Transcription enhancement associated domain (TEAD) transcription factor inhibitors and their uses

Abstract

Provided herein are compounds represented by (IA), (IB), or (II), as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Also provided are methods, uses, and kits involving the compounds of the present invention and pharmaceutical compositions thereof for treating and / or preventing diseases in a subject (e.g., proliferative diseases (e.g., cancer), inflammatory diseases (e.g., fibrosis), and autoimmune diseases (e.g., sclerosis)). Provided are methods of inhibiting the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, or TEAD4) and / or inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., a TEAD)) in a subject.

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. (USSN) 62 / 953,381, filed December 24, 2019, which is incorporated herein by reference. [Background technology]

[0002] 2. Background of the Invention The Hippo signaling pathway plays a central role in the control of organ size and tumor suppression. YAP and transcriptional enhanced associate domains (TEADs) are the main effectors of the Hippo signaling pathway. Signaling involves a core kinase cascade leading to phosphorylation of YAP (Yes1-associated protein) / TAZ (transcriptional coactivator with PDZ-binding motifs). Physiological or pathological inactivation leads to dephosphorylation and nuclear accumulation. Nuclear YAP / TAZ binds to TEADs 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., sarcomas, 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 have been identified as tumor suppressors, and mutations in these genes have been associated with a variety of human cancers. In addition, elevated YAP levels have been associated with certain human cancers.

[0003] Attachment of fatty acid palmitate to cysteine ​​residues regulates protein trafficking, membrane localization, and signaling activity. TEAD transcription factors possess intrinsic palmitoylase-like activity and have been found to undergo autopalmitoylation. TEAD transcription factors act as canonical partners for the Hippo pathway effector YAP, which in several contexts is associated with resistance to targeted therapy, including resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC (Chaib et al., 2017; Hsu et al., 2016). EGFR tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) (Mok et al., 2009; Rosell et al., 2012; Soria et al., 2018). However, within months to years, acquired resistance mechanisms inevitably develop, limiting the efficacy of clinical EGFR inhibitor treatment (Cortot and Jaenne, 2014). In most cases, drug resistance to EGFR-targeted therapy occurs after a dramatic response to initial clinical treatment, followed by a prolonged period of non-proliferative minimal residual disease (MRD) or dormancy, after which drug-resistant tumors gradually emerge and grow. Previous preclinical studies suggest that upon EGFR TKI treatment, EGFR-mutated tumor cells can enter a drug-resistant state reminiscent of sleep in patients, allowing the cells to avoid apoptosis and survive under drug treatment (Hata et al., 2016; Sharma et al., 2010). Over time, drug-resistant cells can acquire drug resistance through either mutational or non-mutational mechanisms (Hata et al., 2016).Although the establishment of this state has been proposed to be largely stochastic and largely influenced by epigenetic mechanisms ( Guler et al., 2017 ; Sharma et al., 2010 ), the mechanistic basis of how cancer cells initially evade apoptosis in response to drug treatment – ​​an absolute requirement for entering a drug-resistant state – or maintain resistance in the presence of drug treatment remains poorly understood.

[0004] Previous work has demonstrated that ERK 1 / 2 reactivation occurs within just a few days of EGFR TKI treatment of EGFR-mutant cells, despite sustained EGFR inhibition (Ercan et al., 2012; Tricker et al., 2015). Concomitant inhibition of MEK effectively prevents ERK 1 / 2 reactivation, resulting in a greater initial response to apoptosis than single-agent EGFR inhibition, and leading to durable tumor control in vitro and in vivo (Ercan et al., 2012; Tricker et al., 2015). The combination of EGFR (osimertinib) and MEK (selumetinib) inhibitors has been studied in patients resistant to prior EGFR TKIs and is also under evaluation as initial treatment for advanced EGFR-mutant NSCLC in a phase II clinical trial (NCT03392246; Ramalingam et al., 2019). However, even with this combination, acquired resistance still occurs, either through bypassing EGFR / MEK inhibition or by unknown mechanisms that do not involve reactivation of EGFR downstream signaling (Tricker et al., 2015). Due to the key regulatory functions of transcription factors TEAD, YAP, and TEAD-YAP complex in development, cell growth and proliferation, tissue homeostasis, and regeneration, it is important to develop modulators of the activity of these transcription factors (e.g., TEAD, YAP), including selective modulators (e.g., selective inhibitors), for use as research tools and therapeutic agents in the treatment of various diseases associated with these transcription factors. It is also important to develop therapeutic agents for treating proliferative diseases associated with these transcription factors (e.g., TEAD, YAP), which may be resistant to certain antiproliferative agents (e.g., cancers resistant to inhibitors of EGFR and / or MEK), via combination therapy using modulators of transcription factors TEAD, YAP, EGFR, and / or MEK. Summary of the Invention

[0005] SUMMARY OF THE PRESENT APPLICATION The present disclosure is based in part on the discovery that breaking tumor dormancy that occurs with oncogene-targeted therapy, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of cancer, e.g., lung cancer (e.g., EGFR-mutated non-small cell lung cancer (NSCLC)), is an attractive therapeutic strategy. However, the mechanisms governing the establishment of tumor dormancy are poorly understood. It has recently been found that blocking ERK1 / 2 reactivation following EGFR TKI treatment with combined EGFR / MEK inhibition allows cells to survive by entering a senescence-like dormancy characterized by extensive epigenetic remodeling and high YAP / TEAD activity. YAP / TEAD directly represses pro-apoptotic BMF and limits drug-induced apoptosis by initiating an epithelial-to-mesenchymal transition (EMT) program and engaging the EMT transcription factor SLUG. Pharmacological co-inhibition of YAP or TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR / MEK inhibitor-induced apoptosis. Thus, YAP activation may promote survival of EGFR-mutated NSCLC cells in the chronic absence of EGFR signaling. Terminating this surviving cell population, for example by inhibiting TEAD and / or YAP, may enhance the efficacy of targeted therapies and ultimately lead to durable treatment responses in cancer patients.

[0006] Described herein are compounds of Formulas (IA), (IB), and (II) that are TEAD inhibitors, as well as pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof, and mixtures thereof.

[0007] The compounds of formula (IA), (IB), and (II), and their pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, prodrugs, and compositions may inhibit the activity of a transcription factor (e.g., TEAD) in a biological sample or subject. In some embodiments, the transcription factor is a transcription enhancer associated domain (TEAD). In some embodiments, the compounds of formula (IA), (IB), or (II) are selective for a particular TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4) compared to other TEADs. Described herein are methods of studying the inhibition of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) using the compounds of the present invention, and their pharma-ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, prodrugs, and compositions. The compounds of the invention described herein may also be used as therapeutics for the prevention and / or treatment of diseases associated with overexpression of transcription factors (e.g., TEADs such as TEAD1, TEAD2, TEAD3, TEAD4) and / or aberrant (e.g., increased or unwanted) activity thereof. The compounds described herein may be useful for treating and / or preventing diseases or conditions, e.g., diseases (e.g., proliferative diseases (e.g., cancer, benign neoplasms), inflammatory diseases (e.g., fibrosis), autoimmune diseases (e.g., sclerosis)) in a subject in need thereof.To treat and / or prevent the diseases described herein (e.g., proliferative diseases (e.g., cancer, benign neoplasms, e.g., cancer resistant to a modulator of another transcription factor (e.g., YAP, EGFR, MEK), inflammatory diseases (e.g., fibrosis), autoimmune diseases (e.g., sclerosis)), the compounds described herein may be optionally administered in combination with additional pharmaceutical agents, such as modulators of other transcription factors (e.g., YAP, EGFR, MEK), for inhibiting transcription factors (e.g., TEADs such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject and / or biological sample, and for inhibiting transcription of genes (e.g., genes controlled or regulated by transcription factors (e.g., TEADs such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and / or biological sample. Also provided are uses, pharmaceutical compositions, and kits that include the compounds described herein.

[0008] In one aspect, the present disclosure provides a compound of formula (IA): [ka] and pharma- ceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof, wherein R 2 , R 2B , X 1 , rings B, m, and D 1 is as defined herein. 1 In some embodiments, the warhead binds to a TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, the warhead binds non-covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4. In some embodiments, the warhead binds covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4.

[0009] Exemplary compounds represented by formula (IA) include, but are not limited to, the following: [ka] [ka] and pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0010] Exemplary compounds represented by formula (IA) include, but are not limited to, the following: [ka] and pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0011] In one aspect, the present disclosure provides a compound of formula (IB): [ka] and pharma- ceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof, wherein R 2 , R A1 , X 1 , rings B, m, and D 1 is as defined herein. 1In some embodiments, the warhead binds to a TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, the warhead binds non-covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4. In some embodiments, the warhead binds covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4. In some embodiments, the warhead binds non-covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4.

[0012] Exemplary compounds represented by formula (IB) include, but are not limited to, the following: [ka] and pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0013] Exemplary compounds represented by formula (IB) include, but are not limited to, the following: [ka] and pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0014] In some embodiments, the compound of formula (IB) has the formula: [ka] But it is not represented.

[0015] In one aspect, the present disclosure provides a compound of formula (II): [ka] and pharma- ceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof, wherein R 1 , R 2 , X 1 , rings B, W, Z, x, y, and D 1 is as defined herein. 1 In some embodiments, the warhead binds to a TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, the warhead binds non-covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4. In some embodiments, the warhead binds covalently to a TEAD, e.g., TEAD1, TEAD2, TEAD3, TEAD4.

[0016] Exemplary compounds represented by formula (II) include, but are not limited to, the following: [ka] and pharma- ceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof.

[0017] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein and, optionally, a pharma- ceutically acceptable excipient. In an embodiment, the pharmaceutical composition as described herein comprises a therapeutically or prophylactically effective amount of a compound as described herein. The pharmaceutical composition may be useful for treating and / or preventing a disease (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease) in a subject in need thereof, for inhibiting the activity of a transcription factor (e.g., a TEAD such as TEAD1, TEAD2, TEAD3, TEAD4), or for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., a TEAD such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and / or a biological sample (e.g., a tissue, a cell). In an embodiment, the proliferative disease is a cancer (e.g., a sarcoma, a lung cancer, a thyroid cancer, a breast cancer, a liver cancer, a pancreatic cancer, a gastric cancer, an ovarian cancer, a colon cancer, a colon cancer, a skin cancer, an esophageal cancer; a cancer). In some embodiments, the cancer is a sarcoma (e.g., Kaposi's sarcoma). In some embodiments, the cancer is carcinoma. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer, mesothelioma). In some embodiments, the cancer has a mutation in a gene of the Hippo signaling pathway. In some embodiments, the cancer has a mutation in EGFR. In some embodiments, the cancer has a mutation in MEK. In some embodiments, the cancer is EGFR-mutated non-small cell lung cancer. In some embodiments, the cancer is resistant to an anti-proliferative agent (e.g., a cancer resistant to an inhibitor of EGFR and / or MEK). In some embodiments, the cancer is resistant to an inhibitor of EGFR (e.g., osimertinib) and / or an inhibitor of MEK (e.g., trametinib). In some embodiments, the cancer is resistant to a tyrosine kinase inhibitor (TKI). In some embodiments, the disease is an inflammatory disease (e.g., fibrosis). In some embodiments, the disease is an autoimmune disease (eg, sclerosis).

[0018] In another aspect, described herein are methods for treating and / or treating diseases (e.g., proliferative diseases, inflammatory diseases, autoimmune diseases) using the compounds described herein, which may be administered in combination with additional pharmaceutical agents, such as modulators of other transcription factors (e.g., YAP, EGFR, MEK). Exemplary proliferative diseases that may be treated include proliferative diseases, such as diseases associated with overexpression or increased activity of TEAD, e.g., cancer, or cancer that is resistant to a modulator (e.g., inhibitor) of another transcription factor (e.g., YAP, EGFR, MEK). In some embodiments, the cancer is selected from the group consisting of sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer; cancer. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer, mesothelioma). In some embodiments, the cancer is sarcoma (e.g., Kaposi's sarcoma). In some embodiments, the disease is an inflammatory disease (e.g., fibrosis). In some embodiments, the disease is an autoimmune disease (e.g., sclerosis).

[0019] Another aspect relates to a method of inhibiting the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a biological sample (e.g., a cell, a tissue) using a compound described herein, which may optionally be administered in combination with an additional pharmaceutical agent, such as a modulator of other transcription factors (e.g., YAP, EGFR, MEK). In another aspect, described herein is a method of inhibiting the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject using a compound described herein. In some embodiments, the method involves inhibition of a TEAD (e.g., TEAD2). Another aspect relates to a method of inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) using a compound described herein, which may optionally be administered in combination with an additional pharmaceutical agent, such as a modulator of other transcription factors (e.g., YAP, EGFR, MEK).

[0020] Described herein is a method for administering an effective amount of a compound or pharmaceutical composition thereof as described herein to a subject in need thereof, which may be administered in combination with an additional pharmaceutical agent, such as a modulator of another transcription factor (e.g., YAP, EGFR, MEK). Also described is a method for contacting a biological sample (e.g., tissue, cell) with an effective amount of a compound or pharmaceutical composition thereof as described herein, which may be administered in combination with an additional pharmaceutical agent, such as a modulator of another transcription factor (e.g., YAP, EGFR, MEK). In some embodiments, the method described herein further includes administering an additional pharmaceutical agent to the subject. In some embodiments, the method described herein further includes contacting the biological sample (e.g., tissue, cell) with an additional pharmaceutical agent (e.g., an anti-proliferative agent). In some embodiments, the additional pharmaceutical agent is a modulator of another transcription factor (e.g., YAP, EGFR, MEK). In some embodiments, the additional pharmaceutical agent is a transcription inhibitor (e.g., an inhibitor of EGFR and / or MEK). In some embodiments, the additional pharmaceutical agent is a kinase inhibitor. In some embodiments, the additional pharmaceutical agent is an agent for treating lung cancer (e.g., non-small cell lung cancer (NSCLC)).

[0021] In another aspect, the disclosure provides compounds of formula (IA), (IB), and (II), as well as pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, optionally administered in combination with additional pharmaceutical agents, e.g., modulators of other transcription factors (e.g., YAP, EGFR, MEK), for use in treating a disease in a subject (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease). In another aspect, the present disclosure provides compounds of formula (IA), (IB), and (II), as well as pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, which may be administered in combination with additional pharmaceutical agents, e.g., modulators of other transcription factors (e.g., YAP, EGFR, MEK), for use in inhibiting the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) or inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor, e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject and / or biological sample (e.g., tissue, cell).

[0022] Another aspect of the present disclosure relates to a kit comprising a container with a compound or pharmaceutical composition as described herein. The kit described herein may include a single dose or multiple doses of the compound or pharmaceutical composition. The kit may also be useful in the method of the present disclosure. In some embodiments, the kit further includes instructions for using the compound or pharmaceutical composition. The kit described herein may also include information (e.g., prescription information) from regulatory authorities such as the U.S. Food and Drug Administration (FDA) as necessary.

[0023] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the detailed description, examples, drawings, and claims.

[0024] definition Definitions of certain functional groups and chemical terms are described in more detail below. Chemical elements are defined in accordance with the principles of the Handbook of Chemistry and Physics, vol. 75 th The Periodic Table of the Elements, Ed., inside cover, is identified in accordance with the CAS version, and specific functional groups are generally defined as set forth therein. In addition, the general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in the text of the CAS version of the Periodic Table of the Elements, Ed., inside cover, and in the text of the CAS version of the Periodic Table of the Elements, Ed., inside cover, and specific functional groups are generally defined as set forth therein. In addition, the general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in the text of the CAS version of the Periodic Table of the Elements, Ed., inside cover, and ... specific functional groups are generally defined as set forth therein. 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. The disclosure is not intended to be limited in any way by the illustrative recitation of substituents presented herein.

[0025] The compounds described herein may contain one or more asymmetric centers, and therefore may exist in various isomeric forms, for example 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 a mixture 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; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively as mixtures of various isomers.

[0026] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 " is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to cover.

[0027] "Hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes at least one chain, each node of which ("carbon unit") includes at least one carbon atom 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", which are not hydrogen) on the chain(s) of carbon atoms. A chain of carbon atoms consists of carbon atoms connected in series ("chain atoms") and does not include hydrogen or heteroatoms. However, the non-chain substituents of a hydrocarbon chain may include any atom, including hydrogen, carbon, and heteroatoms. For example, a hydrocarbon chain -C A H(C B H 2 C C H 3 )- is a 1-carbon unit, C A For example, the hydrocarbon chain -C A H(C B H 2 C C H 3 )- is a 1-carbon unit, C A Only, C A On top of the 1 hydrogen atom and the non-chain substituent -(C B H 2 C C H 3 The term "C x "Hydrocarbon chain" (where x is a positive integer) refers to a hydrocarbon chain that contains x number of carbon units (singular or plural) between the two radicals of the hydrocarbon chain. If the feasible value of x is greater than 1, the smallest feasible value of x is used in the definition of the hydrocarbon chain. For example, -CH(C 2 H 5 )- is C 1 is a hydrocarbon chain, [ka] is C 3 It is a hydrocarbon chain. When a range of values ​​is used (e.g., C 1~6 Hydrocarbon chain), the meaning of ranges is as described herein. For example, C 3~10 A hydrocarbon chain refers to a hydrocarbon chain having 3, 4, 5, 6, 7, 8, 9, or 10 chain atoms in the shortest chain of carbon atoms immediately between the two radicals of the hydrocarbon chain. The hydrocarbon chain may be saturated (e.g., -(CH 2 ) 4 The hydrocarbon chain may also be unsaturated and contain one or more C=C and / or C≡C bonds anywhere in the hydrocarbon chain. Illustrative examples include -CH=CH-(CH 2 ) 2 -, -CH 2 -C≡C-CH 2 -, and -C≡C-CH═CH- are all examples of unsubstituted and unsaturated hydrocarbon chains. In some embodiments, the hydrocarbon chain is unsubstituted (e.g., -C≡C- or -(CH 2 ) 4 In some embodiments, the hydrocarbon chain is substituted (e.g., —CH(C 2 H 5 )- and -CF 2 Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl ring. Illustrative examples include: [ka] are all examples of hydrocarbon chains. In contrast, in some embodiments, [ka] is not within the scope of the hydrocarbon chains described herein. x When a chain atom of a hydrocarbon chain is replaced by a heteroatom, the resulting group isx-1 In contrast to hydrocarbon chains, C in which chain atoms are replaced by heteroatoms x These are called hydrocarbon chains. For example, [ka] is a C in which one chain atom is replaced by an oxygen atom. 3 It is a hydrocarbon chain.

