthesis of tert-butyl trans-3-hydroxy-4-(phenylsulfonylmethyl)pyrrolidine-1-carboxylate (compound 3) To a solution of (methylsulfonyl)benzene (421 mg, 2.7 mmol) in THF (10 mL), nBuLi (2.5 M in THF, 1.3 mL, 3.2 mmol) was added, and the mixture was stirred at −78 °C for 10 min. tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 2.7 mmol) was then added, and the mixture was stirred at −78 °C under N for 2 h and allowed to warm slowly to room temperature. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL), and the organics were washed with water (50 mL), dried over anhydrous NaSO, concentrated, and purified by preparative HPLC to give compound 3 as a clear oil (660 mg, 52% yield). LC-MS (ESI) m / z: 286 [M-55] + .

[0292] Step 2: Synthesis of tert-butyl trans-3-(phenylsulfonylmethyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) To a solution of compound 3 (100 mg, 0.29 mmol) in DMF (5 mL) was added NaH (12 mg, 0.29 mmol), the mixture was stirred at room temperature for 10 minutes, then 1-(bromomethyl)-4-(trifluoromethyl)benzene (70 mg, 0.29 mmol) was added, the mixture was stirred at room temperature under N for 2 hours, quenched with water (50 mL), extracted with ethyl acetate (50 mL), the organics were washed with water (50 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give compound 5 as a yellow oil (130 mg, 90% yield). LC-MS (ESI) m / z: 400 [M+H-100] + .

[0293] Step 3: Synthesis of trans-3-(phenylsulfonylmethyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine (compound 6) A mixture of compound 5 (130 mg, 0.26 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature for 2 hours, and the mixture was concentrated to give crude compound 6 as a yellow oil (80 mg, 77% yield), which was used directly in the next step. LC-MS (ESI) m / z: 400 [M+H] + .

[0294] Step 4: Synthesis of 1-(trans-3-(phenylsulfonylmethyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (Compound VII-6) A mixture of compound 6 (90 mg, 0.2 mmol), acryloyl chloride (19 mg, 0.2 mmol), and TEA (44 mg, 0.4 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC to give compound VII-6 as a white solid (20 mg, 22% yield). LC-MS (ESI) m / z: 454 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.95 (dd, J = 7.2, 5.1 Hz, 2H), 7.73 (dq, J = 22.2, 7.5 Hz, 5H), 7.52 (d, J = 8.0 Hz, 2H), 6.59 - 6.41 (m, 1H), 6.13 (dd, J = 16.8, 2.2 Hz, 1H), 5.75 - 5.53 (m, 1H), 4.58 (d, J = 6.8 Hz, 2H), 4.08 - 3.36 (m, 7H), 2.71 - 2.52 (m, 1H).

[0295] Scheme 12. Synthesis of Compound VII-5 [ka] Step 1: Synthesis of tert-butyl trans-3-hydroxy-4-(phenylthio)pyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (420 mg, 2.2 mmol) and sodium benzenethiolate (300 mg, 2.27 mmol) in DMF (5 mL) was stirred overnight at room temperature under N. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organics were washed with water (50 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give compound 3 as an oil (500 mg, 76% yield). LC-MS (ESI) m / z: 196 [M+H-100] + .

[0296] Step 2: Synthesis of tert-butyl trans-3-(phenylthio)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) To a solution of compound 3 (500 mg, 0.84 mmol) in DMF (5 mL) was added NaH (34 mg, 0.84 mmol), and the mixture was stirred at room temperature for 10 min. Then, 1-(bromomethyl)-4-(trifluoromethyl)benzene (202 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature under N for 2 h, diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organics were washed with water (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 5 as a yellow oil (300 mg, 78% yield), which was used directly in the next step. LC-MS (ESI) m / z: 354 [M+H-100] + .

[0297] Step 3: Synthesis of tert-butyl trans-3-(phenylsulfonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 6) A mixture of compound 5 (3000 mg, 0.66 mmol) and mCPBA (284 mg, 1.65 mmol) in DCM (10 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give compound 6 as a yellow oil (230 mg, 72% yield). LC-MS (ESI) m / z: 386 [M+H-100] + .