[0028] "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an 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, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has one carbon atom ("C 1 In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 An example of an alkyl group is methyl (C 1), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ) is included. C 1~6 Other examples of alkyl groups are methyl (C 1 ), ethyl (C 2 ), Propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C 6 ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), n-dodecyl (C 12 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., -CH 3 In some embodiments, the alkyl group is an unsubstituted C 1~12 Alkyl (unsubstituted C 1~6 Alkyl, e.g., -CH 3(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 or s-Bu), unsubstituted isobutyl (i-Bu), etc.). In some embodiments, the alkyl group is a substituted C 1~10 In some embodiments, the alkyl group is a substituted C 1~12 Alkyl (substituted C 1~6 Alkyl, e.g., -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or benzyl (Bn), etc.

[0029] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C 1~20 In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms ("C 1~10 In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C1~6 In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ("C 1~5 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 In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a "perfluoroalkyl" group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a "perchloroalkyl" group. An example of a haloalkyl group is -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CCl 3 , -CFCl 2 , -CF 2 Cl and the like.

[0030] 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, either within the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroalkyl" refers to a saturated group having from 1 to 20 carbon atoms and one or more heteroatoms in the parent chain). 1~20 In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~12In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~11 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in 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 refers to 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 refers to a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~7 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 3 carbon atoms and one heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkyl group refers to a saturated group having one carbon atom and one heteroatom ("heteroC 1 In some embodiments, a heteroalkyl group refers to a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~12 In some embodiments, the heteroalkyl group is a substituted heteroC 1~12 It is an alkyl.

[0031] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds but no triple bonds ("C 2~20 In some embodiments, an alkenyl group is an alkyl group having 2 to 20 carbon atoms ("C 2~20 alkenyl), 2 to 12 carbon atoms ("C 2~12 alkenyl), 2 to 10 carbon atoms ("C 2~10 alkenyl), 2 to 8 carbon atoms ("C 2~8 alkenyl), 2 to 7 carbon atoms ("C 2~7 alkenyl) or 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 20 carbon atoms ("C 2~20 In some embodiments, the alkenyl group has 2 to 12 carbon atoms ("C 2~12 In some embodiments, the alkenyl group has 2 to 11 carbon atoms ("C 2~11 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the 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 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 1 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkenyl group has one carbon atom ("C 1 The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). 1~4 An example of an alkenyl group is methylidenyl (C 1 ), ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2~4 An example of an alkenyl group is ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2~6 Examples of alkenyl groups are the aforementioned C 2~4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In some embodiments, the alkenyl group is a substituted C 2~10 Alkenyl. In an alkenyl group, a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH 3 or [ka] can be in the (E)- or (Z)-configuration.

[0032] The term "heteroalkenyl" refers to an alkenyl group further including at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroalkenyl" ...). 1~20 In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~20 In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~12 In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~11In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~10 In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~9 In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~7 In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, heteroalkenyl groups have 1 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1~6Unless 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 1~20 In some embodiments, the heteroalkenyl group is a substituted heteroC 1~20 It is alkenyl.

[0033] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (see "C 2~20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C 2 In some embodiments, an alkynyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkynyl group has one carbon atom ("C 1 In some embodiments, an alkynyl group is an alkynyl group having 2 to 20 carbon atoms ("C 2~12alkynyl), 2 to 12 carbon atoms ("C 2~12 alkynyl), 2 to 10 carbon atoms ("C 2~10 alkynyl), 2 to 8 carbon atoms ("C 2~8 alkynyl), 2 to 7 carbon atoms ("C 2~7 alkynyl), or 2 to 6 carbon atoms ("C 2~6 The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2~4 Examples of alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 1~4 Examples of alkynyl groups include, but are not limited to, methylidinyl (C 1 ), ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 2~6 Examples of alkenyl groups are the aforementioned C 2~4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 ) and the like. Additional examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). 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 2~20 In some embodiments, the alkynyl group is a substituted C 2~20 It is alkynyl.

[0034] 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, either within the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain) and / or located at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl" ... at least one heteroatom within the parent chain). 1~20 In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~20 In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1~10 In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~10 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1~9 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1~7 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1~6In some embodiments, a heteroalkynyl group refers to a group having from 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkynyl group refers to a group having up to 1 to 2 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 1~2 In some embodiments, a heteroalkynyl group refers to a group having from 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1~6 Unless 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 1~20 In some embodiments, the heteroalkynyl group is a substituted heteroC 1~20 It is alkynyl.

[0035] The term "carbocyclyl" or "carbocyclic" refers to a ring system having from 3 to 14 ring carbon atoms ("C 3~14 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms ("C 3~13In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms ("C 3~12 In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms ("C 3~11 In some embodiments, a carbocyclyl group has 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 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, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~ In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 Carbocyclyl). 3~6 The carbocyclyl group is cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like. 3~8 The carbocyclyl group is the C 3~6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and the like. 3~10 The carbocyclyl group may be any of the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. 3~8 The carbocyclyl group is the C 3~10 Carbocyclyl groups, as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14), and the like. As the examples above illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. As the examples above illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (containing, for example, a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also encompasses ring systems in which a carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups and the point of attachment is on the carbocyclic ring, in which case the number of carbons is designated without interruption as the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 In certain embodiments, a carbocyclyl includes, where valence permits, 0, 1, or 2 C=C double bonds in the carbocyclic ring system.

[0036] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 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 An example of a cycloalkyl group is cyclopentyl (C 5 ) and cyclohexyl (C 6 ) is included. C 3~6 Examples of cycloalkyl groups are the C 5~6 Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) is included. C 3~8 Examples of cycloalkyl groups are the C 3~6 Cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In some embodiments, the cycloalkyl group is a substituted C 3~10 In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0037] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl"), and can be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in either or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclic ring as defined above is fused with one or more carbocyclyl groups (where the point of attachment is on either the carbocyclyl ring or the heterocyclic ring), or a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclic ring), in which case the number of ring members is designated through the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., 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 an unsubstituted 3- to 10-membered heterocyclyl.In some embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl. In some embodiments, the heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, where one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valences permit.

[0038] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0039] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. C 6Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to an aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary bicyclic heterocyclyl groups are 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 are included.

[0040] "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 among the cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among the cyclic array). 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 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"; for example, anthracyl). "Aryl" also encompasses ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, but where the radical or point of attachment is on the aryl ring. In such instances, the number of carbon atoms is designated through the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., 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 some embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0041] "Aralkyl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In some embodiments, an aralkyl is an optionally substituted benzyl. In some embodiments, an aralkyl is a benzyl. In some embodiments, an aralkyl is an optionally substituted phenethyl. In some embodiments, an aralkyl is a phenethyl.

[0042] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" encompasses ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups and the point of attachment is on the heteroaryl ring, in such cases the number of ring members is designated through the number of ring members in the heteroaryl ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups and the point of attachment is on either the aryl ring or the heteroaryl ring, in such cases the number of ring members is designated through the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl ring or the heteroaryl ring, in which case the number of ring members is as specified in the fused polycyclic (aryl / heteroaryl) ring system.In polycyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring (e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl)). In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl is a substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, in which 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered, bicyclic heteroaryl, where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0043] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0044] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms, respectively, include, without limitation, triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0045] "Heteroaralkyl" is a subset of alkyl and heteroaryl, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0046] "Partially unsaturated" refers to a group that contains at least one double or triple bond. "Partially unsaturated" ring systems are further intended to encompass rings with multiple sites of unsaturation, but are not intended to encompass aromatic groups (e.g., aryl or heteroaryl groups) as defined herein. Similarly, "saturated" refers to a group that contains no double or triple bonds, i.e., all single bonds.

[0047] The alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, when they are divalent bridging groups, use the suffix -ene and are further referred to as, for example, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

[0048] A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to substituted or unsubstituted. Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). 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 is substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means replaced with acceptable substituents (e.g., substituents that result in a stable compound upon replacement, e.g., compounds that do not spontaneously undergo rearrangement, cyclization, transformation such as elimination, or other reactions). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituents are the same or different at each position. The term "substituted" is intended to encompass substitution with any of the acceptable substituents of an organic compound, any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents, and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is not limited in any manner by the exemplary substituents described herein.

[0049] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO 2 , -N 3 , -SO2 H、-SO 3 H、-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 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R 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 SO 2 R aa 、-NR bbSO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R 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 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, 3-14 membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; Alternatively, the two geminal hydrogens on a carbon atom can be substituted with the groups =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNRbb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb , or =NOR cc has been replaced by; R aa In each case, independently, 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, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each of the cases is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 ORcc , -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, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; R cc each occurrence independently represents hydrogen, 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, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R ccThe groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd In each case, independently, halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R 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(R ff ) 2, -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R 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 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R ggsubstituted with a group or two geminal R dd The substituents may be joined to form =O or =S; where X - is the counterion; R ee In each case, independently, 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, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff each occurrence 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 5-10 membered heteroaryl, or two R ff The groups are joined to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; and R ggIn each case, independently, halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 - , -NH 2 (C 1~6 Alkyl) + X - , -NH 3 + 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), -CO 2 H, -CO 2 (C 1~6 alkyl), -OC(=O)(C 1~6 Alkyl), -OCO 2 (C 1~6 alkyl), -C(=O)NH 2 , -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), -NHCO 2 (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)NH 2 , -OC(=NH)N(C 1~6 Alkyl) 2 , -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1~6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1~6 Alkyl), -SO 2 N(C 1~6 Alkyl) 2 , -SO 2 NH(C 1~6 Alkyl), -SO 2 NH 2 , -SO 2 C 1~6 Alkyl, -SO 2 O.C. 1~6 Alkyl, -OSO 2 C 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)NH 2 , -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 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 may be joined to form =O or =S; where X - is the counter ion.

[0050] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (e.g., containing one formal negative charge). Anionic counterions can also be multivalent, such as divalent or trivalent (e.g., containing more than one formal negative charge). Exemplary counterions are halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HCO 3 - , HSO 4 -, 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, glyconic acid, etc.), BF 4 - , P.F. 4 - , P.F. 6 - , AsF 6 - , SbF 6 - , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] - , B(C 6 F 5 ) 4 - , B.P.h. 4 - , Al(OC(CF 3 ) 3 ) 4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me 5 Br 6 ) - Exemplary counterions, which may be multivalent, include CO 3 2- , H.P.O. 4 2- , P.O. 4 3- , B 4 O 7 2- , S.O. 4 2- , S 2 O 3 2-, carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, glyconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

[0051] In certain embodiments, each carbon atom substituent is independently a halogen, a substituted (e.g., substituted with one or more halogens) or an unsubstituted C 1~6 Alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, -NO 2 , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)R aa , -OCO 2 R aa , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , or -NR bb C(=O)N(R bb ) 2 In some embodiments, each carbon atom substituent is independently a halogen, a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, -NO 2 , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)R aa , -OCO 2 R aa , -OC(=O)N(Rbb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , or -NR bb C(=O)N(R bb ) 2 Here, R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group when attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl); and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In some embodiments, each carbon atom substituent is independently a halogen, a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, or -NO 2 In some embodiments, each carbon atom substituent is independently a halogen, a substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C 1~10 Alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, or -NO 2 Here, R aais hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group when attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl); and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, or a nitrogen protecting group (eg, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0052] In some embodiments, the molecular weight of the carbon atom substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms.

[0053] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0054] 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)SRX1 , -C(=O)N(R X1 ) 2 , -C(=S)R X1 , -C(=S)N(R X1 ) 2 , and -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 where R X1 is 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 is 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 are aldehydes (-CHO), carboxylic acids (-CO 2H), 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)).

[0055] "Alkoxy" or "alkoxyl" refers to a radical of the formula: --O-alkyl.

[0056] Nitrogen atoms may be substituted or unsubstituted, where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2, -SO 2 R cc , -SO 2 OR 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, 3-14 membered heterocyclyl, C 6~14 aryl, and 5-14 membered heteroaryl, or two R attached to the N atom cc The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd group, and where R aa , R bb , R cc and R dd is as defined above.

[0057] In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 or a nitrogen protecting group, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, or a nitrogen protecting group. [1] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(Rcc ) 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, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0058] 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. For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a nitrogen protecting group (e.g., a -C(=O)R aa ) is a moiety containing a nitrogen atom to which is directly attached. In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of 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.

[0059] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as, but not limited to, 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-tetrahydrothioxanthy]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), ), 2-trimethylsilylethyl carbamate (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), 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-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monyl methyl 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-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl 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,In some embodiments, the at least one nitrogen protecting group is a carbamate group (e.g., a nitrogen protecting group (e.g., -C(=O)OR, aaIn some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of 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-tetrahydrothioxanthy]methyl carbamate (DBD-Tmoc), ), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (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 t-Butyl 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-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate methylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-di Methoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N -dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanyl methyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropyl methyl 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 2,4,6-trimethylbenzyl carbamate.

[0060] Sulfonamide groups (e.g., -S(=O) 2 R aa Nitrogen protecting groups such as, but not limited to, 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-trimethyl ...tb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mtb), 4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mt In some embodiments, the at least one nitrogen protecting group is a sulfonamide group (e.g., a nitrogen protecting group (e.g., -S(=O)), a phenyl group (e.g., ... 2 R aaIn certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from 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-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethyl-4- ...b), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4,6-trimethyl-4-methoxybenzenesulfonamide (Mtb), 2,4, methylbenzenesulfonamide (Mts), 2,6-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.

[0061] Other nitrogen protecting groups include, but are not limited to, 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, N-1,1,4,4-tetramethyldiphenylamine, N-phenylpropanediol ... Silylazacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline- 3-yl)amine, quaternary ammonium salt, 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-dimethyl Thiomethyleneamine, 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-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-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 phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0062] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of 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-dimethylphenylamine derivatives, N-phenyl-p- ... Lupyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane 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, 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-picolylamine N-Oxide, N-1,1-Dimethylthiomethyleneamine, N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorosalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic 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 phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In some embodiments, when there are two nitrogen protecting groups, together with the nitrogen atom to which the nitrogen protecting group is attached, is N,N'-isopropylidenediamine.

[0063] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0064] In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 or an oxygen protecting group. In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 Alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , or an oxygen protecting group, where R aais hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, or oxygen protecting groups.

[0065] 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, but are not limited to, -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R 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 where 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, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0066] Exemplary oxygen protecting groups include, but are not limited to, 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, methyl (MEM), 2,2,2-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]phenyl ]-4-Methoxypiperidin-4-yl (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-trichloro Ethyl, 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, Bis(phenyl)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-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (I PDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formic acid, benzoyl formate, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methoxyacetic acid, triphenylmethoxyacetic acid, phenoxyacetic acid, p-Chlorophenoxyacetic acid, 3-phenylpropionic acid, 4-oxopentanoate (levriate), 4,4-(ethylenedithio)pentanoate (levrinoyl dithioacetal), pivalic acid, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitoic acid), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoic acid, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(di bromomethyl)benzoic acid, 2-formylbenzenesulfonic acid, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, chlorodiphenylacetic acid, isobutyric acid, monosuccinic acid, (E)-2-methyl-2-butenoic acid, o-(methoxyacyl)benzoic acid, α-naphthoate, nitric acid, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, boric acid, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenic acid, sulfuric acid, methanesulfonic acid (mesylate), benzylsulfonic acid, and tosylic acid (Ts).

[0067] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which it is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUN), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-Methoxyethoxymethyl (MEM), 2,2,2-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)phenyl]-4-methoxypiperidin-4-yl (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-trichloro ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 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, 4,4'-dimethoxy- 3'''-[N-(imidazolylmethyl)]trityl ether (IDTr-OR), 4,4'-dimethoxy-3'''-[N-(imidazolylethyl)carbamoyl]trityl ether (IETr-OR), 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), diethylisopropylsilyl (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 tartrate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantate, 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-methoxamine dibenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethanoate), 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).

[0068] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0069] In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 Alkyl, -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 or a sulfur protecting group, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~10 In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1~6 alkyl, or sulfur protecting groups.

[0070] In certain embodiments, a substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NRbb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R 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 where 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. Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0071] In some embodiments, the molecular weight of the substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In some embodiments, the substituent consists of atoms of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon. In some embodiments, the substituent consists of atoms of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen. In some embodiments, the substituent consists of atoms of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine. In some embodiments, the substituent consists of atoms of carbon, hydrogen, fluorine, and / or chlorine. In some embodiments, the substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In some embodiments, the substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0072] As used herein, a "leaving group" (LG) is an art-understood term that refers to a molecular fragment that leaves with an electron pair in a heterolytic bond cleavage, where the molecular fragment is an anionic or neutral molecule. A "leaving group" (LG) is an art-understood term that refers to an atom or molecular fragment that leaves with an electron pair in a heterolytic bond cleavage, where the molecular fragment is an anionic or neutral molecule. 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 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo), as well as activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO 2 R 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 , -OSO 2 R aa , -OP(R cc ) 2 , -OP(R cc ) 3 , -OP(=O) 2 R aa , -OP(=O)(R aa ) 2 ,-OP(=O)(OR cc ) 2 , -OP(=O) 2 N(R bb ) 2 , and -OP(=O)(NR bb ) 2 , where R aa , R bb , and R cc is as defined herein. Exemplary leaving groups include, but are not limited to, halo (e.g., fluoro, chloro, bromo, iodo), and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO 2 R 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 , -OSO 2 R aa , -OP(R cc ) 2 , -OP(R cc ) 3 , -OP(=O) 2 R aa , -OP(=O)(R aa ) 2 ,-OP(=O)(OR cc ) 2 , -OP(=O)2 N(R bb ) 2 , and -OP(=O)(NR bb ) 2 , where R aa , R bb , and R cc is as defined herein. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the leaving group is toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O) 2 (CF 2 ) 3 CF 3(nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group, such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfur-containing moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0073] 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 excessive 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 (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 the salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (such as ion exchange). Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-type salts such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109, 109, 109, 109, 109, 108, 1 + (C 1~4 Alkyl) 4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0074] The term "solvate" refers to a form of a compound associated with a solvent, usually by solvolysis. The term "solvate" refers to a form of a compound or a salt thereof 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 of formula (IA), (IB), or (II) may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some instances, the solvate will 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 hydrates, ethanolates, and methanolates.

[0075] The term "stoichiometric solvate" refers to a solvate comprising a compound (e.g., a compound disclosed herein) and a solvent, where the solvent molecules are an integral part of the crystal lattice, where they interact strongly with the compound and with each other. Removal of the solvent molecules causes instability of the crystalline network, which will subsequently collapse into an amorphous phase or recrystallize as a new crystalline form with reduced solvent content.

[0076] The term "non-stoichiometric solvate" refers to a solvate comprising a compound (e.g., a compound disclosed herein) and a solvent, where the solvent content may vary without significant change in the crystal structure. The amount of solvent in the crystal lattice depends only on the partial pressure of the solvent in the surrounding atmosphere. In a fully solvated state, a non-stoichiometric solvate may, but need not, exhibit an integer molar ratio of solvent:compound. During drying of a non-stoichiometric solvate, a portion of the solvent may be removed without significantly disturbing the crystalline network, and the resulting solvate may subsequently be resolvated to give the original crystalline form. Unlike a stoichiometric solvate, the desolvation and resolvation of a non-stoichiometric solvate is not accompanied by a phase transition, and all solvation states represent the same crystalline form.

[0077] The term "hydrate" refers to a compound that is associated with 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 may be, for example, a compound of the general formula R·xH 2 O (where R is a compound and x is a number greater than 0). A given compound may form more than one type of hydrate, such as monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R 0.5H 2 O)), and polyhydrates (x is a number greater than 1, e.g. dihydrates (R 2H 2 O) and hexahydrate (R 6H 2 O)) Include.

[0078] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from the formal migration of at least one 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 depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., reactions that provide tautomeric pairs) may be catalyzed by acids or bases. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different)enamine tautomerizations.

[0079] It will also be understood that 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 termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0080] Stereoisomers that are not mirror images of one another are called "diastereomers" and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center (e.g., it is bonded to four different groups), a pair of enantiomers is possible. Enantiomers may 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 and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0081] The term "crystal" or "crystalline form" refers to a solid form that exhibits substantial three-dimensional order. In some embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In some embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form includes one or more sharply defined peaks.

[0082] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) in a specific crystal packing arrangement. The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates). All polymorphs have the same elemental composition. Different crystalline forms usually 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 polymorphs of a compound may be prepared by crystallization under different conditions.

[0083] The term "prodrug" refers to a compound having a cleavable group and which becomes a compound of formula (IA), (IB) and (II) by solvolysis or under physiological conditions, which is pharmacologic in vivo, including derivatives of the compounds of formula (IA), (IB) and (II). Examples include, but are not limited to, ester derivatives, etc. Examples include, but are not limited to, choline ester derivatives, etc., N-alkylmorpholine esters, etc. Other derivatives of the compounds of the present invention are active in both their acid and acid derivative forms, but often provide advantages of solubility, tissue compatibility, or delayed release to mammalian organisms in the acid-sensitive form (see Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but often provide advantages of solubility, tissue compatibility, or delayed release to mammalian organisms in the acid-sensitive form (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, for example, esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic groups pendant on the compounds of the present invention are specific prodrugs. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic groups pendant on the compounds described herein are specific prodrugs. In some cases, it may be desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C2 ~C 8 Alkynyl, Aryl, C 7 ~C 12 Substituted aryl, and C 7 ~C 12 Arylalkyl esters are sometimes preferred.

[0084] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or older adults)), and / or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs), and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In some embodiments, the animal is a mammal. The animal may be male or female at any stage of development. The non-human animal may be a transgenic animal.

[0085] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound of the invention or a pharmaceutical composition thereof.

[0086] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a "condition" as described herein (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof). In some embodiments, treatment may be administered after one or more signs or symptoms have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0087] The terms "prevent", "preventing", or "prevention" refer to prophylactic treatment of subjects who do not have a disease and who are at risk of developing the disease or of regression of the disease. In some embodiments, the subject is at higher risk of developing the disease or of regression of the disease than the average healthy member of the population.

[0088] The terms "disease," "disease," and "disorder" are used interchangeably.

[0089] 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 compared to a vehicle.

[0090] An "effective amount" of a compound of formula (IA), (IB), or (II) refers to an amount sufficient to induce a desired biological response, i.e., treat a disease, e.g., inhibit TEAD. As will be appreciated by those skilled in the art, an effective amount of a compound of formula (IA), (IB), or (II) may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective amount of a compound of the present invention may reduce tumor burden or stop tumor growth or its spread.

[0091] A "therapeutically effective amount" of a compound of formula (IA), (IB), or (II) is an amount sufficient to provide a therapeutic benefit in treating a disease or to delay or minimize one or more symptoms associated with a disease. 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 disease. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that reduces or averts the symptoms or causes of a disease, or an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0092] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent or prevent the recurrence of a disease or one or more symptoms associated with a disease. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent alone or in combination with another agent, which provides a prophylactic benefit in terms of preventing a disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic effectiveness of another prophylactic agent. In some embodiments, a prophylactically effective amount is an amount sufficient to bind to and / or inhibit a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, a prophylactically effective amount is an amount sufficient to bind to a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and / or inhibit a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, a prophylactically effective amount is an amount sufficient to prevent a disease and / or condition (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease). In some embodiments, a prophylactically effective amount is an amount sufficient to bind to a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and treat and / or prevent a disease and / or condition (e.g., a proliferative disease, an inflammatory disease, an autoimmune disease). In some embodiments, a prophylactically effective amount is an amount sufficient to bind to a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and / or inhibit a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).

[0093] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and tissue needle biopsies); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, organelles (such as those obtained by lysing cells and centrifuging or otherwise separating their components). 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, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biological molecules derived from a first biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei. Biological samples also include transgenic biological samples such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei, or cells or cell lines derived from the biological samples.

[0094] The term "tissue" refers to any biological tissue (including a group of cells, body parts, or organs) or part thereof of a subject, including blood vessels and / or lymphatic vessels, which is the target to which the compounds, particles, and / or compositions of the present invention are delivered. The tissue may be a non-normal or unhealthy tissue, which may need to be treated. The tissue may also be a normal or healthy tissue that is at higher than normal risk of becoming non-normal or unhealthy, which may need to be prevented. In some embodiments, the tissue is the central nervous system. In some embodiments, the tissue is the brain.

[0095] "Proliferative disease" refers to a disease caused by abnormal growth or expansion by cell doubling (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 neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, as seen in proliferative retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, lymphomas, non-Hodgkin's lymphomas, Waldenstrom's hypergammaglobulinemia, MYD88-mutated Waldenstrom's hypergammaglobulinemia, activated B-cell diffuse large B-cell lymphoma, leukemia, sarcomas, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer, and cancer. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), sarcomas, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer; cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0096] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue, where the growth of the mass exceeds and is out of step with that of normal tissue. A neoplasm or tumor may be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well differentiated, characteristically have a slower rate of growth than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the propensity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasia. In some cases, a "benign" tumor may later give rise to a malignant neoplasm, which may result from additional genetic changes in a subpopulation of neoplastic cells in the tumor; these tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, a "malignant neoplasm" is generally poorly differentiated (anaplasia) and characterized by rapid growth with progressive infiltration, invasion, and destruction of surrounding tissue. Moreover, malignant neoplasms generally have the propensity to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasize" refer to the spread or migration of cancerous cells from the primary original tumor to another organ or tissue, typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the histological type of the primary original tumor, rather than that of the organ or tissue in which the secondary (metastatic) tumor resides. For example, prostate cancer that has migrated to bone is referred to as metastatic prostate cancer, and includes cancerous prostate cancer cells growing in bone tissue.

[0097] The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; cancer of the adrenal gland; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer cancer) (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); cancer of connective tissue; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric 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 cancers) (e.g., leukemias such as acute lymphoblastic 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);Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), MYD88-mutated Waldenström's hypergammaglobulinemia, activated B-cell (ABC) diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue Lymphomas such as mycosis fungoides (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Cezari's disease, etc.). -cell NHL such as angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous cellulitis-like T-cell lymphoma, and anaplastic large cell lymphoma; mixtures of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HC)). C), 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 mastocytosis); cancer of muscle; myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myeloid metaplasia (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), islet cell tumors); 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., prostate adenocarcinoma); rectal cancer; striated These include myosarcomas; cancers of the salivary glands; skin cancers (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancers (e.g., appendix cancer); soft tissue sarcomas (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 cancers (e.g., seminoma, testicular embryonal carcinoma); thyroid cancers (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancers (e.g., Paget's disease of the vulva);

[0098] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in healthy subjects to heal wounds and restore blood flow to tissues after injury. Healthy subjects control angiogenesis through a number of means, including angiogenic stimulatory growth factors and angiogenic inhibitors. Many pathologies, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal or pathological angiogenesis refers to angiogenesis that is more profound than that in normal subjects, particularly angiogenesis in adults that is not associated with normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to supply diseased tissue and / or destroy normal tissue; in the case of cancer, the new blood vessels allow tumor cells to escape and lodge in the blood circulation in other organs (tumor metastasis). In some embodiments, the angiogenesis is pathological angiogenesis.

[0099] The term "inflammatory disease" refers to a disease caused by or resulting in inflammation. The term "inflammatory disease" may also refer to a dysregulated inflammatory response by macrophages, granulocytes, and / or T-lymphocytes that causes an exaggerated response leading to abnormal tissue damage and / or cell death. Inflammatory diseases can be either acute or chronic inflammatory illnesses and can result from infectious or non-infectious causes.Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, osteoarthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, and the like. syndrome, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, beryllium poisoning, talc, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed hypercalcaemia, Hypersensitivity reactions (e.g. poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, ophthalmitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, The following diseases are included: connectivitis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, pharyngitis, myelitis, myocarditis, nephritis, omphalitis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enteritis. Eye inflammatory diseases include, but are not limited to, postoperative inflammation.In some embodiments, the inflammatory disorder is fibrosis, and the fibrosis is idiopathic pulmonary fibrosis, liver cirrhosis, cystic fibrosis, systemic sclerosis, progressive renal disease, or cardiovascular fibrosis.

[0100] "Autoimmune disease" refers to a disease resulting from an inappropriate immune response of the subject's body to substances and tissues normally present in the body. In other words, the immune system mistakes a part of the body as a pathogen and attacks its own cells. This may be restricted to an organ (e.g., in autoimmune thyroiditis) or may involve specific tissues in various locations (e.g., Goodpasture's disease, which can affect the basement membrane in both the lungs and kidneys). Treatment of autoimmune diseases is typically by immunosuppression, e.g., medicines that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, and cardiomyopathies. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disorder is sclerosis. In some embodiments, the sclerosis is systemic sclerosis (scleroderma) or multiple sclerosis.

[0101] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, often beneficial, effect. For example, a therapeutic agent may treat, ameliorate, and / or prevent a disease. A therapeutic agent may be a biologic or a small molecule therapeutic agent, as disclosed herein.

[0102] A "transcription factor" is a type of protein involved in the process of transcribing DNA into RNA and / or modulating the transcription of one or more genes. Transcription factors can act independently or in complexes with other proteins to either stimulate or repress transcription. Transcription factors contain at least one DNA-binding domain that confers them 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 lack DNA-binding domains and are therefore not transcription factors. These exemplary human transcription factors include, but are not limited to, YAP, EGFR, MEK, TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4), 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, ARID3A, 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, BARH L1, BARHL2, BARX1, BARX2, BATF, BATF2, BATF3, BAZ2A, BAZ2B, BBX, BCL11A, BCL11B, BCL6, BCL6B, BHLH A15, BHLHA9, BHLHE22, BHLHE23, BHLHE40, BHLHE41, BNC1, BNC2, BORCS-MEF2B, BPTF, BRF2, BSX, C11or f95, CAMTA1, CAMTA2, CARF, CASZ1, CBX2, CC2D1A, CCDC169-SOHLH2, CCDC17, CDC5L, CDX1, CDX2, CDX4,CEBPA、CEBPB、CEBPD、CEBPE、CEBPG、CEBPZ、CENPA、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、GCM2、GFI1、GFI1B、GLI1、GLI2、GLI3、GLI4、GLIS1、GLIS2、GLIS3、GLMP、GLYR1、GMEB1、GMEB2、GPBP1、GPBP1L1、GRHL1、GRHL2、GRHL3、GSC、GSC2、GSX1、GSX2、GTF2B、GTF2I、GTF2IRD1、GTF2IRD2、GTF2IRD2B、GTF3A、GZF1、HAND1、HAND2、HBP1、HDX、HELT、HES1、HES2、HES3、HES4、HES5、HES6、HES7、HESX1、HEY1、HEY2、HEYL、HHEX、HIC1、HIC2、HIF1A、HIF3A、HINFP、HIVEP1、HIVEP2、HIVEP3、HKR1、HLF、HLX、HMBOX1、HMG20A、HMG20B、HMGA1、HMGA2、HMGN3、HMX1、HMX2、HMX3、HNF1A、HNF1B、HNF4A、HNF4G、HOMEZ、HOXA1、HOXA10、HOXA11、HOXA13、HOXA2、HOXA3、HOXA4、HOXA5、HOXA6、HOXA7、HOXA9、HOXB1、HOXB13、HOXB2、HOXB3、HOXB4、HOXB5、HOXB6、HOXB7、HOXB8、HOXB9、HOXC10、HOXC11、HOXC12、HOXC13、HOXC4、HOXC5、HOXC6、HOXC8、HOXC9、HOXD1、HOXD10、HOXD11、HOXD12、HOXD13、HOXD3、HOXD4、HOXD8、HOXD9、HSF1、HSF2、HSF4、HSF5、HSFX1、HSFX2、HSFY1、HSFY2、IKZF1、IKZF2、IKZF3、IKZF4、IKZF5、INSM1、INSM2、IRF1、IRF2、IRF3、IRF4、IRF5、IRF6、IRF7、IRF8、IRF9、IRX1、IRX2、IRX3、IRX4、IRX5、<h2 style=";text-align:left;direction:ltr">IRX6、ISL1、ISL2、ISX、JAZF1、JDP2、JRK、JRKL、JUN、JUNB、JUND、KAT7、KCMF 1、KCNIP3、KDM2A、KDM2B、KDM5B、KIN、KLF1、KLF10、KLF11、KLF12、KLF13、KL F14、KLF15、KLF16、KLF17、KLF2、KLF3、KLF4、KLF5、KLF6、KLF7、KLF8、KLF9、 KMT2A、KMT2B、L3MBTL1、L3MBTL3、L3MBTL4、LBX1、LBX2、LCOR、LCORL、LEF1、L EUTX、LHX1、LHX2、LHX3、LHX4、LHX5、LHX6、LHX8、LHX9、LIN28A、LIN28B、LIN 54、LMX1A、LMX1B、LTF、LYL1、MAF、MAFA、MAFB、MAFF、MAFG、MAFK、MAX、MAZ、MB D1、MBD2、MBD3、MBD4、MBD6、MBNL2、MECOM、MECP2、MEF2A、MEF2B、MEF2C、MEF 2D、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, MXD4 MXI1、MYB、MYBL1、MYBL2、MYC、MYCL、MYCN、MYF5、MYF6、MYNN、MYOD1、MYOG、M YPOP、MYRF、MYRFL、MYSM1、MYT1、MYT1L、MZF1、NACC2、NAIF1、NANOG、NANOGNB 、NANOGP8、NCOA1、NCOA2、NCOA3、NEUROD1、NEUROD2、NEUROD4、NEUROD6、NEU ROG1、NEUROG2、NEUROG3、NFAT5、NFATC1、NFATC2、NFATC3、NFATC4、NFE2、NFE 2L1、NFE2L2、NFE2L3、NFE4、NFIA、NFIB、NFIC、NFIL3、NFIX、NFKB1、NFKB2、N FX1、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、<h2 style=";text-align:left;direction:ltr">RLF、RORA、RORB、RORC、RREB1、RUNX1、RUNX2、RUNX3、RXRA、RXRB、RXRG、SAFB 、SAFB2、SALL1、SALL2、SALL3、SALL4、SATB1、SATB2、SCMH1、SCML4、SCRT1、S CRT2、SCX、SEBOX、SETBP1、SETDB1、SETDB2、SGSM2、SHOX、SHOX2、SIM1、SIM2 、SIX1、SIX2、SIX3、SIX4、SIX5、SIX6、SKI、SKIL、SKOR1、SKOR2、SLC2A4RG、SM AD1, SMAD3, 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、S OX8、SOX9、SP1、SP100、SP110、SP140、SP140L、SP2、SP3、SP4、SP5、SP6、SP7、S P8、SP9、SPDEF、SPEN、SPI1、SPIB、SPIC、SPZ1、SRCAP、SREBF1、SREBF2、SRF、 SRY、ST18、STAT1、STAT2、STAT3、STAT4、STAT5A、STA5B、STT6、T、TAL1、TAL2 、TBP、TBPL1、TBPL2、TBR1、TBX1、TBX10、TBX15、TBX18、TBX19、TBX2、TBX20、 TBX21、TBX22、TBX3、TBX4、TBX5、TBX6、TCF12、TCF15、TCF20、TCF21、TCF23、T CF24、TCF3、TCF4、TCF7、TCF7L1、TCF7L2、TCFL5、TEAD1、TEAD2、TEAD3、TEAD 4、TEF、TERB1、TERF1、TERF2、TET1、TET2、TET3、TFAP2A、TFAP2B、TFAP2C、TFA P2D、TFAP2E、TFAP4、TFCP2、TFCP2L1、TFDP1、TFDP2、TFDP3、TFE3、TFEB、TFE C、TGIF1、TGIF2、TGIF2LX、TGIF2LY、THAP1、THAP10、THAP11、THAP12、THAP2、THAP3、THAP4、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、ZNF51、 1、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、ZNF90、ZNF91、ZNF92、ZNF93、ZNF98、ZNF99、ZSCAN1、ZSCAN10、ZSCAN12、ZSCAN16、ZSCAN18、ZSCAN2、ZSCAN20、ZSCAN21、ZSCAN22、ZSCAN23、ZSCAN25、ZSCAN26、ZSCAN29、ZSCAN30、ZSCAN31、ZSCAN32、ZSCAN4、ZSCAN5A、ZSCAN5B、Includes ZSCAN5C, ZSCAN9, ZUFSP, ZXDA, ZXDB, ZXDC, and ZZZ3.