[0298] Step 4: Synthesis of trans-3-(phenylsulfonyl)-4-(4-(trifluoromethyl)benzyloxy)-pyrrolidine (compound 7) A mixture of compound 6 (100 mg, 0.2 mmol) and TFA (3 mL) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give crude compound 7 as a yellow oil (80 mg, 100% yield). LC-MS (ESI) m / z: 386 [M+H] + .

[0299] Step 5: Synthesis of 1-(trans-3-(phenylsulfonyl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (VII-5) A mixture of compound 7 (80 mg, 0.2 mmol), acryloyl chloride (19 mg, 0.2 mmol), and TEA (44 mg, 0.4 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC to give compound VII-5 as a white solid (12 mg, 13% yield). LC-MS (ESI) m / z: 440 [M+H] + . 1H NMR (400 MHz, CD3OD) δ (ppm) 7.85 (d, J = 7.7 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.51 (dt, J = 27.0, 6.9 Hz, 4H), 7.25 (dd, J = 14.3, 8.1 Hz, 2H), 6.58 - 6.37 (m, 1H), 6.19 (dd, J = 16.8, 1.6 Hz, 1H), 5.67 (dd, J = 18.1, 7.4 Hz, 1H), 4.55 - 4.31 (m, 3H), 4.22 - 3.83 (m, 3H), 3.79 - 3.52 (m, 2H).

[0300] Scheme 13. Synthesis of Compound VI-2 [ka] Step 1: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (compound 3) To a solution of 6-bromopyridazin-3(2H)-one (1 g, 5.75 mmol) in 1,4-dioxane (32 mL) and HO (8 mL) was added 1-methyl-1H-pyrazol-4-ylboronic acid (0.794 g, 6.3 mmol), KCO (1.58 g, 11.5 mmol), and PdCl(PPh) (0.121 mg, 0.17 mmol). The mixture was stirred at 110 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give the desired compound 3 as a solid (900 mg, 88.5% yield). LC-MS (ESI) m / z: 177[M+H] + .

[0301] Step 2: Synthesis of tert-butyl trans-3-hydroxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)pyrrolidine-1-carboxylate (Compound 5) To a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (800 mg, 4.55 mmol) in EtOH (40 mL) was added tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1681 mg, 9.10 mmol) and CsCO (4436 mg, 13.65 mmol). The mixture was stirred at 80 °C for 16 h, diluted with water (100 mL), extracted with EtOAc (3 × 50 mL), and the combined organics were washed with brine (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give the desired compound 5 as an oil (500 mg, 30.5% yield). LC-MS (ESI) m / z: 362 [M+H] + .

[0302] Step 3: Synthesis of tert-butyl trans-3-(3-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 7) To a solution of tert-butyl trans-3-hydroxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)pyrrolidine-1-carboxylate (450 mg, 1.25 mmol) in DMF (10 mL) was added NaH (60%, 60 mg, 2.50 mmol) and the mixture was stirred at 0° C. under N for 0.5 h, then 1-(bromomethyl)-4-(trifluoromethyl)benzene (326 mg, 1.37 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, diluted with water (100 mL), extracted with EtOAc (3 x 50 mL), and the combined organics were washed with brine (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give the desired compound 7 as a solid (300 mg, 46.3% yield). LC-MS (ESI) m / z: 520 [M+H] + .

[0303] Step 4: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-2-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)pyridazin-3(2H)-one (compound 8) A mixture of tert-butyl trans-3-(3-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (250 mg, 0.2 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The mixture was basified with NaHCO solution to pH 8 and extracted with EtOAc (3×50 mL), and the combined organics were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 8 as an oil (200 mg, crude). LC-MS (ESI) m / z: 420 [M+H] + .

[0304] Step 5: Synthesis of 2-(trans-1-acryloyl-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (Compound VI-2) To a solution of 6-(1-methyl-1H-pyrazol-4-yl)-2-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)pyridazin-3(2H)-one (180 mg, 0.43 mmol) in THF (10 mL) was added acryloyl chloride (39 mg, 0.43 mmol) and EtN (87 mg, 0.86 mmol). The mixture was stirred at 0 °C for 1 h, concentrated, and purified by preparative HPLC to give the desired compound VI-2 as a solid (127 mg, 62.6% yield). LC-MS (ESI) m / z: 474 [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.11 (d, J = 4.9 Hz, 1H), 7.84 - 7.73 (m, 2H), 7.68 (d, J = 6.9 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.03 (dd, J = 9.7, 3.0 Hz, 1H), 6.66 (dd, J = 16.7, 10.3 Hz, 1H), 6.21 (ddd, J = 16.8, 5.5, 2.3 Hz, 1H), 5.72 (ddd, J = 10.2, 6.5, 2.3 Hz, 1H), 5.56 - 5.44 (m, 1H), 4.76 (qd, J = 12.9, 4.0 Hz, 2H), 4.44 - 4.30 (m, 1H), 4.14 - 3.90 (m, 2H), 3.87 - 3.50 (m, 5H).

[0305] Scheme 14. Synthesis of Compound VI-3 [ka] Step 1: Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (compound 3) To a solution of 5-iodopyridazin-3(2H)-one (1 g, 4.5 mmol) in dioxane (32 mL) and HO (8 mL) was added (1-methyl-1H-pyrazol-4-yl)boronic acid (0.63 g, 5.0 mmol), KCO (1.24 g, 9.0 mmol), and PdCl(PPh) (95 mg, 0.135 mmol). The mixture was stirred at 110 °C for 14 h under N. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and purified by column chromatography on silica gel (eluted with DCM / MeOH = 10:1) to give the desired compound 3 as a solid (500 mg, 63% yield). LC-MS (ESI) m / z: 177[M+H] + .

[0306] Step 2: Synthesis of tert-butyl trans-3-hydroxy-4-(4-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)pyrrolidine-1-carboxylate (Compound 5) To a solution of 5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (500 mg, 2.84 mmol) in EtOH (40 mL) was added tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1050 mg, 5.68 mmol) and CsCO (2769 mg, 8.52 mmol). The mixture was stirred at 80 °C for 16 h, diluted with water (100 mL), extracted with EtOAc (3 × 50 mL), and the combined organics were washed with brine (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (eluted with DCM / MeOH = 10:1) to give the desired compound 5 as an oil (500 mg, 48.7% yield). LC-MS (ESI) m / z: 362 [M+H] + .

[0307] Step 3: Synthesis of tert-butyl trans-3-(4-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (Compound 7) To a solution of tert-butyl trans-3-hydroxy-4-(4-(1-methyl-1H-pyrazol-4-yl)-6-oxopyridazin-1(6H)-yl)pyrrolidine-1-carboxylate (450 mg, 1.25 mmol) in DMF (10 mL) was added NaH (60 mg, 2.50 mmol), and the mixture was stirred at 0 °C under N for 0.5 h. Then, 1-(bromomethyl)-4-(trifluoromethyl)benzene (326 mg, 1.37 mmol) was added. The resulting mixture was stirred at room temperature for 16 h, diluted with water (100 mL), extracted with EtOAc (3 × 50 mL), and the combined organics were washed with brine (100 mL), dried over anhydrous NaSO, concentrated, and purified by column chromatography on silica gel (eluted with EA / PE = 1:1) to give the desired compound 7 as a solid (300 mg, 46.3% yield). LC-MS (ESI) m / z: 420[M-100] + .

[0308] Step 4: Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)-2-(trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)pyridazin-3(2H)-one (compound 8) A mixture of compound 7 (250 mg, 0.5 mmol) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 2 hours. The mixture was basified with NaHCO solution to pH 8 and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 8 as an oil (200 mg, crude). LC-MS (ESI) m / z: 420 [M+H] + .

[0309] Step 5: Synthesis of 2-(trans-1-acryloyl-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (Compound VI-3) To a solution of compound 8 (180 mg, 0.43 mmol) in THF (10 mL) was added acryloyl chloride (39 mg, 0.43 mmol) and EtN (87 mg, 0.86 mmol). The mixture was stirred at 0 °C for 1 h, concentrated, and purified by preparative HPLC to give the desired compound VI-3 as a solid (19 mg, 9.4% yield). LC-MS (ESI) m / z: 474 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 8.31 (dd, J = 4.5, 2.2 Hz, 1H), 8.13 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 2.1 Hz, 1H), 6.61 (ddd, J = 16.7, 10.3, 2.2 Hz, 1H), 6.18 (d, J = 16.5 Hz, 1H), 5.70 (d, J = 11.6 Hz, 1H), 5.51 (dd, J = 20.2, 5.1 Hz, 1H), 4.86 - 4.66 (m, 2H), 4.29 (d, J = 20.6 Hz, 1H), 4.13 - 3.94 (m, 1H), 3.94 - 3.76 (m, 5H), 3.74 - 3.54 (m, 1H).