[0103] The term "TEAD" refers to transcriptional enhancer associated domain (TEAD) transcription factors. TEADs are basic transcription factors of the Yes-associated protein (YAP) / PDZ-binding domain (TAZ) transcriptional coactivator of the Hippo signaling pathway. Examples of TEADs include, but are not limited to, TEAD1, TEAD2, TEAD3, and TEAD4. For TEAD2, exemplary NCBI sequences from GenBank are NM_001256660.2 (Homo sapiens) and NM_001256659.2 (Homo sapiens). Exemplary genes controlled or regulated by TEADs include, but are not limited to, TGF, CYR61, WNT5A / B, DKK1, TGFB2, BMP4, AREG, EGFR, PD-L1, MYC, LATS2, amino acid transporters SLC38A1 / SLC7A5, and glucose transporter GLUT3. TEAD binds to DNA sequences including, but not limited to, the MCAT DNA sequence and the 5'-GGAATG-3' consensus sequence. [Brief description of the drawings]

[0104] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1A] Figures 1A-1K show that combined EGFR / MEK inhibition promotes senescence-like dormancy. Figure 1A shows the percentage of confluency over time indicating proliferation of PC-9 cells treated with DMSO, 100 nM osimertinib (O) alone, or in combination with 30 nM trametinib (T), where combined osimertinib and trametinib treatment is designated "OT." [Figure 1B] Figure 1B shows images of control cells (at 1 week) or dormant PC-9 cells (at 15 weeks) when treated under the conditions of Figure 1A discussed above. Scale bar, 200 μm. [Figure 1C]FIG. 1C shows that cells were treated as in FIG. 1A for 6 weeks, followed by drug washout. [Figure 1D] FIG. 1D shows Western blot analysis of EGFR downstream signaling following treatment with OT for the indicated times or for 21 days, followed by drug washout (recovery). [Figure 1E] FIG. 1E shows the percentage barcodes shared among replicates receiving the indicated treatments in barcoded PC-9 cells. [Figure 1F] Figure IF shows the relative abundance of individual barcodes. Shared and unique indicate barcodes shared by >2 replicates or ≦2 replicates, respectively. In Figure IF, shared data is shown in darker grey; unique data is shown in lighter grey. [Figure 1G] Figure 1G shows Gene Set Enrichment Analysis (GSEA) of the Hallmark gene set comparing dormant cells vs. DMSO-treated control cells. Normalized Enrichment Scores (NES) are shown for gene sets with FDR <0.1 in at least two cell lines. [Figure 1H] Figure 1H shows senescence-associated β-galactosidase (SA-β-gal) staining of cells treated for 10 days as indicated. Scale bar, 100 μm. [Figure 1I-J] Figure 1I shows quantification of the cells in Figure 1H. Figure 1J shows GSEA of the senescence signature comparing dormant OT-treated PC-9 cells vs. control cells. [Figure 1K]FIG. 1K shows immunofluorescence (IF) staining of H3K9Me3 in control or dormant cells treated with OT for 10 days. Scale bar, 20 μm. Mean ± SEM is shown in all plots, except as seen in FIG. 1I, which shows mean ± SD. ANOVA was used for statistical analysis, as seen in FIG. 1I, or t-test, as seen in FIG. 1K. ***, P<0.001; **, P<0.01. See also FIG. 8A-8C, FIG. 9A-9B, and FIG. 10A-10D.

[0105] [Figure 2A] Figures 2A-2J show that establishment of cell dormancy following EGFR / MEK inhibition is highly dependent on YAP / TEAD activation. Figure 2A shows principal component analysis of ATAC-seq data from cells treated for 2 weeks as indicated. [Figure 2B] FIG. 2B shows ATAC-seq signal intensity centered around upregulated (up) or downregulated (down) peaks in dormant, osimertinib- and trametinib (OT)-treated cells vs. DMSO-treated control cells. [Figure 2C] Figure 2C shows the analysis of enriched transcription factor motifs, Figure 2D shows the GSEA of the YAP / TEAD signature (Zhang et al., 2009; see references below), and Figure 2E on the left shows the ATAC-seq signal intensity centered around upregulated (up) or downregulated (down) peaks in cells treated with OT vs. osimertinib. [Figure 2D] Figure 2C shows the analysis of enriched transcription factor motifs, Figure 2D shows the GSEA of the YAP / TEAD signature (Zhang et al., 2009; see references below), and Figure 2E on the left shows the ATAC-seq signal intensity centered around upregulated (up) or downregulated (down) peaks in cells treated with OT vs. osimertinib. [Figure 2E]Figure 2C shows the analysis of enriched transcription factor motifs, Figure 2D shows the GSEA of the YAP / TEAD signature (Zhang et al., 2009; see references below), and Figure 2E on the left shows the ATAC-seq signal intensity centered around upregulated (up) or downregulated (down) peaks in cells treated with OT vs. osimertinib. Figure 2E on the right shows the analysis of enriched transcription factor motifs in upregulated peaks. [Figure 2F] FIG. 2F shows QPCR analysis of YAP target gene expression. [Figure 2G] FIG. 2G shows regrowth of EGFR mutant NSCLC cells after 3 weeks of treatment with the indicated drug combinations followed by washout. [Figure 2H] FIG. 2H shows Western blot analysis of YAP protein levels in YAP1 knockout (KO) and control (CTRL) cells. [Figure 2I] FIG. 2I shows the confluency over time indicating proliferation of the cells in FIG. 2H treated for 21 days as indicated, followed by drug washout. [Figure 2J] FIG. 2J shows tumor volumes of mice bearing xenograft tumors of CTRL or YAP1 KO cells treated with vehicle or OT followed by treatment cessation and follow-up. Data from 6 / 8 live mice per group are plotted. Right: tumor volumes upon regrowth indicated by arrows. Means ± SEM are shown in all plots except FIG. 2F, which shows mean ± SD. ANOVA was used for statistical analysis in all except FIG. 2J, where t-test was used. ***, P<0.001; *, P<0.05. See also FIG. 11A-11E.

[0106] [Figure 3A]Figures 3A-3J show that YAP activation is required for cancer cell viability upon combined inhibition of EGFR / MEK. Figure 3A shows normalized YAP activity in PC-9 cells transduced with a fluorescent YAP / Hippo pathway reporter (PC-9 YAP reporter cells) subjected to the indicated treatments. [Figure 3B] FIG. 3B shows IF staining of YAP nuclear localization following the indicated treatments. [Figure 3C] FIG. 3C shows normalized YAP activity and apoptosis in PC-9 YAP reporter cells treated with osimertinib and trametinib (OT). [Figure 3D] FIG. 3D shows an analysis of the overlap between YAP-high cells (red) and apoptotic cells (green) after 80 h of treatment in PC-9 YAP reporter cells. [Figure 3E-F] Figure 3E shows apoptosis in PC-9 cells treated with the indicated drugs or drug combinations. Figure 3F shows apoptosis in EGFR mutant NSCLC cells treated as indicated. Peak apoptosis values ​​over 72 hours are shown. [Figure 3G-H] Figure 3G shows apoptosis in YAP1 knockout (KO) or control (CTRL) cells treated as indicated. Figure 3H on the left shows Western blot analysis of YAP protein levels in YAP1 KO cells transduced with wild-type YAP1. Figure 3H on the right shows cells treated with OT and analyzed as in Figure 2G. Only data from drug-treated cells are shown. [Figure 3I] FIG. 3I shows the percentage of YAP high cells in the YAP reporter cell population of PC-9 treated as indicated. [Figure 3J]Figure 3J shows various means for EGFR-mutated NSCLC cells to undergo EGFR inhibition and escape apoptosis. Mean ± SEM is shown in all plots except as in Figure 3I, where SD is shown. ANOVA was used for statistical analysis in all except Figure 3D, where Fisher's exact test was used. ***, P<0.001. See also Figure 12.

[0107] [Figure 4A-B] Figures 4A-4I show that YAP-high, senescence-like dormancy also occurs in vivo. Figure 4A shows tumor volume growth curves for PC-9 xenograft tumors harvested for single-cell RNA sequencing (scRNA-seq) and immunohistochemistry (IHC). Figure 4B shows the fluorescence-activated cell sorting (FACS) sorting scheme for live and dead cells used to obtain scRNA-seq samples from dissociated xenograft tumors. [Figure 4C-D] Figure 4C shows YAP, EMT, and Fridman senescence signature enrichment in single cells from xenograft tumors. Figures 4D-4E show IHC staining of YAP in xenograft tumors or in residual tumors from EGFRL858 / T790M mice treated with vehicle or osimertinib for 2 weeks, as seen in Figure 4E. [Figure 4E] Figures 4D-4E show IHC staining of YAP in xenograft tumors or in residual tumors from EGFRL858 / T790M mice treated with vehicle or osimertinib for 2 weeks, as seen in Figure 4E. [Figure 4F] FIG. 4F shows quantification of FIG. 4D and FIG. 4F. [Figure 4G-H]Figure 4G shows quantification of infiltrating T cells in the same tumors as in Figure 4E based on CD4 / CD8 IHC. Figures 4H-4I show IHC staining for YAP and pERK in WZ4002- or WZ4002 / trametinib-resistant tumors from EGFRL858 / T790M mice, as seen in Figure 4H, or in residual tumors from an EGFR-mutated NSCLC patient treated with osimertinib / selumetinib for 11 months, as seen in Figure 4I. [Figure 4I] Figures 4H-4I show IHC staining of YAP and pERK in WZ4002- or WZ4002 / trametinib-resistant tumors from EGFRL858 / T790M mice, as seen in Figure 4H, or in residual tumors from EGFR-mutated NSCLC patients treated with osimertinib / selumetinib for 11 months, as seen in Figure 4I. Statistical analysis used Kolmogorov-Smirnov test, as seen in Figure 4C, ANOVA (when more than two groups, as seen in Figure 4F, and Figure 4H), or t-test (when more than two groups, as seen in Figure 2F, Figure 4G, or Figure 4I). ***, P<0.001; **, P<0.01; ns, not significant. See also Figures 13A-13C.

[0108] [Figure 5A] Figures 5A-5I show that YAP mediates apoptosis evasion by abrogating the induction of pro-apoptotic BMF. Figure 5A shows Western blot analysis of EGFR downstream signaling at the indicated proteins (YAP, pEGFR, EGFR, pAKT, pERK, ERK, pS6, S6, BIM, tubulin) in PC-9 and HCC4006 cells treated for 24 hours with osimertinib, trametinib, or a combination of osimertinib and trametinib (OT) as indicated. [Figure 5B-C]Figure 5B shows the RNA-seq samples used in Figure 5C. Figure 5C shows the expression of genes regulating apoptosis in YAP1 KO cells treated with OT vs. CTRL cells treated with OT. Colors indicate log2 fold change values ​​where p<0.001. [Figure 5D] FIG. 5D shows QPCR analysis of BMF expression in CTRL or YAP1 KO cells treated for 24 hours in vitro or 3 days in vivo as indicated. [Figure 5E-G] Figure 5E shows a schematic diagram of the endogenous BMF locus in PC-9 HA-BMF cells. Figure 5F shows Western blot analysis of BMF, BIM, and YAP expression in PC-9 HA-BMF cells transfected with non-targeting (NT) or YAP siRNA and treated as indicated for 24 hours. Figure 5G shows QPCR analysis of BMF expression in CTRL or YAP1 KO cells transduced as indicated and treated with either DMSO or OT for 24 hours. [Figure 5H-I] Figure 5H shows peak apoptosis over 72 hours of treatment in PC-9 and HCC4006 cells transfected with NT or BMF siRNA. Figure 5I shows the mechanism of YAP / TEAD-mediated suppression of apoptosis in EGFR-mutated NSCLC cells subjected to EGFR / MEK inhibition. Mean values ​​± SD are shown in all plots except Figure 5H, which shows mean values ​​± SEM. ANOVA was used for statistical analysis. ***, P<0.001; **, P<0.01; ns, not significant (P>0.05). See also Figures 14A-14G.

[0109] [Figure 6A] Figures 6A-6I show that YAP abrogates BMF induction by the implicated EMT transcription factor SLUG. Figure 6A shows GSEA of EMT signatures in YAP1 knockout (KO) cells vs. control cells treated with osimertinib and trametinib (OT) for 24 hours. [Figure 6B-C]Figure 6B shows QPCR analysis of EMT transcription factor expression in untreated EGFR mutant NSCLC cells, and Figure 6C shows co-immunoprecipitation analysis of the interaction between YAP, TEAD, and SLUG in PC-9 cells treated with DMSO or OT for 48 h. [Figure 6D-E] Figure 6D shows Western blot analysis of YAP and SLUG protein levels in PC-9 or HCC4006 cells transfected with non-targeting (NT), YAP, or SLUG siRNA, and Figure 6E shows QPCR analysis of BMF expression in cells of Figure 6D treated with DMSO or OT for 24 hours. [Figure 6F] FIG. 6F shows apoptosis in the cells of FIG. 6D treated with DMSO or OT. [Figure 6G-H] Figure 6G shows the number of peaks called MACS2 (FDR<0.01). Figure 6H shows ChIP-seq signal traces in the BMF locus. H3K27Ac was used to identify enhancer regions. [Figure 6I] Figure 6I shows the mechanism by which YAP / TEAD / SLUG complexes suppress BMF expression upon combined inhibition of EGFR / MEK. Mean values ​​± SD as in Figure 6E or mean values ​​± SEM as in Figure 6F are shown. ANOVA was used for statistical analysis. ***, P<0.001; **, P<0.01.