[0310] Scheme 15. Synthesis of Compound VIII-1 [ka] Step 1: Synthesis of trans-tert-butyl 3-hydroxy-4-(pyridin-2-yloxy)pyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (973 mg, 5.26 mmol), pyridin-2(1H)-one (500 mg, 5.26 mmol), and CsCO (1710 mg, 5.26 mmol) in DMF (10 mL) was stirred overnight at 80 °C under N. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The organics were washed with brine (50 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 50% v / v) to give compound 3 as a yellow oil (500 mg, 52.5% yield). LC-MS (ESI) m / z: 182 [M+H] + .

[0311] Step 2: Synthesis of trans-tert-butyl 3-(pyridin-2-yloxy)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (Compound 5) To a mixture of compound 3 (140 mg, 0.5 mmol) and NaH (20 mg, 0.5 mmol) in DMF (5 mL) was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (119 mg, 0.5 mmol), and the mixture was stirred under N at room temperature for 2 h, quenched with water (100 mL), extracted with ethyl acetate (50 mL), and the organics were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound 5 as a yellow oil (160 mg, 73% yield), which was used directly in the next step. LC-MS (ESI) m / z: 383 [M+H-56] + .

[0312] Step 3: Synthesis of 2-(trans-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yloxy)pyridine (Compound 6) A mixture of compound 5 (160 mg, 0.36 mmol) and TFA (3 mL) in DCM (10 mL) was stirred at room temperature for 2 hours, and the mixture was concentrated to give crude compound 6 as a yellow oil (130 mg, 106% yield). LC-MS (ESI) m / z: 339 [M+H] + .

[0313] Step 4: Synthesis of 1-(trans-3-(pyridin-2-yloxy)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (VIII-1)) A mixture of compound 6 (130 mg, 0.36 mmol), acryloyl chloride (32 mg, 0.36 mmol), and TEA (107 mg, 1.06 mmol) in DCM (10 mL) was stirred at room temperature under N for 2 h. The mixture was concentrated, and the residue was purified by preparative HPLC (MeCN / HO / TFA) to give the product as a yellow oil (42 mg, 29% yield). LC-MS (ESI) m / z: 393 [M+H] + . 1 H-NMR (400 MHz, CD3OD): δ (ppm) 7.63 (d, J = 7.3 Hz, 2H), 7.58 - 7.42 (m, 4H), 6.72 - 6.52 (m, 2H), 6.47 - 6.25 (m, 2H), 5.82 (dt, J = 10.4, 1.9 Hz, 1H), 5.45 - 5.24 (m, 1H), 4.85 - 4.65 (m, 2H), 4.21 (dddd, J = 21.2, 17.5, 10.6, 5.6 Hz, 3H), 4.01 - 3.87 (m, 1H), 3.75 (ddd, J = 17.2, 12.6, 3.6 Hz, 1H).

[0314] Compounds I-1, I-6, and VII-11 were synthesized according to general synthetic route II shown in Scheme 16 below, using specific reagents detailed in Table 10. The synthesis of compound I-9 is shown in Scheme 17. Scheme 16. General synthetic route II [ka] [Table 11] Scheme 17. Synthesis of Compound I-9 [ka]

[0315] Step 1: Synthesis of (3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (compound 3) A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (4 g, 21.6 mmol), TMSN3 (2.664 g, 23.2 mmol), and the chiral catalyst (1S,2S)-(-)-[1,2-cyclohexanediamino-N,N'-bis(3,5-di-t-butylsalicylidene)]chromium(III) chloride (328 mg, 0.42 mmol) was stirred overnight at room temperature under N2. The reaction mixture was treated with MeOH (60 mL) and K2CO3 (1.788 g, 12.8 mmol) and subsequently stirred at room temperature for 5 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (300 mL × 2), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 30% v / v) to give compound 3 as a clear oil (3.5 g, 96% ee, 71% yield). LC-MS (ESI) m / z: 129 [M+H-100] + .