[0110] [Figure 7A] Figures 7A-7I show the development of novel covalent TEAD inhibitors targeting YAP dependency upon combined EGFR / MEK inhibition. Figure 7A shows the YAP1 mutants used in the rescue experiments in Figure 7B and viability. [Figure 7B-C]Figure 7B shows the viability (Cell Titer Glo) of CTRL cells transduced with YAP1 mutants as seen in Figure 7A or PC-9 YAP1 KO cells treated with osimertinib and trametinib (OT) for 72 hours. Figure 7C on the top shows the structure of compound MYF-01-37. Figure 7C on the bottom shows MYF-01-37 binding to the palmitoylation pocket of TEAD1 based on molecular docking. Cysteine ​​359 targeted by MYF-01-37 is indicated. [Figure 7D-E] FIG. 7D shows the effect of MYF-01-37 or the corresponding reversible control on YAP / TEAD interaction. FIG. 7E on the left shows a Western blot analysis of myc-tagged TEAD1 expression in PC-9 cells transduced as indicated. FIG. 7E on the right shows a QPCR analysis of CTGF expression in transduced PC-9 cells after 24 hours of treatment with compounds XAV939 or MYF-01-37. The structure of compound XAV939 is: [ka] It is. [Fig. 7F-G] Figure 7F shows YAP activity in PC-9 YAP reporter cells after 72 hours of treatment with OT or OT in combination with XAV939 (XAV) or MYF-01-37 (MYF). Figure 7G shows QPCR analysis of BMF expression in cells of Figure 7E treated for 24 hours as indicated. [Figure 7H-I] Figure 7H shows apoptosis in PC-9 and HCC4006 cells treated as indicated. Figure 7I shows percentage confluence and regrowth of PC-9 and HCC4006 cells after 2 weeks of treatment as indicated and drug washout. Mean values ​​± SEM are shown in all plots except Figure 7E, which shows mean values ​​± SD. ANOVA was used for statistical analysis. ***, P<0.001; **, P<0.01. See also Figures 15A-15F.

[0111] [Figure 8A]FIG. 8A shows Western blot analysis of EGFR and ERK phosphorylation in the EGFR-mutated NSCLC cell line HCC4006 treated with osimertinib alone or in combination with trametinib for the indicated times. [Figure 8B] Figure 8B shows EGFR mutant NSCLC cells H1975 and HCC4006 treated as indicated for 6 weeks followed by washing out of all drugs. Cell growth was monitored manually by weekly determination of the percentage of wells >50% confluent. [Figure 8C] Figure 8C in the top panel shows that PC-9 cells were grown to ~40% confluence and then treated with DMSO or a combination of osimertinib and trametinib for 21 days, followed by drug washout. After the cells re-entered the exponential growth phase (~40% confluence), the recovering cells were treated again with the same drug combination. Arrows indicate the time points of the representative images. Figure 8C in the bottom panel shows representative images of DMSO-treated PC-9 cells, dormant PC-9 cells, and recovered PC-9 cells.

[0112] [Figure 9A] Figure 9A shows barcode abundance plots for osimertinib- and osimertinib / trametinib-treated samples. In Figure 9A, shared data is shown in darker grey; unique data is shown in lighter grey. [Figure 9B] FIG. 9B shows the overlap of shared barcodes between osimertinib-treated and osimertinib / trametinib-treated samples.

[0113] [Figure 10A] FIG. 10A shows GSEA of senescence-associated signatures comparing dormant HCC827 and HCC4006 cells treated with osimertinib and trametinib (OT) vs. DMSO-treated control cells. [Figure 10B]Figure 10B shows secreted cytokines / chemokines in conditioned medium of dormant cells treated with OT. Log2 fold change (dormant vs. control) is shown. [Figure 10C] Figure 10C shows differentially expressed SASP genes in dormant PC-9, HCC827, and HCC4006 cells vs. DMSO-treated control cells. Genes encoding SASP factors listed in Coppe et al., 2010 and / or included in the Luminex panel used in Figure 10B are shown. Colors indicate log2 fold change values ​​where p<0.05. [Figure 10D] FIG. 10D shows Western blot analysis of p27Kip, p16INK4a, and p21Cip1 protein levels in PC-9, HCC827, and HCC4006 cells treated with OT for the indicated periods or for 21 days, followed by drug washout (recovery).

[0114] [Figure 11A] Figure 11A shows ATAC-seq signal traces at the CTGF locus in PC-9 cells treated with DMSO for 48 hours or osimertinib or osimertinib + trametinib for 2 weeks, highlighting a putative distal enhancer site upstream of the CTGF TSS. [Figure 11B] FIG. 11B shows that viable and dormant PC-9 cells were manually counted from Incucyte images after 21 days of treatment with osimertinib and trametinib (OT) alone or in combination with structurally divergent tankyrase inhibitors. [Figure 11C] FIG. 11C shows regrowth of PC-9 cells following 3 weeks of treatment with osimertinib / trametinib alone or in combination with the indicated drugs, followed by washout of the drugs. [Figure 11D] FIG. 11D is a table showing the drug targets and concentrations used in the assay. [Figure 11E]Figure 11E shows the proliferation of YAP1 knockout (KO) and control (CTRL) cells treated with single agent osimertinib or osimertinib / trametinib. Mean values ​​± SD (as in Figure 11B) or mean values ​​± SEM (as in Figures 11C-11D) are shown. ANOVA was used for statistical analysis. ***, P<0.001.

[0115] [Figure 12] FIG. 12 shows Western blot analysis of YAP and LATS phosphorylation in EGFR mutant NSCLC cells, PC-9 (human non-small cell lung cancer), HCC827 (human lung cancer), and HCC4006 (human non-small cell lung cancer) cell lines treated as indicated.

[0116] [Figure 13A] FIG. 13A shows the complete FACS sorting scheme used to obtain scRNA-seq samples from dissociated PC-9 xenograft tumors. [Figure 13B] FIG. 13B shows IHC staining for YAP, CD4, CD8, and TTF-1 in residual tumors from EGFRL858 / T790M mice treated with vehicle or osimertinib for 2 weeks. [Figure 13C] FIG. 13C shows relative tumor volumes of EGFRL858 / T790M treated with osimertinib or osimertinib / selumetinib for 4 weeks, followed by resting treatment (arrows) and follow-up.

[0117] [Figure 14A-C]Figure 14A shows Western blot analysis of the indicated protein levels in PC-9 control (CTRL) cells and YAP1 knockout (KO) cells treated with osimertinib and trametinib (OT) for 24 hours. Figure 14B shows that cells were treated as shown in Figure 14A, and active BAX protein was immunoprecipitated from cell extracts using a conformation-specific BAX antibody. Immunoprecipitated BAX was detected by Western blotting using an antibody that recognizes all BAX proteins. Figure 14C shows that cells were treated as shown in Figure 14A, fractionated into cytosolic and mitochondrial fractions, and cytochrome c levels were detected using Western blotting. ATP synthase subunit alpha (CVa) and MEK were used as controls for the mitochondrial and cytosolic fractions, respectively. [Fig. 14D-E] Figure 14D shows Sanger sequencing traces around the BMF start codon (ATG) in the PC-9 HA-BMF single cell clones used in the study. Figure 14E shows Western blot analysis of induction of HA-tagged BMF following 6h stimulation with 500ng / ml doxycycline in PC-9, HCC827, and HCC4006 cells stably transfected with doxycycline-inducible HA-BMF coding constructs. [Fig. 14F-G] Figure 14F shows apoptosis over time in PC-9, HCC827, and HCC4006 cells stably transfected with doxycycline-inducible HA-BMF coding constructs in response to the indicated treatments. Apoptosis was measured using an Incucyte live cell analysis system instrument as shown in Figure 3D. Figure 14G shows QPCR analysis of BMF expression in PC-9 and HCC4006 cells transfected with non-targeting (NT) or BMF siRNAs and treated with either DMSO or OT for 24 hours. Mean values ​​± SEM (as shown in Figure 14F) or mean values ​​± SD (as shown in Figure 14G) are shown. ANOVA was used for statistical analysis. ***, P<0.001.

[0118] [Figure 15A-B] Figures 15A-15B show mass spectra (left) and zero-charge mass spectra (right) of TEAD2 protein treated with DMSO (as seen in Figure 15A) or with a 20-fold molar excess of compound MYF-01-37 (as seen in Figure 15B) for 6 hours at 37° C. Peaks corresponding to unlabeled protein are marked with red (plus sign "+" symbol) glyphs, whereas MYF-01-37 labeled protein peaks are indicated with green glyphs. [Figure 15C] Figure 15C shows the MS (left) and MS / MS (right) spectra corresponding to tryptic digest peptide 377SPMC*EYLVNFLHK389 of TEAD2 (where C* indicates MYF-01-37 modified cysteine). Ions of type b and y are indicated by blue (star "*" symbol) and red (plus sign "+" symbol) glyphs, respectively. Inhibitors derived from thiolated ions are marked by green (carat "^" symbol) glyphs. [Fig. 15D-E] Figure 15D shows the structure of the MYF-01-37 biotin conjugate, and Figure 15E shows competitive pull-down of TEAD from MDA-MB-231 cell lysates using biotinylated MYF-01-37 after 6 h incubation with the indicated concentrations of unlabeled MYF-01-37. [Figure 15F] FIG. 15F shows a dose response graph depicting the viability of depicted EGFR mutant NSCLC cell lines (PC-9, HCC827, H3255, HCC4006, H1975, HCC2279) treated at specific concentrations with depicted compounds (MYF-01-37, TED-347) and corresponding reversible control compounds lacking covalently bound warheads.

[0119] [Figure 16A] 16A-16B show apoptosis in NSCLC cell lines treated as indicated. [Figure 16B] 16A-16B show apoptosis in NSCLC cell lines treated as indicated. [Figure 16C] Figure 16C on the left shows Western blot analysis of YAP expression in control (CTRL) and YAP1 KO H3122 and EBC-1 cells, and Figure 16C on the right shows apoptosis in CTRL and YAP1 KO H3122 and EBC-1 cells treated as indicated. [Figure 16D] Figure 16D shows that PC-9 cells were treated as indicated in the scheme on the left, followed by drug washout. When the confluency of wells treated with constant osimertinib / trametinib reached >90% confluency, cell regrowth was monitored and quantified. Mean values ​​± SEM are shown. ANOVA was used for statistical analysis. ***, P<0.001.

[0120] [Figure 17] 17 shows the % cell viability of NCI-H226 human mesothelioma cells following 5-day treatment with exemplary compounds IA-05, IA-04, II-1, II-2, and IA-02 (at the concentrations indicated) versus the log concentration (nM) and IC50 values ​​of the indicated compounds. The structures of these compounds are shown in Example 1 below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0121] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE PRESENTINVENTION The present disclosure provides inhibitors of transcription factors (e.g., TEADs, such as TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, the compounds of the present invention inhibit the activity of TEADs (e.g., TEAD1, TEAD2, TEAD3, TEAD4). The present disclosure further provides, for example, a method of inhibiting the transcription of genes (e.g., genes controlled or regulated by transcription factors (e.g., TEADs, such as TEAD1, TEAD2, TEAD3, TEAD4) using the compounds described herein as biological probes to study the inhibition of the activity of transcription factors (e.g., TEADs, such as TEAD1, TEAD2, TEAD3, TEAD4), as well as a method of using the compounds described herein as therapeutics in the treatment and / or prevention of diseases associated with overexpression of transcription factors (e.g., TEADs, such as TEAD1, TEAD2, TEAD3, TEAD4) and / or abnormal activity of transcription factors (e.g., TEADs, such as TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, the compounds covalently inhibit TEAD1. In some embodiments, the compound covalently inhibits TEAD2. In some embodiments, the compound covalently inhibits TEAD3. In some embodiments, the compound covalently inhibits TEAD4. In some embodiments, the disease to be treated and / or prevented includes, but is not limited to, proliferative diseases, inflammatory diseases, and autoimmune diseases. Proliferative diseases include, but are not limited to, cancer (e.g., sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer; cancer). In some embodiments, the cancer is a sarcoma (e.g., Kaposi's sarcoma). In some embodiments, the cancer is carcinoma. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer, mesothelioma). In some embodiments, the cancer is associated with overexpression and / or abnormal activity of transcription factors (e.g., TEADs such as TEAD1, TEAD2, TEAD3, TEAD4). In some embodiments, the disease is an inflammatory disease (e.g., fibrosis). In some embodiments, the disease is an autoimmune disease (eg, sclerosis).Also provided by the disclosure are pharmaceutical compositions, kits, methods, and uses of the compounds of formula (IA), (IB), or (II) as described herein.

[0122] compound Certain aspects of the present disclosure relate to compounds described herein that inhibit the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4). The compounds described herein may be useful for treating and / or preventing a disease (e.g., a proliferative disease (e.g., cancer), an inflammatory disease (e.g., fibrosis), an autoimmune disease (e.g., sclerosis), or a disease associated with the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject, for inhibiting the activity of a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) or for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., a TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject or biological sample. In some embodiments, the compounds described herein are compounds of formula (IA), (IB), or (II), or pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives (e.g., deuterated forms), prodrugs, compositions, or mixtures thereof. In some embodiments, the compounds described herein are compounds of formula (IA), (IB), or (II), or pharma- ceutically acceptable salts thereof. In some embodiments, the compounds described herein are compounds of formula (IA), or pharma- ceutically acceptable salts thereof. In some embodiments, the compounds described herein are compounds of formula (IB), or pharma- ceutically acceptable salts thereof. In some embodiments, the compounds described herein are compounds of formula (II), or pharma- ceutically acceptable salts thereof.

[0123] In some embodiments, the compounds described herein have formula (IA): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: Ring B is cyclohexyl or phenyl; R 2 is halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN, but Here, R c1 is hydrogen, optionally substituted acyl, 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 when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; Here, R c2 each instance of is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally R c2 when there are two, they are taken together with the intervening atoms to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; R 2B is -N(R c2 ) 2 , -OR c1, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; X 1 is -O-, -O(alkylene)-, alkylene, -S-, -SCH 2 -, -N(R da )- or -N(R da )CH 2 - is; R da is hydrogen, optionally substituted C 1~6 is an alkyl, an optionally substituted acyl, or a nitrogen protecting group; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and D 1 is the formula (i-1)~(i-23), (i-26)~(i-31), (i-34)~(i-40), (i-42), or (i-43): [ka] [ka] [ka] A warhead represented by any one of the following formulas: L 3 is a bond or an optionally substituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -C=O-, -O-, -S-, -NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b-, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O) 2 -, -S(=O) 2 O-, -OS(=O) 2 -, -S(=O) 2 NR L3a -, or -NR L3a S(=O) 2 -, where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group, and L3b each occurrence of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b the groups are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; L 4 is a bond or an optionally substituted branched or unbranched C 1~6 It is a hydrocarbon chain; R E1 , R E2 , and R E3 each independently is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -CH 2 OR EE , -CH 2 N(R EE ) 2 , -CH 2 S.R. EE , -OR EE , -N(R EE ) 2 , -Si(R EE ) 3 , or -SR EE , where R EEeach instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring; or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; R E4 is a leaving group; R E5 is a halogen; R E6 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; Each occurrence of Y is independently O, S, or NR E7 where R E7 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; a is 1 or 2; and Each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, valences permitting.

[0124] In some embodiments, the compounds described herein have formula (IA): [ka] or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the compounds described herein have formula (IB): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: R A1 is -O(R a2 ) or -N(R a3 ) 2 is; R a2 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and R a3 each occurrence is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -SO 2 (R a4 ), or a nitrogen protecting group, or optionally R a3 when there are two, they are taken together with the intervening atoms to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; and R a4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; Ring B is cyclohexyl or phenyl; R 2 is halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR c1 , -NO 2 , -N(Rc2 ) 2 , -SR c1 , -CN, or -SCN, Here, R c1 is hydrogen, optionally substituted acyl, 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 when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; Here, R c2 each instance of is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally R c2 when there are two, they are taken together with the intervening atoms to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; X 1 is -O-, -O(alkylene)-, alkylene, -S-, -SCH 2 -, -N(R da )- or -N(R da )CH 2 - is; R da is hydrogen, optionally substituted C 1~6 alkyl, or nitrogen protecting groups; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and D 1 is the formula (i-1)~(i-23), (i-26)~(i-31), (i-34)~(i-40), (i-42), or (i-43): [ka] [ka] [ka] A warhead represented by any one of the following formulas: L 3 is a bond or an optionally substituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -C=O-, -O-, -S-, -NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O) 2 -, -S(=O) 2 O-, -OS(=O) 2 -, -S(=O) 2 NR L3a -, or -NR L3a S(=O) 2 -, where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group, and L3b each occurrence is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b the groups are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; L 4 is a bond or an optionally substituted branched or unbranched C 1~6 It is a hydrocarbon chain; RE1 , R E2 , and R E3 each independently is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -CH 2 OR EE , -CH 2 N(R EE ) 2 , -CH 2 S.R. EE , -OR EE , -N(R EE ) 2 , -Si(R EE ) 3 , or -SR EE where R EE each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring; or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; R E4 is a leaving group; R E5 is a halogen; R E6 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; Each occurrence of Y is independently O, S, or NR E7 where R E7 is hydrogen, substituted or unsubstituted C 1~6alkyl, or nitrogen protecting groups; a is 1 or 2; and Each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, valences permitting; provided that the compound has the formula: [ka] But it is not represented.