[0316] Step 2: Synthesis of (3R,4R)-tert-butyl 3-azido-4-(4-(trifluoromethyl)benzyloxy)-pyrrolidine-1-carboxylate (5) A mixture of compound 3 (3 g, 13.1 mmol), 1-(bromomethyl)-4-(trifluoromethyl)benzene (3.1 g, 13.1 mmol), and 60% NaH (0.6 g, 15.7 mmol) in DMF (20 mL) was stirred at 0 °C under N for 6 h. The reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL), and the organics were washed with water (100 mL), dried over anhydrous NaSO, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether = 20% v / v) to give compound 5 as an oil (3.8 g, 75% yield). LC-MS (ESI) m / z: 287 [M+H-100] + .

[0317] Step 3: Synthesis of (3R,4R)-tert-butyl 3-amino-4-(4-(trifluoromethyl)benzyloxy)-pyrrolidine-1-carboxylate (compound 7) A mixture of compound 5 (1000 mg, 2.58 mmol), PPh3 (814 mg, 3.1 mmol), and HO (930 mg, 51.6 mmol) in THF (40 mL) was stirred at 70 °C under N2 for 5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (300 mL), and the organics were washed with water (200 mL), dried over anhydrous Na2SO4, concentrated, and purified by preparative HPLC to give compound 7 as a yellow oil (800 mg, 86% yield). LC-MS (ESI) m / z: 261 [M+H-100] + .

[0318] Step 4: Synthesis of (3R,4R)-tert-butyl 3-(pyrimidin-2-ylamino)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidine-1-carboxylate (compound 9) A mixture of compound 7 (600 mg, 1.6 mmol), 2-chloropyrimidine (240 mg, 1.84 mmol), and DIPEA (420 mg, 3.24 mmol) in n-BuOH (6 mL) was stirred overnight at 70 °C under N. The reaction mixture was concentrated and purified by preparative HPLC to give compound 9 as an oil (500 mg, 71% yield). LC-MS (ESI) m / z: 439 [M+H] + .

[0319] Step 5: Synthesis of N-((3R,4R)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-3-yl)pyrimidin-2-amine (compound 10) A mixture of compound 9 (400 mg, 0.91 mmol) and TFA (1 mL) in DCM (3 mL) was stirred under N at room temperature for 2 h. The mixture was concentrated to give crude compound 10 as a yellow oil (400 mg, 97% yield), which was used directly in the next step. LC-MS (ESI) m / z: 339 [M+H] + .

[0320] Step 6: Synthesis of 2-fluoro-1-((3R,4R)-3-(pyrimidin-2-ylamino)-4-(4-(trifluoromethyl)benzyloxy)pyrrolidin-1-yl)prop-2-en-1-one (I-9) A mixture of compound 10 (200 mg, 0.58 mmol), 2-fluoroacrylic acid (60 mg, 0.69 mmol), HATU (256 mg, 0.69 mmol), and DIEA (224 mg, 1.74 mmol) in DMF (5 mL) was stirred overnight at room temperature under N. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product as a white solid (150 mg, 63% yield). LC-MS (ESI) m / z: 411 [M+H] + . 1H-NMR (400 MHz, CD3OD) δ (ppm): 8.44 (s, 2H), 7.82 - 7.50 (m, 4H), 6.83 (dd, J = 8.3, 4.9 Hz, 1H), 5.50 (dt, J = 47.1, 3.3 Hz, 1H), 5.27 (dt, J = 16.5, 3.4 Hz, 1H), 4.82 (dd, J = 13.3, 8.8 Hz, 2H), 4.68 - 4.57 (m, 1H), 4.28 - 3.67 (m, 5H).

[0321] Scheme 18. Synthesis of Compound I-6 [ka] Step 1: Synthesis of (4-(trifluoromethyl)phenyl)methane-d2-ol (compound 2) To a solution of methyl 4-(trifluoromethyl)benzoate (4.08 g, 20 mmol) in THF (100 mL) was added LiAlD (1.764 g, 42 mmol) in several portions at 0 °C. The resulting mixture was stirred at 0 °C and monitored by LC-MS. After completion of the reaction, saturated aqueous NH Cl (150 mL) was carefully added, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure to give the desired product as an oil (3.418 g, 96.0% yield), which was used directly in the next step. LC-MS (ESI) m / z: 161 [M - 17] + .

[0322] Step 2: Synthesis of 1-(chloromethyl-d2)-4-(trifluoromethyl)benzene (compound 3) To a solution of compound 2 (3.3 g, 18.54 mmol) in DCM (100.0 mL) was added SOCl (5.84 g, 40.79 mmol). The resulting solution was stirred at 50 °C for 2 h and monitored by LC-MS. After completion of the reaction, the mixture was washed with water (150 mL), saturated NaHCO (100 mL × 3), and brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product as a colorless liquid (3.578 g, 98.2%), which was used directly without further purification. LC-MS (ESI) m / z: 161 [M − 36] + .

[0323] Step 3: Synthesis of tert-butyl (3R,4R)-3-azido-4-((4-(trifluoromethyl)phenyl)methoxy-d2)pyrrolidine-1-carboxylate (Compound 5) To a solution of compound 4 (chiral, 2.07 g, 9.08 mmol) in DMF (50.0 mL) was added NaH (346 mg, 8.65 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then compound 3 (1.7 g, 8.65 mmol) was added. The resulting mixture was stirred at 0 °C for 3 h and monitored by LC-MS. After completion of the reaction, the mixture was diluted with cold HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organics were washed with brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under vacuum to give the desired product as a pale yellow liquid (2.0 g, 59.6%), which was used directly without further purification. LC-MS (ESI) m / z: 289 [M-100+H] + .

[0324] Step 4: Synthesis of tert-butyl (3R,4R)-3-amino-4-((4-(trifluoromethyl)phenyl)methoxy-d2)pyrrolidine-1-carboxylate (Compound 6) A mixture of compound 5 (1.80, 4.64 mmol) and Pd / C (10%, 24.7 mg) in EtOH (100 mL) was stirred under H (1 atm) at room temperature for 16 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the desired product as a pale yellow liquid (1.68 g, 100%), which was used directly in the next step without further purification. LC-MS (ESI) m / z: 263 [M-100+H] + .

[0325] Step 5: Synthesis of tert-butyl (3R,4R)-3-((5-fluoropyrimidin-2-yl)amino)-4-((4-(trifluoromethyl)phenyl)methoxy-d2)pyrrolidine-1-carboxylate (compound 8) Compound 6 (1.149 g, 3.175 mmol) and 1,4-dioxane (30 mL) were added to a three-neck flask, followed by 2-bromo-5-fluoropyrimidine (0.843 g, 4.763 mmol), Pd(dba) (0.290 g, 0.318 mmol), Xantphos (0.551 g, 0.953 mmol), and CsCO (195.5 mg, 9.525 mmol). The flask was evacuated and refilled with N three times. The resulting mixture was stirred at 90 °C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure to leave the crude product, which was purified by flash column chromatography on silica gel (eluting with 1% MeOH in DCM) to give the desired compound 8 as a brown solid (0.66 g, 45.4% yield). LC-MS (ESI) m / z: 359 [M+H-100] + .

[0326] Step 6: Synthesis of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)phenyl)methoxy-d2)pyrrolidin-3-yl)pyrimidin-2-amine (Compound 9) To a solution of compound 8 (0.40 g, 0.873 mmol) in DCM (20.0 mL) was added TFA (1.493 g, 13.10 mmol). The resulting solution was stirred at 0 °C for 3 h and monitored by LC-MS. After completion of the reaction, the mixture was washed with HO (30 mL × 2) and saturated aqueous NaHCO (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired product 9 as a viscous colorless liquid (0.30 g, 96.0% yield), which was used directly in the next step without further purification. LC-MS (ESI) m / z: 359 [M+H] + .