[0126] In some embodiments, the compounds described herein have formula (IB): [ka] or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the compounds described herein have formula (II): [ka] or a pharma- ceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: Ring B is cyclohexyl or phenyl; W is -C(R a )= or -N=; and R a is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN; Z is -C(R b )= or -N=; and R bis hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN; However, if at least one of W and Z is -C(R a )= or -C(R b )=is; R 1 each occurrence of is independently selected from halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN; R 3 each occurrence of is independently selected from halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN; Here, R c1 is hydrogen, optionally substituted acyl, 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 when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; Here, R c2each instance of is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally R c2 when there are two, they are taken together with the intervening atoms to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; X 1 is -O-, -O(alkylene)-, alkylene, -S-, -SCH 2 -, -N(R da )- or -N(R da )CH 2 - is; R da is hydrogen, optionally substituted C 1~6 is an alkyl, an optionally substituted acyl, or a nitrogen protecting group; x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; y is 0, 1, 2, 3, or 4; D 1 is the formula (i-1)~(i-23), (i-26)~(i-31), (i-34)~(i-40), (i-42), or (i-43): [ka] [ka] A warhead represented by any one of the following formulas: L 3 is a bond or an optionally substituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -C=O-, -O-, -S-, -NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NRL3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O) 2 -, -S(=O) 2 O-, -OS(=O) 2 -, -S(=O) 2 NR L3a -, or -NR L3a S(=O) 2 -, where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group, and L3b each occurrence is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b the groups are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; L 4 is a bond or an optionally substituted branched or unbranched C 1~6 It is a hydrocarbon chain; R E1 , R E2 , and R E3 each independently is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -CH 2 OR EE , -CH 2 N(R EE ) 2 , -CH 2 S.R. EE , -OR EE , -N(REE ) 2 , -Si(R EE ) 3 , or -SR EE where R EE each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring; or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; R E4 is a leaving group; R E5 is a halogen; R E6 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; Each occurrence of Y is independently O, S, or NR E7 where R E7 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; a is 1 or 2; and Each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, valences permitting; provided that the compound has the formula: [ka] [ka] is not represented by either

[0128] In some embodiments, the compounds described herein have formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0129] Ring B Formulae (IA), (IB), and (II) include a B ring.

[0130] Ring B (Formulas (IA) and (IB)) In some embodiments, in the compounds of formula (IA) or (IB), the substituent R when on ring B is 2 is zero. In some embodiments, in a compound represented by formula (IA) or (IB), the substituent R when on ring B is 2 is 1 or greater. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, R 2 At least one instance of R is halogen (e.g., F, Cl, Br, or I). 2 At least one instance of R is optionally substituted acyl (e.g., -C(=O)Me). 2 At least one of the groups may be an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 2 is alkyl optionally substituted with halogen. 2 In at least one of the cases, an optionally substituted C 1~6 In some embodiments, R 2At least one of the following is optionally substituted with halogen: 1~6 In some embodiments, R 2 -CF if at least one of 3 In some embodiments, R 2 is substituted or unsubstituted methyl. 2 is substituted or unsubstituted ethyl. 2 is substituted or unsubstituted propyl. 2 At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R 2 At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R 2 At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). 2 At least one instance of R is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). 2 At least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). 2 is benzyl. 2 is substituted or unsubstituted phenyl. 2is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R 2 -OR if at least one of c1 (e.g., -OH or -OMe). In some embodiments, R 2 If at least one of the following is true, then -N(R c2 ) 2 (For example, -NMe 2 In some embodiments, R 2 -SR if at least one of c1 (For example, -SMe). In some embodiments, R 2 -NO if at least one of 2 In some embodiments, R 2 In one embodiment, at least one of R 2 In at least one instance of R is -SCN. In some embodiments, m is 0 or 1; and R 2 is optionally substituted alkyl. In some embodiments, m is 1; and R 2 is optionally substituted alkyl. In some embodiments, m is 0 or 1; and R 2 is an arbitrarily substituted C 1~6 In some embodiments, m is 1; and R 2 is an arbitrarily substituted C 1~6 In some embodiments, m is 0 or 1; and R 2 is C optionally substituted with halogen 1~6 In some embodiments, m is 1; and R 2 is C optionally substituted with halogen 1~6In some embodiments, m is 0 or 1; and R 2 -CF 3 In some embodiments, m is 1; and R 2 -CF 3 It is.

[0131] In one embodiment, R 2 -OR if at least one of c1 , -N(R c2 ) 2 , or -SR c1 and R c1 and R c2 is as defined herein.

[0132] R c1 and R c2 (Formulas (IA), (IB), and (II)). Formulas (IA), (IB), and (II) are defined herein as R c1 and R c2 In some embodiments, in formula (IA) or (IB), R attached to ring B is 2 -OR if at least one of c1 , -N(R c2 ) 2 , or -SR c1 and R c1 and R c2 is as defined herein. In some embodiments, in formula (II), R attached to ring A is 3 -OR if at least one of c1 , -N(R c2 ) 2 , or -SR c1 and R c1 and R c2 is as defined herein. In some embodiments, in formula (II), R attached to ring A is 1 -OR if at least one of c1 , -N(R c2 ) 2 , or -SRc1 and R c1 and R c2 is as defined herein. In certain embodiments, in formula (II), the substituent Z or W in ring A is -OR c1 , -N(R c2 ) 2 , or -SR c1 and R c1 and R c2 is as defined herein. In certain embodiments, R c1 is hydrogen. In some embodiments, R c1 is optionally substituted acyl (e.g., -C(=O)Me). In some embodiments, R c1 is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R c1 is substituted or unsubstituted methyl. In some embodiments, R c1 is substituted or unsubstituted ethyl. In some embodiments, R c1 is substituted or unsubstituted propyl. In some embodiments, R c1 is an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R c1 is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R c1 is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). c1 is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). c1 is an optionally substituted aryl (e.g., a substituted or unsubstituted 6-10 membered aryl). In some embodiments, R c1is benzyl. In some embodiments, R c1 is substituted or unsubstituted phenyl. In some embodiments, R c1 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R c1 is an oxygen protecting group when attached to an oxygen atom. c1 is a sulfur protecting group when attached to a sulfur atom.

[0133] In one embodiment, R c2 is hydrogen. c2 At least one instance of R is optionally substituted acyl (e.g., -C(=O)Me). c2 At least one of the groups may be an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R c2 is substituted or unsubstituted methyl. c2 is substituted or unsubstituted ethyl. c2 is substituted or unsubstituted propyl. c2 At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R c2 At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R c2At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). c2 At least one instance of R is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). c2 At least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). c2 is benzyl. c2 is substituted or unsubstituted phenyl. c2 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R c2 In at least one instance of R is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). c2When there are two, they are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or a substituted or unsubstituted heteroaryl ring (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl, where one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur); or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl, where one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0134] Ring B (Formulas (IA) and (IB)) In certain embodiments, for formulas (IA) and (IB), ring B is phenyl. In certain embodiments, ring B is phenyl. 2 In some embodiments, Ring B is phenyl substituted with one or more of the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] and m is 0 or 1. In some embodiments, ring B is represented by the formula: [ka] and m is 0, 1, 2, or 3. In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] where R 2 is halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, Ring B is of the formula: [ka] where R 2 is halogen, optionally substituted acyl, or optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] where R 2 is optionally substituted with halogen, optionally substituted acyl, or alkyl halogen. [ka] is the expression: [ka] In one embodiment, the moiety [ka] is the expression: [ka] In some embodiments, ring B is represented by the formula: [ka] m is 0 or 1; and R 2 is optionally substituted alkyl or halogen. In some embodiments, Ring B has the formula: [ka] m is 0 or 1; and R 2 is optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] m is 1; and R 2 is optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] m is 0 or 1; and R 2 is an arbitrarily substituted C 1~6 In some embodiments, Ring B is of the formula: [ka] m is 1; and R 2 is an arbitrarily substituted C 1~6 In some embodiments, Ring B is of the formula: [ka] m is 0 or 1; and R 2 is C optionally substituted with halogen 1~6 In some embodiments, Ring B is of the formula: [ka] m is 1; and R 2is C optionally substituted with halogen 1~6 In some embodiments, Ring B is of the formula: [ka] m is 0 or 1; and R 2 -CF 3 In some embodiments, ring B is phenyl or cyclohexyl, m is 1; and R 2 -CF 3 It is.

[0135] In some embodiments, ring B is cyclohexyl. In some embodiments, ring B is a substituent R 2 In some embodiments, Ring B is a cyclohexyl substituted with one or more of the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] and m is 0 or 1. In some embodiments, ring B is represented by the formula: [ka] and m is 0, 1, 2, or 3. In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In one embodiment, the moiety [ka] is the expression: [ka] In one embodiment, the moiety [ka] is the expression: [ka] In one embodiment, the moiety [ka] is the expression: [ka] In some embodiments, ring B is represented by the formula: [ka] m is 0 or 1; and R 2 is halogen or optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] m is 1; and R 2 is optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] m is 0 or 1; and R 2 is an arbitrarily substituted C 1~6 In some embodiments, Ring B is of the formula: [ka] m is 1; and R 2 is an arbitrarily substituted C 1~6In some embodiments, Ring B is of the formula: [ka] m is 0 or 1; and R 2 is halogen or C optionally substituted with halogen 1~6 In some embodiments, Ring B is of the formula: [ka] m is 1; and R 2 is C optionally substituted with halogen 1~6 In some embodiments, Ring B is of the formula: [ka] m is 0 or 1; and R 2 -F, -Me, -CF 3 In some embodiments, ring B has the formula: [ka] m is 0 or 1; and R 2 -CF 3 In some embodiments, ring B has the formula: [ka] m is 1; and R 2 -CF 3 It is.

[0136] In certain embodiments, ring B has the formula: [ka] In some embodiments, in compounds of formula (IA) or (IB), ring B is represented by the formula: [ka] It is expressed as:

[0137] Ring B (formula II) In one embodiment, in the compound of formula (II), the substituent R when on ring B is 3 is zero. In some embodiments, the substituent R when on ring B is 3 is 1 or greater. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10. In some embodiments, R 3 At least one instance of R is halogen (e.g., F, Cl, Br, or I). 3 is -F. In some embodiments, x is 2; and R 3 Both of R are halogen (e.g., F, Cl, Br, or I). 3 In one embodiment, at least one of R 3 is -F. In some embodiments, x is 2; and R 3 In some embodiments, both of R 3 In one embodiment, at least one of R 3 At least one instance of R is optionally substituted acyl (e.g., -C(=O)Me). 3 At least one of the groups may be an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 3 is alkyl optionally substituted with halogen. 3 In at least one of the cases, an optionally substituted C 1~6 In some embodiments, R 3If at least one of 1~6 In some embodiments, R is an alkyl group optionally substituted with halogen. 3 -CF if at least one of 3 In some embodiments, R 3 is substituted or unsubstituted methyl. 3 is substituted or unsubstituted ethyl. 3 is substituted or unsubstituted propyl. 3 At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R 3 At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R 3 At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 14-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). 3 At least one instance of R is optionally substituted carbocyclyl. 3 In at least one of the cases, an optionally substituted C 3~14 In some embodiments, R 3 In at least one of the cases, an optionally substituted C 3~10 In some embodiments, R 3 At least one instance of R is optionally substituted adamantyl. 3 In at least one of the cases, an optionally substituted C 3~7 In some embodiments, R 3is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). 3 At least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). 3 is benzyl. 3 is substituted or unsubstituted phenyl. 3 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R 3 -OR if at least one of c1 (e.g., -OH or -OMe). In some embodiments, R 3 If at least one of the following is true, then -N(R c2 ) 2 (For example, -NMe 2 In some embodiments, R 3 -SR if at least one of c1 (For example, -SMe). In some embodiments, R 3 -NO if at least one of 2 In some embodiments, R 3 In one embodiment, at least one of R 3 In at least one instance of R is -SCN. In some embodiments, x is 1 or 2; and R 3 is optionally substituted alkyl. In some embodiments, x is 1 or 2; and R3 is halogen, optionally substituted alkyl, or optionally substituted carbocyclyl. In some embodiments, x is 1 or 2; and R 3 is halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~14 In some embodiments, x is 1 or 2; and R 3 is an arbitrarily substituted C 1~6 In some embodiments, x is 1 or 2; and R 3 is halogen, C optionally substituted with halogen 1~6 Alkyl, or optionally substituted C 3~14 In some embodiments, x is 1; and R 3 is C optionally substituted with halogen 1~6 In some embodiments, x is 1 or 2; and R 3 -CF 3 , -F, or an optionally substituted adamantyl. In some embodiments, x is 1 or 2; and R 3 -CF 3 It is.

[0138] In some embodiments, ring B is phenyl. In some embodiments, ring B is a substituent R 3 In some embodiments, Ring B is phenyl substituted with one or more of the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] and m is 0 or 1. In some embodiments, ring B is represented by the formula: [ka] and m is 0, 1, 2, or 3. In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] where R 3 is halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclyl. [ka] where R 3 is halogen, optionally substituted acyl, optionally substituted alkyl, or optionally substituted carbocyclyl. In some embodiments, ring B has the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] where R 3 is halogen, optionally substituted acyl, alkyl optionally substituted with halogen, or optionally substituted C 3~14 In some embodiments, the moiety is [ka] is the expression: [ka] In some embodiments, ring B is represented by the formula: [ka] x is 0 or 1; and R 3 is an optionally substituted alkyl or an optionally substituted carbocyclyl. In some embodiments, Ring B has the formula: [ka] x is 1; and R 3 is an optionally substituted alkyl or an optionally substituted carbocyclyl. In some embodiments, Ring B has the formula: [ka] x is 0 or 1; and R 3 is an arbitrarily substituted C 1~6 Alkyl or optionally substituted C 3~14 In some embodiments, Ring B is of the formula: [ka] x is 0 or 1; and R 3 is an arbitrarily substituted C 1~6 In some embodiments, Ring B is a group represented by the formula: [ka] x is 1; and R 3 is an arbitrarily substituted C 1~6 Alkyl or optionally substituted C 3~14 In some embodiments, Ring B is of the formula: [ka] x is 0 or 1; and R 3 is C optionally substituted with halogen 1~6 Alkyl or optionally substituted C 3~14 In some embodiments, Ring B is of the formula: [ka] x is 1; and R 3 is C optionally substituted with halogen 1~6 Alkyl or optionally substituted C 3~14 In some embodiments, Ring B is of the formula: [ka] x is 0 or 1; and R 3 -CF 3 or adamantyl. In some embodiments, Ring B is phenyl or cyclohexyl, x is 1; and R 3 -CF 3 In some embodiments, ring B is phenyl or cyclohexyl, x is 1; and R 3 is adamantyl.

[0139] In some embodiments, ring B is cyclohexyl. In some embodiments, ring B is a substituent R 3 In some embodiments, Ring B is a cyclohexyl substituted with one or more of the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] and x is 0, 1, or 2. In some embodiments, ring B is represented by the formula: [ka] and x is 0, 1, 2, or 3. In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In some embodiments, ring B is represented by the formula: [ka] In one embodiment, the moiety [ka] is the expression: [ka] In some embodiments, ring B is represented by the formula: [ka] x is 0, 1, or 2; and R 3 is halogen or optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] x is 1 or 2; and R 3 is halogen or optionally substituted alkyl. In some embodiments, Ring B has the formula: [ka] x is 1 or 2; and R 3 is a halogen or an optionally substituted C 1~6 In some embodiments, Ring B is of the formula: [ka] x is 2; and R 3 is halogen. In some embodiments, ring B has the formula: [ka] x is 1 or 2; and R 3 is halogen or C optionally substituted with halogen 1~6 In some embodiments, Ring B is of the formula: [ka] x is 2; and R 3 is halogen or C optionally substituted with halogen 1~6 In some embodiments, Ring B is of the formula: [ka] x is 1 or 2; and R 3 -F or -CF 3 In some embodiments, ring B has the formula: [ka] x is 1 or 2; and R 3 is -F.

[0140] In certain embodiments, ring B has the formula: [ka] x is 0, 1, 2, or 3; and R 3 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclyl. In some embodiments, Ring B has the formula: [ka] It is expressed as:

[0141] D 1 Represented by Warhead As generally defined herein, formulae (IA), (IB) and (II) include a substituent D 1 where D 1 is the formula (i-1)~(i-23), (i-26)~(i-31), (i-34)~(i-40), (i-42), or (i-43): [ka] [ka] [ka] A warhead represented by any one of the following formulas: L 3 is a bond or an optionally substituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -C=O-, -O-, -S-, -NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O) 2 -, -S(=O) 2 O-, -OS(=O) 2 -, -S(=O) 2 NR L3a -, or -NR L3a S(=O) 2 -, where RL3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group, and L3b each occurrence is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b the groups are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; L 4 is a bond or an optionally substituted branched or unbranched C 1~6 It is a hydrocarbon chain; R E1 , R E2 , and R E3 each independently is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -CH 2 OR EE , -CH 2 N(R EE ) 2 , -CH 2 S.R. EE , -OR EE , -N(R EE ) 2 , -Si(R EE ) 3 , or -SR EE where R EE each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R EE groups are joined to form an optionally substituted heterocyclic ring; or R E1 and R E3, or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; R E4 is a leaving group; R E5 is a halogen; R E6 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; Each occurrence of Y is independently O, S, or NR E7 where R E7 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; a is 1 or 2; and Each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, valences permitting.