[0327] Step 7: Synthesis of 5-fluoro-N-((3R,4R)-4-((4-(trifluoromethyl)phenyl)methoxy-d2)pyrrolidin-3-yl)pyrimidin-2-amine (I-6) To a solution of compound 9 (260.0 mg, 0.726 mmol) and DIPEA (516 mg, 4 mmol) in DCM (15.0 mL) was added acryloyl chloride (65.7 mg, 0.726 mmol) dropwise. The resulting solution was stirred at 0 °C for 20 min and monitored by LC-MS. After the reaction was complete, the mixture was concentrated and purified by flash column chromatography on silica gel (eluted with 1% MeOH in DCM) to give the desired product as a white solid (90 mg, 30.0% yield). LC-MS (ESI) m / z: 413 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.43 (s, 1H), 7.74 - 7.58 (m, 5H), 6.62- 6.54 (m, 1H), 6.16 (dt, J = 16.8, 3.2 Hz, 1H), 5.70 - 5.65 (m, 1H), 4.75 (d, J = 5.6 Hz, 0.29H), 4.38 (dt, J = 18.4, 6.0 Hz, 1H), 4.09 (dt, J = 21.6, 2.0 Hz, 1H), 3.75-3.55 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): -60.88, -60.89, -156.10, -156.11.

[0328] Scheme 19: Synthesis of Compound I-7 [ka] Step 1: Synthesis of tert-butyl trans-3-((5-fluoropyrimidin-2-yl)amino)-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (Compound 3) A mixture of tert-butyl trans-3-amino-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidine-1-carboxylate (500 mg, 1.39 mmol), 2-chloro-5-fluoropyrimidine (274.3 mg, 2.07 mmol), Pd(dba) (127.3 mg, 0.139 mmol), Xantphos (241.3 mg, 0.417 mmol), and CsCO (905.7 mg, 2.78 mmol) in 1,4-dioxane (15 mL) was stirred at 90 °C under N for 16 h. The mixture was then concentrated and purified by flash column chromatography on silica gel (eluted with 1% DCM in MeOH) to give compound 3 as a brown liquid (450 mg, 71.0% yield). LC-MS (ESI) m / z: 357 [M+H-100]. + .

[0329] Step 2: Synthesis of 5-fluoro-N-(trans-4-((4-(trifluoromethyl)benzyl)oxy)pyrrolidin-3-yl)pyrimidin-2-amine (compound 4) To a solution of compound 3 (0.30 g, 0.66 mmol) in DCM (8.0 mL) was added TFA (2.25 g, 19.8 mmol). The mixture was stirred at 0 °C for 3 h, diluted with DCNM (50 mL), washed with HO (30 mL × 2) and saturated NaHCO solution (30 mL × 2), and the DCM layer was concentrated under reduced pressure to give crude compound 4 as a viscous colorless oil (0.23 g, 97.9% yield), which was used directly in the next step. LC-MS (ESI) m / z: 357 [M+H] + .

[0330] Step 3: Synthesis of 2-fluoro-1-(trans-3-((...

Claims

1. Compound of formula (I'): 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, composition, or mixture thereof, wherein R and R ４ are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ａ , -N(R ａ ) ２ , -SR ａ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)N(R ａ ) ２ , -OC(=O)R ａ , -N(R ａ ) C(=O)R ａ , -CN, and -NO ２ Selected from: R １ , R ２ , and R ３ are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ａ , -N(R ａ ) ２ , -SR ａ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)N(R ａ ) ２ , -OC(=O)R ａ , -N(R ａ ) C(=O)R ａ , -CN, and -NO ２ Selected from: Z １ is an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; R ａ each occurrence of is independently hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an oxygen protecting group, a sulfur protecting group, or a nitrogen protecting group, or two R ａ When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; m is 1 or 2; q is 1 or 2; t is 0, 1, 2, 3, or 4; z is 0, 1, 2, or 3.

2. The compound of formula (I') has the formula: 【Chemistry 2】 Compounds of or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

3. R ４ The compound of claim 1, wherein is hydrogen, halogen, -OR a or optionally substituted heterocyclyl, where R a is optionally substituted alkyl.

4. The compound of formula (I') has the formula: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 Things, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

5. Compound of formula (II): 【Chemistry 4】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R １ , R ２ , and R ３ are each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｂ , -N(R ｂ ) ２ , -SR ｂ , -C(=O)R ｂ , -C(=O)OR ｂ , -C(=O)N(R ｂ ) ２ , -OC(=O)R ｂ , -N(R ｂ ) C(=O)R ｂ , -CN, and -NO ２ Selected from: R ５ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｂ , -N(R ｂ ) ２ , -SR ｂ , -C(=O)R ｂ , -C(=O)OR ｂ , -C(=O)N(R ｂ ) ２ , -OC(=O)R ｂ , -N(R ｂ ) C(=O)R ｂ , -CN, and -NO ２ Selected from: R ｂ Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R ｂ When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; Provided that the compound has the formula: 【Chemistry 5】 (The condition is that the product is not a

6. R ５ The compound of claim 5, wherein is optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(=O)N(Rb)2, -N(Rb)2, optionally substituted C1-C6 alkyl, or optionally substituted aryl.

7. The compound of formula (II) has the formula: 【Chemistry 6-1】 【Chemistry 6-2】 【Chemistry 6-3】 Things, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

8. The compound of formula (II) has the formula (II-a): 【Chemistry 7】 The In the formula, R １ , R ２ , or R ３ The compound of claim 5 , wherein at least one of is not hydrogen.

9. Compound of formula (III): 【Chemistry 8】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R ６ is -CF ３ or -C≡C-H; R ７ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｃ , -N(R ｃ ) ２ , -SR ｃ , -C(=O)R ｃ , -C(=O)OR ｃ , -C(=O)N(R ｃ ) ２ , -OC(=O)R ｃ , -N(R ｃ ) C(=O)R ｃ , -CN, or -NO ２ and R ８ Each instance of is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｃ , -N(R ｃ ) ２ , -SR ｃ , -C(=O)R ｃ , -C(=O)OR ｃ , -C(=O)N(R ｃ ) ２ , -OC(=O)R ｃ , -N(R ｃ ) C(=O)R ｃ , -CN, or -NO ２ and R ｃ Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R ｃ When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle; X １ and X ２ are each independently -N= or -C(H)=; n is 0, 1, or 2).

10. R ７ The compound of claim 9, wherein R 1 is -H or an optionally substituted heteroaryl, and R 8 is -H.

11. The compound of formula (III) is represented by formula (III-a) or formula (III-b): 【Chemistry 9】 10. The compound of claim 9,

12. The compound of formula (III) has the formula: 【Chemistry 10】 Things, 10. The compound of claim 9, which is: or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

13. Compound of formula (IV): 【Chemistry 11】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R ９ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｄ , -N(R ｄ ) ２ , -SR ｄ , -C(=O)R ｄ , -C(=O)OR ｄ , -C(=O)N(R ｄ ) ２ , -OC(=O)R ｄ , -N(R ｄ ) C(=O)R ｄ , -CN, or -NO ２ and R ｄ Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R ｄ When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

14. R ９ -C(=O)N(R ｄ ) ２ or -CN, and at least one instance of R d is optionally substituted alkyl.

15. The compound of formula (IV) has the formula: 【Chemistry 12】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

16. Compound of formula (V) 【Chemistry 13】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R １０ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｅ , -N(R ｅ ) ２ , -SR ｅ , -C(=O)R ｅ , -C(=O)OR ｅ , -C(=O)N(R ｅ ) ２ , -OC(=O)R ｅ , -N(R ｅ ) C(=O)R ｅ , -CN, or -NO ２ and R ｅ Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R ｅ When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

17. R １０ 17. The compound of claim 16, wherein is optionally substituted heteroaryl or optionally substituted aryl.

18. The compound of formula (V) has the formula: 【Chemistry 14】 Things, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

19. Compound of formula (VI): 【Chemistry 15】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R １１ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR ｆ , -N(R ｆ ) ２ , -SR ｆ , -C(=O)R ｆ , -C(=O)OR ｆ , -C(=O)N(R ｆ ) ２ , -OC(=O)R ｆ , -N(R ｆ ) C(=O)R ｆ , -CN, or -NO ２ and R ｆ Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, or two R ｆ When present, instances of can be taken together with the heteroatom to which they are attached to form an optionally substituted heterocycle.

20. R １１ The compound of claim 19, wherein is optionally substituted heteroaryl or -H.

21. The compound of formula (VI) having the formula: 【Chemistry 16】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

22. formula: 【Chemistry 17】 or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

23. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharma- ceutically acceptable excipient.

24. A pharmaceutical composition for use in treating cancer, including sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, prostate cancer, pancreatic cancer, colorectal cancer, ovarian cancer, skin cancer, esophageal cancer, or carcinoma, comprising a compound according to any one of claims 1 to 22.

25. A pharmaceutical composition for inhibiting TEAD1, TEAD2, TEAD3, or TEAD4 transcription factors, comprising a compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

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