[0142] In one embodiment, D 1 is a warhead represented by any one of formulas (i-1) to (i-23), (i-26) to (i-31), (i-34) to (i-40), (i-42), or (i-43). 1 is the formula [ka] In one embodiment, the warhead is represented by D 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and optionally wherein C 1~4 The 1-2 carbon units of an alkyl group are -C=O-, -NR L3a -, or -NR L3a C(=O)-; where R L3ais hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E1 , R E2 , and R E3 Each of D is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and optionally wherein C 1~4 The 1-2 carbon units of an alkyl group are -C=O- or -NR L3a - has been replaced by; where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E1 , R E2 , and R E3 Each of D is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and optionally wherein C 1~4 The 1-2 carbon units of an alkyl group are -C=O- or -NR L3a - has been replaced by; where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E1 , R E2 , and R E3 Each of D is independently hydrogen or optionally substituted alkyl. 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and where C 1~4 A single carbon unit of an alkyl is -C=O- or -NR L3a - has been replaced by ;R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E1 , R E2 , and R E3 Each of is independently hydrogen or an optionally substituted C 1~6 In some embodiments, D 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and where C 1~4 A single carbon unit of an alkyl is -C=O- or -NR L3a - has been replaced by ;R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E1 , R E2 , and R E3 Each of is independently hydrogen, or -NH 2 , -NH(optionally substituted alkyl), or -N(optionally substituted alkyl) 2 C optionally substituted with 1~6 In some embodiments, D 1 is the expression: [ka] In one embodiment, the warhead is represented by D 1 is the expression: [ka] In one embodiment, the warhead is represented by D 1 is the expression: [ka] In one embodiment, the warhead is represented by D 1 is the expression: [ka] In one embodiment, D 1 is the expression: [ka] In one embodiment, D 1 is the expression: [ka] In one embodiment, D 1 is the expression: [ka] In one embodiment, D 1 is the formula [ka] It is expressed as:

[0143] In one embodiment, L 3 is a bond. In some embodiments, L3 is -NH-. In some embodiments, L 3 is a bond. 3 In some embodiments, R E1 and R E2 is hydrogen. In some embodiments, R E1 , R E2 , and R E3 are all hydrogen. E3 is -CH 2 NMe 2 It is. In one embodiment, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, the Warhead D 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and optionally wherein C 1~4 The 1-2 carbon units of an alkyl group are -C=O- or -NR L3a - has been replaced by; where R L3ais hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E4 is a leaving group (e.g., an optionally substituted C 1~6 and each instance of z is independently 0, 1, 2, or 3, valences permitting. 1 is the formula [ka] where L 3 is a bond or an optionally substituted C 1~4 alkyl, and optionally wherein C 1~4 The 1-2 carbon units of an alkyl group are -C=O- or -NR L3a - has been replaced by; where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group; Y is O; and R E4 is a leaving group (e.g., unsubstituted or substituted C 1~6 and each instance of z is independently 0, 1, 2, or 3, valences permitting. 1 is the formula [ka] where L 3 is the unsubstituted C 1~4 alkyl, and optionally wherein C 1~4 A single carbon unit of an alkyl group is -NR L3a - has been replaced by; where R L3a is hydrogen or a substituted or unsubstituted C 1~6 alkyl; Y is O; and R E4 is unsubstituted or substituted C 1~6 and each instance of z is independently 0, 1, 2, or 3, valences permitting. 1 is the expression: [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, the warhead is represented by: [ka] In some embodiments, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, the warhead is represented by: [ka] In some embodiments, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, D 1 is the formula [ka] In one embodiment, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, R 3' is the formula [ka] In one embodiment, R 3' is the formula [ka] It is a warhead represented by.

[0144] In one embodiment, R 3 is a warhead represented by formula (i-1) to (i-23), (i-26) to (i-31), (i-34) to (i-40), (i-42), or (i-43). In some embodiments, the warhead is represented by formula [ka] In one embodiment, R 3 is the formula [ka] In one embodiment, R 3 is the formula [ka] In one embodiment, R 3 is the formula [ka] In one embodiment, R 3 is the expression: [ka] In one embodiment, R 3 is the expression: [ka] In one embodiment, L 3 is a bond. 3 In some embodiments, R E1 and R E2 is hydrogen. In some embodiments, R E1 , R E2 , and R E3 are all hydrogen. E3 is -CH2 NMe 2 It is.

[0145] In one embodiment, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, the warhead is represented by: [ka] In some embodiments, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, D 1 The Warhead is a formula [ka] In one embodiment, D 1 The Warhead is a formula [ka] In some embodiments, the warhead is represented by the formula [ka] It is expressed as:

[0146] In one embodiment, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, the warhead is represented by: [ka] In some embodiments, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] It is expressed as:

[0147] In one embodiment, the warhead has the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In one embodiment, D 1 is the formula [ka] In one embodiment, the warhead is represented by D 1 is the formula [ka] In one embodiment, the warhead is represented by the formula [ka] In one embodiment, D 1 The Warhead is a formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] In some embodiments, the warhead is represented by the formula [ka] It is expressed as:

[0148] In one embodiment, L 3 is a bond (e.g., a single bond, a double bond, or a triple bond). 3 is a single bond. 3 is a double bond. 3 is a triple bond. 3 is an arbitrarily substituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -C=O-, -O-, -S-, -NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O) 2 -, -S(=O) 2 O-, -OS(=O) 2 -, -S(=O) 2 NR L3a -, or -NR L3a S(=O) 2 -, where R L3a is hydrogen, substituted or unsubstituted C 1~6 alkyl, or a nitrogen protecting group, and L3beach occurrence is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R L3b The groups are linked to form an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring. 4 is a bond (e.g., a single bond, a double bond, or a triple bond). 4 is an optionally substituted branch C 1~6 In some embodiments, L is a hydrocarbon chain (e.g., i-Pr). 4 is an optionally substituted unbranched C 1~6 A hydrocarbon chain (e.g., n-Pr or n-Bu). In some embodiments, R E1 is H. In some embodiments, R E1 At least one instance of R is halogen (e.g., F, Cl, Br, or I). E1 At least one instance of R is optionally substituted alkyl (e.g., Me or Et). E1 At least one instance of R is optionally substituted alkenyl (e.g., optionally substituted vinyl). E1 is optionally substituted alkynyl. E1 At least one instance of R is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). E1 At least one instance of R is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl containing zero, one, or two double bonds in the heterocyclic ring system, where one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur).E1 At least one of R is substituted or unsubstituted aryl (e.g., substituted or unsubstituted 6- to 10-membered aryl). E1 is substituted or unsubstituted phenyl. E1 is a substituted or unsubstituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). E1 In one embodiment, at least one of R E1 In at least one of the cases, -CH 2 OR EE Here, R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. E In at least one of the cases 1 is -CH 2 N(R EF ) 2 or -N(R EF ) 2 Here, R EF is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and optionally wherein two R EF The groups are joined to form an optionally substituted heterocyclic ring. E1 In at least one of the cases, -CH 2 S.R. EE or -SR EE (For example, -CH 2In some embodiments, R E1 -OR if at least one of EE (For example, -OMe). In some embodiments, R E1 In at least one of the cases, -Si(R EG ) 3 Here, R EG Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl (e.g., -Si(Me) 3 ).

[0149] In one embodiment, R E2 is H. In some embodiments, R E2 At least one instance of R is halogen (e.g., F, Cl, Br, or I). E2 At least one instance of R is optionally substituted alkyl (e.g., Me or Et). E2 At least one instance of R is optionally substituted alkenyl (e.g., optionally substituted vinyl). E2 is optionally substituted alkynyl. E2 At least one instance of R is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). E2 At least one instance of R is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl containing zero, one, or two double bonds in the heterocyclic ring system, where one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). E2At least one of R is substituted or unsubstituted aryl (e.g., substituted or unsubstituted 6- to 10-membered aryl). E2 is substituted or unsubstituted phenyl. E2 is a substituted or unsubstituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). E2 In one embodiment, at least one of R E2 In at least one of the cases, -CH 2 OR EE Here, R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. E2 In at least one of the cases, -CH 2 N(R EF ) 2 or N(R EF ) 2 Here, R EF is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and optionally wherein two R EF The groups are joined to form an optionally substituted heterocyclic ring. E2 In at least one of the cases, -CH 2 S.R. EE or -SR EE (For example, -CH 2 In some embodiments, R E2-OR if at least one of EE (For example, -OMe). In some embodiments, R E2 In at least one of the cases, -Si(R EG ) 3 Here, R EG Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl (e.g., -Si(Me) 3 In some embodiments, R E3 is H. In some embodiments, R E3 At least one instance of R is halogen (e.g., F, Cl, Br, or I). E3 At least one instance of R is optionally substituted alkyl (e.g., Me or Et). E3 At least one instance of R is optionally substituted alkenyl (e.g., optionally substituted vinyl). E3 is optionally substituted alkynyl. E3 At least one instance of R is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). E3 In at least one of the cases, R is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl containing zero, one, or two double bonds in the heterocyclic ring system, where one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). E3 At least one of R is substituted or unsubstituted aryl (e.g., substituted or unsubstituted 6- to 10-membered aryl). E3is substituted or unsubstituted phenyl. E3 is a substituted or unsubstituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). E3 In one embodiment, at least one of R E3 In at least one of the cases, -CH 2 OR EE Here, R EE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. E3 In at least one of the cases, -CH 2 N(R EF ) 2 or -N(R EF ) 2 Here, R EF is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and optionally wherein two R EF The groups are joined to form an optionally substituted heterocyclic ring. E3 In at least one of the cases, -CH 2 S.R. EE or -SR EE (For example, -CH 2 In some embodiments, R E3 -OR if at least one of EE (For example, -OMe). In some embodiments, R E3In at least one of the cases, -Si(R EG ) 3 Here, R EG Each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl (e.g., -Si(Me) 3 In some embodiments, R E1 and R E3 are joined to form an optionally substituted carbocyclic ring (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). E1 and R E3 are joined to form an optionally substituted heterocyclic ring (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl containing zero, one, or two double bonds in the heterocyclic ring system, where one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R E2 and R E3 are joined to form an optionally substituted carbocyclic ring (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). E2 and R E3 are joined to form an optionally substituted heterocyclic ring (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl containing zero, one, or two double bonds in the heterocyclic ring system, where one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R E1 and R E2 are joined to form an optionally substituted carbocyclic ring (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system).E1 and R E2 are joined to form an optionally substituted heterocyclic ring (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl containing zero, one, or two double bonds in the heterocyclic ring system, where one, two, or three atoms in the heterocyclic ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R E4 is a leaving group (e.g., a halogen, or a sulfonate ester, e.g., -O (tosylate) or -O (mesylate)). In some embodiments, R E5 is halogen (e.g., F, Cl, Br, or I). In some embodiments, R E6 is H. In some embodiments, R E6 is a substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Bn, Et, perfluoroethyl, Pr, perfluoropropyl, Bu, or perfluorobutyl). E6 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, at least one instance of Y is O. In certain embodiments, at least one instance of Y is S. In certain embodiments, at least one instance of Y is NR E7 Here, R E7 is hydrogen, substituted or unsubstituted C 1~6 In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, at least one instance of z is 0. In some embodiments, at least one instance of z is 1. In some embodiments, at least one instance of z is 2. In some embodiments, at least one instance of z is 3. In some embodiments, at least one instance of z is 4. In some embodiments, at least one instance of z is 5. In some embodiments, at least one instance of z is 6.

[0150] In one embodiment, D 1 is a warhead represented by formula (i-1) to (i-19), (i-22), (i-23), (i-27) to (i-29), (i-34) to (i-29), or (i-43). 1 is the formula [ka] In one embodiment, the warhead is represented by D 1 is the formula [ka] In one embodiment, the warhead is represented by D 1 is the formula, [ka] In one embodiment, the warhead is represented by D 1 is the formula, [ka] It is a warhead represented by.

[0151] Linker X 1 Formula (IA) comprises ring B being represented by the formula: [ka] A linker X is attached to the moiety represented by 1 and formula (IB) includes ring B having the formula: [ka] A linker X is attached to the moiety represented by 1 Formula (II) includes ring B having the formula: [ka] A linker X is attached to the moiety represented by 1 Includes:

[0152] In some embodiments, in the compounds represented by formula (IA), (IB), and (II), X 1 is -O-, -O(alkylene)-, alkylene, -S-, -SCH 2 -, -N(R da )- or -N(R da )CH 2 - but here R da is as defined herein. In some embodiments, X 1 is -O-, -O(CH 2 ) 1~10 -, -(CH 2 ) 1~10 -, -S-, -SCH 2 -, -N(R da )- or -N(R da )CH 2 - but here R da is as defined herein. In some embodiments, X 1 is -O-, -O(CH 2 ) 1~6 -, -(CH 2 ) 1~6 -, -S-, or -N(R da )-, where R da is as defined herein.

[0153] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 is -O-.

[0154] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 is -O(alkylene)-. In some embodiments, X 1 -O(CR d ) 1~6 and R d is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN. d is hydrogen. d At least one instance of R is halogen (e.g., F, Cl, Br, or I). d At least one instance of R is optionally substituted acyl (e.g., -C(=O)Me). d At least one of the groups may be an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R d is alkyl optionally substituted with halogen. 2 In at least one of the cases, an optionally substituted C 1~6 In some embodiments, R d is substituted or unsubstituted methyl. d is substituted or unsubstituted ethyl. d is substituted or unsubstituted propyl. d At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R d At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R d At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). dis an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). d At least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). d is benzyl. d is substituted or unsubstituted phenyl. d is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R d -OR if at least one of c1 (e.g., -OH or -OMe). In some embodiments, R d If at least one of the following is true, then -N(R c2 ) 2 (For example, -NMe 2 In some embodiments, R d -SR if at least one of c1 (For example, -SMe). In some embodiments, R d -NO if at least one of 2 In some embodiments, R d In one embodiment, at least one of R d At least one of the cases is -SCN.

[0155] In some embodiments, in the compound represented by formula (IA) or (IB), X 1is the expression: [ka] Represented by;l C is the expression: [ka] indicates the point of attachment to the part represented by l; and B indicates the point of attachment to ring B; and n1 is 1, 2, 3, 4, 5, or 6. In some embodiments, X 1 is the expression: [ka] Represented by;l C is the expression: [ka] indicates the point of attachment to the part represented by l; and B indicates the point of attachment to ring B; and n1 is 1, 2, 3, or 4. In some embodiments, X 1 is the expression: [ka] Represented by;l C is the expression: [ka] indicates the point of attachment to the part represented by l; and B indicates the point of attachment to ring B; and n1 is 1, 2, 3, 4, 5, or 6. In some embodiments, X 1 is the expression: [ka] Represented by;l C is the expression: [ka] indicates the point of attachment to the part represented by l; and Bindicates the point of attachment to ring B; and n1 is 1, 2, 3, 4, 5, or 6. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n1 is 1, 2, 3, or 4. In some embodiments, n1 is 1, 2, or 3. In some embodiments, X 1 is the expression: [ka] In one embodiment, X 1 is the expression: [ka] It is expressed as:

[0156] In one embodiment, in the compound represented by formula (II), X 1 is the expression: [ka] Represented by;l A is the expression: [ka] indicates the point of attachment to the part represented by l; and B indicates the point of attachment to ring B; and n1 is 1, 2, 3, 4, 5, or 6. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n1 is 1, 2, 3, or 4. In some embodiments, n1 is 1, 2, or 3. In some embodiments, X 1 is the expression: [ka] In one embodiment, X1 is the expression: [ka] In one embodiment, X 1 is the expression: [ka] It is expressed as:

[0157] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 is alkylene. In some embodiments, X 1 is -(CR d ) n1 - but here R d and n1 is as defined herein. In some embodiments, X 1 is -(CR d ) n1 - but here R d is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN; and n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 1 is -(CR d ) n1 - but here R d is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1, -CN, or -SCN; and n1 is 1, 2, 3, 4, 5, or 6. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n1 is 7. In some embodiments, n1 is 8. In some embodiments, n1 is 9. In some embodiments, n1 is 10. In some embodiments, n1 is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n1 is 1, 2, 3, 4, or 5. In some embodiments, n1 is 1, 2, 3, or 4. In some embodiments, n1 is 1, 2, or 3. In some embodiments, X 1 is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 In one embodiment, X 1 is -CH 2 In one embodiment, X 1 is -CH 2 -or-CH 2 CH 2 In one embodiment, X 1 is -CH 2 CH 2 In one embodiment, X 1 is -CH 2 CH 2 CH 2 -It is.

[0158] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 is -S-.

[0159] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 -SCH 2 -It is.

[0160] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 is -N(R da )-, where R da is as defined herein. In certain embodiments, R da is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group. da is hydrogen. In some embodiments, R da is optionally substituted acyl (e.g., -C(=O)Me). In some embodiments, R da is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R da is an optionally substituted methyl, an optionally substituted ethyl, an optionally substituted propyl, or an optionally substituted butyl. da is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In some embodiments, X 1 is -N(R da )- and R da is hydrogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), or a nitrogen protecting group. 1 is -N(R da )- and R da is hydrogen or an optionally substituted C 1~6 In some embodiments, X is alkyl. 1 is -NH-.

[0161] In some embodiments, in the compound of formula (IA), (IB), or (II), X 1 is -N(R da )CH 2 - but here R dais as defined herein (for example, -NHCH 2 In one embodiment, X 1 -NHCH 2 -It is.

[0162] Substituent R 2B Formula (IA) represents a moiety attached to ring C. [ka] As part of the substituent R 2B In some embodiments, R 2B is -N(R c2 ) 2 , -OR c1 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, where R c1 and R c2 is as defined herein. In certain embodiments, R 2B is -N(R c2 ) 2 (For example, -NH 2 In some embodiments, R 2B is -N(R c2 ) 2 and R c2 Each instance of is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or a nitrogen protecting group. 2B is -N(R c2 ) 2 (For example, -NH 2 In some embodiments, R 2B is -N(R c2 ) 2 and R c2Each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclyl. 2B is -N(R c2 ) 2 and R c2 Each instance of is independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl. 2B is -N(R c2 ) 2 and R c2 is hydrogen. 2B is -NH(R c2 ), where R c2 is optionally substituted alkyl or optionally substituted carbocyclyl. 2B is -NH(R c2 ), where R c2 is an arbitrarily substituted C 1~6 Alkyl or optionally substituted C 3~10 In some embodiments, R 2B is -NHMe or [ka] In some embodiments, R 2B In some embodiments, R 2B teeth, [ka] In some embodiments, R 2B -NMe 2 In some embodiments, R 2B -OR c1 (e.g., -OH or -OMe). In some embodiments, R 2B is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 2Bis alkyl optionally substituted with halogen. 2B In at least one of the cases, an optionally substituted C 1~6 In some embodiments, R 2B If at least one of 1~6 In some embodiments, R is an alkyl group optionally substituted with halogen. 2B is optionally substituted methyl. 2B is substituted or unsubstituted ethyl. 2B is substituted or unsubstituted propyl. 2B At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R 2B At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R 2B At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). 2B is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). 2B At least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). 2B is benzyl. 2B is substituted or unsubstituted phenyl. 2Bis an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0163] In some embodiments, in the compound of formula (IA), the compound has the formula: [ka] The moiety represented by the formula: [ka] where R 2B and R c2 is as described herein. In some embodiments, the formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] where R 2B is optionally substituted alkyl, and R c2 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl. [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] where R 2B is optionally substituted alkyl, and R c2 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl; and 1 is the formula [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R 2B is optionally substituted alkyl, and R c2 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl; and 1 is the formula [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R 2Bis optionally substituted alkyl, and R c2 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl; and 1 is the formula [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R 2B is optionally substituted alkyl, and R c2 In each case, hydrogen, optionally substituted C 1~6 alkyl, or optionally substituted carbocyclyl; and D 1 is the formula [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] It is expressed as:

[0164] Substituent R A1 Formula (IB) represents the moiety attached to ring C. [ka] As part of the substituent R A1 In some embodiments, R A1 is -O(R a2 ) or -N(R a3 ) 2 Here, R a2 and R a3 is as defined herein. In certain embodiments, R A1 is -O(R a2 ) (for example, -OH or -OMe). In some embodiments, R A1 In some embodiments, R A1 is not -OH. In some embodiments, R A1 -OR a2 and R a2 is hydrogen or an optionally substituted alkyl (e.g., an optionally substituted C alkyl group such as an optionally substituted methyl, an optionally substituted ethyl, an optionally substituted propyl, an optionally substituted butyl, etc. 1~6 In some embodiments, R A1 In some embodiments, R A1 In some embodiments, R A1 In some embodiments, R A1 is -O(isopropyl). In some embodiments, R A1 is -O(butyl). In some embodiments, R A1 is -O(n-butyl). In some embodiments, R A1 is -O(t-butyl). In some embodiments, R A1 is -O(i-butyl). In some embodiments, R A1 is -O(s-butyl). In some embodiments, R a2 is hydrogen. In some embodiments, R a2 is optionally substituted acyl (e.g., -C(=O)Me). In some embodiments, R a2 is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6In some embodiments, R a2 is substituted or unsubstituted methyl. In some embodiments, R a2 is substituted or unsubstituted ethyl. In some embodiments, R a2 is substituted or unsubstituted propyl. In some embodiments, R a2 is an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R a2 is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R a2 is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). a2 is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). a2 is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). In some embodiments, R a2 is benzyl. In some embodiments, R a2 is substituted or unsubstituted phenyl. In some embodiments, R a2 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R a2 is an oxygen protecting group.

[0165] In one embodiment, R A1 is -N(R a3 ) 2(For example, -NH 2 In some embodiments, R A1 is -N(R a3 ) 2 Here, R a3 At least one of the following is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (R a4 ) and R a4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl. A1 is -N(R a3 ) 2 Here, R a3 At least one of the following is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, or -SO 2 (R a4 ), and R a4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl. A1 is -N(R a3 ) 2 where R a3 At least one of the following is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, or -SO 2 (R a4 ), and R a4 is an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl. A1 is -NH(R a3 In some embodiments, R A1 is -NH(R a3 ), and Ra3 is as defined herein. In certain embodiments, R A1 is -NH(R a3 ), where R a3 is an arbitrarily substituted C 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, or -SO 2 (R a4 In some embodiments, R A1 teeth, [ka] , or -NMe 2 In some embodiments, R A1 is -NH(optionally substituted alkyl), -NH(optionally substituted carbocyclyl), or -NH(SO 2 (optionally substituted alkyl). In some embodiments, R A1 is -NH(optionally substituted C 1~6 Alkyl, -NH(optionally substituted C 3~10 carbocyclyl), or -NH(SO 2 (Arbitrarily substituted C 1~6 alkyl).

[0166] In one embodiment, R a3 is hydrogen. a3 At least one instance of R is optionally substituted acyl (e.g., -C(=O)Me). a3 At least one of the groups may be an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R a3 In at least one of the cases, an optionally substituted C 1~6 alkyl (e.g., optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl). In some embodiments, R a3 is substituted or unsubstituted methyl. a3is unsubstituted methyl. a3 In some embodiments, both of R a3 are unsubstituted methyl. a3 is substituted methyl. a3 is substituted or unsubstituted ethyl. a3 In some embodiments, at least one of R a3 At least one instance of R is substituted or unsubstituted butyl (e.g., n-butyl, s-butyl, isobutyl, t-butyl). a3 At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R a3 At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R a3 At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). a3 In at least one of the cases, an optionally substituted C 3~14 In some embodiments, R a3 In at least one of the cases, an optionally substituted C 3~10 In some embodiments, R a3 At least one of the following is optionally substituted with halogen: 3~10 Carbocyclyl, -OR c1 (Examples include -OH, -O(alkyl), -CN, -SCN, -NO 2 , or -N(R c2 ) 2 (For example, -NH2 Or -NMe 2 In some embodiments, R a3 At least one instance of R is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted pentyl, optionally substituted cyclohexyl, or optionally substituted cycloheptyl. a3 is optionally substituted cyclopropyl. a3 is unsubstituted cyclopropyl. a3 is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). a3 At least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). a3 is benzyl. a3 is substituted or unsubstituted phenyl. a3 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R a3 In at least one instance of R is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).a3 When there are two, they are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur), or a substituted or unsubstituted heteroaryl ring (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl, where one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl, where one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R a3 If at least one of the following is true, -SO 2 (R a4 ) (For example, -SO 2 Me, -SO 2 Et, [ka] In some embodiments, R a3 If at least one of the following is true, -SO 2 (R a4 ) (For example, -SO 2 Me, -SO 2 Et, -SO 2 (cyclopropyl). In some embodiments, R a3 If at least one of the following is true, -SO 2 (R a4 ), and R a4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted carbocyclyl. a3 If at least one of the following is true, -SO 2 (R a4 ), and R a4 is an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl. a3 If at least one of the following is true, -SO2 In some embodiments, R a3 If at least one of the following is true, then SO 2 Et. In some embodiments, R a3 If at least one of the following is true, -SO 2 Me, -SO 2 Et, or [ka] In some embodiments, R a3 is hydrogen, and R a3 In the other case, an arbitrarily substituted C 1~6 Alkyl, optionally substituted C 3~10 Carbocyclyl, or -SO 2 (R a4 In some embodiments, R a3 is hydrogen, and R a3 The other of the two is optionally substituted methyl, optionally substituted cyclopropyl, or -SO 2 The other case of Me. In some embodiments, R a3 Both of these can be expressed as C 1~6 In some embodiments, R a3 In some embodiments, both of R a3 Both of are methyl.

[0167] In one embodiment, R a3 If at least one of the following is true, -SO 2 (R a4 ), and R a4 is as defined herein. In certain embodiments, R a4 is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R a4 is substituted or unsubstituted methyl. In some embodiments, R a4 is substituted or unsubstituted ethyl. In some embodiments, R a4is substituted or unsubstituted propyl. In some embodiments, R a4 is an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R a4 is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R a4 is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). a4 is an arbitrarily substituted C 3~7 In some embodiments, R a4 is optionally substituted cyclopropyl. In some embodiments, R a4 is optionally substituted cyclobutyl. In some embodiments, R a4 is optionally substituted cyclopentyl. In some embodiments, R a4 is an optionally substituted heterocyclyl (e.g., a substituted or unsubstituted 5-10 membered monocyclic or bicyclic heterocyclic ring, where one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). a4 is optionally substituted aryl (e.g., substituted or unsubstituted 6-10 membered aryl). In some embodiments, R a4 is benzyl. In some embodiments, R a4 is substituted or unsubstituted phenyl. In some embodiments, R a4 is an optionally substituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl where 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R a4At least one instance of R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted carbocyclyl. a4 At least one instance of is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

[0168] In some embodiments, the moiety attached to Ring C is [ka] As part of R A1 teeth, [ka] It is.

[0169] In some embodiments, in the compound of formula (IB), the compound of formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl). In some embodiments, in the compound of formula (IB), the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the formula [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; R a3 each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2(optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; and R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] In one embodiment, the warhead is represented by the formula: [ka] The moiety represented by the formula: [ka] where R a2 is hydrogen or optionally substituted alkyl; R a3 Each occurrence of is optionally hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or -SO 2 (optionally substituted alkyl); and D 1 is the expression: [ka] It is a warhead represented by.

[0170] In some embodiments, the formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] It is expressed as:

[0171] Ring A represented by formula (II) As generally defined herein, in formula (II), the moiety [ka] wherein ring A includes W and Z as defined herein, with the proviso that at least one of W and Z is -C(R a )= or -C(R b In some embodiments, W is -C(R a )= or -N=; and R a is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN. a is hydrogen. In some embodiments, R a is halogen (e.g., F, Cl, Br, or I). In some embodiments, R a is optionally substituted acyl (e.g., -C(=O)Me). In some embodiments, R a is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R a is alkyl optionally substituted with halogen. a is an arbitrarily substituted C 1~6 In some embodiments, R a is substituted or unsubstituted methyl. In some embodiments, R ais substituted or unsubstituted ethyl. In some embodiments, R a is substituted or unsubstituted propyl. In some embodiments, R a is an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R a is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R a is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). a -OR c1 (e.g., -OH or -OMe). In some embodiments, R a is -N(R c2 ) 2 (For example, -NMe 2 In some embodiments, R a -SR c1 (For example, -SMe). In some embodiments, R a -NO 2 In some embodiments, R a In some embodiments, R a is -SCN. In some embodiments, W is -CH= or -N=. In some embodiments, W is -CH=. In some embodiments, W is -N=.

[0172] In certain embodiments, in formula (II), Z is, as valence permits, -C(R b )= or -N=atom; and R b is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, -OR c1 , -NO 2 , -N(R c2 ) 2 , -SR c1 , -CN, or -SCN.b is hydrogen. In some embodiments, R b is halogen (e.g., F, Cl, Br, or I). In some embodiments, R b is optionally substituted acyl (e.g., -C(=O)Me). In some embodiments, R b is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R b is alkyl optionally substituted with halogen. b is an arbitrarily substituted C 1~6 In some embodiments, R b is substituted or unsubstituted methyl. In some embodiments, R b is substituted or unsubstituted ethyl. In some embodiments, R b is substituted or unsubstituted propyl. In some embodiments, R b is an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R b is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R b is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 10-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). b -OR c1 (e.g., -OH or -OMe). In some embodiments, R b is -N(R c2 ) 2 (For example, -NMe 2 In some embodiments, R b -SR c1 (For example, -SMe). In some embodiments, R b -NO 2 In some embodiments, R b In some embodiments, R bis -SCN. In some embodiments, Z is -CH= or -N=. In some embodiments, Z is -CH=. In some embodiments, Z is -N=.

[0173] In some embodiments, both Z and W are -CH=. In some embodiments, Z is -N= and W is -CH=. In some embodiments, Z is -CH= and W is -N=.

[0174] In certain embodiments, ring A has the formula: [ka] It is expressed as:

[0175] In one embodiment, the moiety [ka] A ring A, represented by 1 In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, the moiety [ka] In the formula (I), y is 0, 1, or 2. In some embodiments, the moiety [ka] In the above, y is 0 or 1. 1 At least one instance of R is halogen (e.g., F, Cl, Br, or I). 1 is -F. In some embodiments, y is 1 and R 1 is halogen (e.g., F, Cl, Br, or I). In some embodiments, R 1In one embodiment, at least one of R 1 is -F. In some embodiments, y is 1 and R 1 In some embodiments, R 1 In one embodiment, at least one of R 1 At least one instance of R is optionally substituted acyl (e.g., -C(=O)Me). 1 At least one of the groups may be an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 1 is alkyl optionally substituted with halogen. 1 In at least one of the cases, an optionally substituted C 1~6 In some embodiments, R 1 At least one of the following is optionally substituted with halogen: 1~6 In some embodiments, R 1 -CF if at least one of 3 In some embodiments, R 1 is substituted or unsubstituted methyl. 1 is substituted or unsubstituted ethyl. 1 is substituted or unsubstituted propyl. 1 At least one of the following may be an optionally substituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R 1 At least one of the following is an optionally substituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R 1At least one instance of R is an optionally substituted carbocyclyl (e.g., a substituted or unsubstituted 3- to 14-membered monocyclic carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system). 1 -OR if at least one of c1 (e.g., -OH or -OMe). In some embodiments, R 1 If at least one of the following is true, then -N(R c2 ) 2 (For example, -NMe 2 In some embodiments, R 1 -SR if at least one of c1 (For example, -SMe). In some embodiments, R 1 -NO if at least one of 2 In some embodiments, R 1 In one embodiment, at least one of R 1 At least one of the cases is -SCN.

[0176] In some embodiments, the formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] In one embodiment, the compound is represented by the formula: [ka] The moiety represented by the formula: [ka] It is expressed as:

[0177] Subgenus of compounds of formula (IA) In some embodiments, the compound of formula (IA) has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0178] In some embodiments, the compound of formula (IA) has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0179] In some embodiments, the compound of formula (IA) has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0180] In some embodiments, the compound of formula...

Claims

1. formula: 【Chemistry 1】 A compound represented by the formula: Ring B is cyclohexyl or phenyl; R 2 is optionally substituted alkyl; R 2B is -N(R c2 ) 2 is; R c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two R c2 together with their intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; X 1 is -O-, -O(alkylene)-, -N(R da )-, or -N(R da )CH 2 -, and when X 1 is -O(alkylene)- or -N(R da )CH 2 -, it is bonded to ring A at the -O or -N side; R da is hydrogen; m is 0 or 1; and D 1 teeth, 【Chemistry 2】 or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof.

2. When m is 1, R 2 is optionally substituted C 1～6 2. The compound of claim 1, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, wherein R is an alkyl group.

3. When m is 1, R 2 is -CF 3 3. The compound of claim 2, wherein:

4. R 2B The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, wherein

5. X 1 The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, wherein:

6. X 1 The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, wherein is -NH-.

7. X 1 But -O-CH 2 - and attached to ring A at the -O side, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof.

8. D 1 But the formula: 【Chemistry 3】 8. The compound according to any one of claims 1 to 7, wherein the compound is represented by the formula:

9. 4. The compound of formula: 【Chemistry 4】 2. The compound of claim 1, wherein the compound is:

10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, and a pharma- ceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, for use in treating a proliferative disease in a subject in need thereof.

12. A pharmaceutical composition for use in a method for the treatment of a proliferative disease in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, The pharmaceutical composition, wherein the method comprises administering the pharmaceutical composition to a subject.

13. The pharmaceutical composition according to claim 12, wherein the proliferative disease is cancer.

14. 14. The pharmaceutical composition of claim 13, wherein the cancer is sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, prostate cancer, pancreatic cancer, colon cancer, ovarian cancer, skin cancer, esophageal cancer, or carcinoma.

15. 15. The pharmaceutical composition of claim 14, wherein the sarcoma is Kaposi's sarcoma.

16. The pharmaceutical composition described in claim 14, wherein the lung cancer is non-small cell lung cancer or mesothelioma.

17. The pharmaceutical composition of claim 12, wherein the proliferative disease is an inflammatory disease or an autoimmune disease.

18. The pharmaceutical composition according to claim 17, wherein the inflammatory disease is fibrosis.

19. 18. The pharmaceutical composition according to claim 17, wherein the autoimmune disease is sclerosis.

20. A pharmaceutical composition for use in a method for inhibiting a transcription factor in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, The method includes administering the pharmaceutical composition to a subject; The pharmaceutical composition, wherein the transcription factor is TEAD1, TEAD2, TEAD3, or TEAD4.

21. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, solvate, or hydrate thereof, or a pharmaceutical composition according to claim 10 or 11; and Instructions for administering the active ingredient to a subject or for contacting a biological sample with the active ingredient. Including the kit.

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