Inhibitors of cyclin-dependent kinase 7 and their uses

Abstract

The present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3), or (II-4). The compounds of the present disclosure may be inhibitors of kinases (e.g., cyclin-dependent kinases (CDKs) (e.g., CDK7)). In some embodiments, the compounds disclosed herein are selective for inhibiting the activity of kinases (e.g., CDK7) over certain other kinases (e.g., CDK2, CDK9, CDK12). In some embodiments, the compounds do not bind to or inhibit the 5-hydroxytryptamine (5-HT) receptor. Also provided are pharmaceutical compositions, kits, methods of use, and uses involving the compounds disclosed herein. In some embodiments, the compounds are useful for inhibiting kinase activity, inhibiting cell growth, inducing cellular apoptosis, treating diseases, and / or preventing diseases (e.g., proliferative diseases, cystic fibrosis).

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 877,788, filed July 23, 2019, which is incorporated by reference in its entirety.

[0002] Government support This invention was made with Government support under Grant No. R01 CA179483 awarded by the National Institutes of Health and Grant No. W81XWH-16-1-0252 awarded by the Department of Defense. The Government has certain rights in this invention.

[0003] Background of the Disclosure Members of the cyclin-dependent kinase (CDK) family play critical regulatory roles in cell proliferation. Twenty mammalian CDKs are known. CDK7-CDK13 have been linked to transcription. CDK1, 2, 4 and 6 have been shown to be involved in the cell cycle. CDK7, unique among mammalian CDKs, aggregates kinase activity to regulate both the cell cycle and transcription. CDK7 exists in the cytosol as a heterotrimeric complex and is thought to function as a CDK1 / 2-activating kinase (CAK), such that phosphorylation of conserved residues in CDK1 / 2 by CDK7 is required for full catalytic CDK activity and cell cycle progression (Desai et al., "Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2," Mol. Cell Biol. 15, 345-350 (1995); Kaldis et al., "Analysis of CAK activities from human cells," Eur. J. Biochem. 267, 4213-4221 (2000); Larochelle et al., "Requirements for CDK7 in the assembly of CDK1 / cyclin B and activation of CDK2 revealed by chemical genetics in human cells," Mol. Cell, 25, 839-850 (2007)).CDK7 in the nucleus forms the kinase core of the RNA polymerase II general transcription factor complex and is responsible for phosphorylating the CTD of RNAP II, an essential step in the initiation of gene transcription (Serizawa.et al., "Association of CDK-activating kinase subunits with transcription factor TFIIH." Nature, 374, 280-282 (1995); Shiekhattar et al., "CDK-activating kinase complex is a component of human transcription factor TFIIH." Nature, 374, 283-287 (1995); Drapkin et al., "Human cyclin-dependent kinase-activating kinase exists in three distinct complexes." Proc. Natl. Acad. Sci. USA, 93, 6488-6493 (1996); Liu.et al., "Two cyclin-dependent kinases promote RNA polymerase II transcription and formation of the scaffold complex."Mol.CellBiol.,24,1721-1735(2004);Akhtar et al.,"TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II."Mol.Cell,34,387-393(2009);Glover-Cutter et al.,"TFIIH-associated CDK7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II."Mol. Cell Biol., 29, 5455-5464 (2009)).Taken together, the dual functions of CDK7, namely CAK and CTD phosphorylation, can support crucial aspects of cell proliferation, cell cycle, and transcription.

[0004] Disruption of RNAP II CTD phosphorylation is known to preferentially affect short-half-life proteins, including the anti-apoptotic BCL-2 family of proteins (Konig et al., "The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines." Blood, 1, 4307-4312 (1997); Gojo et al., "The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1." Clin. Cancer Res., 8, 3527-3538 (2002)). Cancer cells demonstrate the ability to evade pro-cell death signaling through upregulation of BCL-2 family members (Llambi et al., "Apoptosis and oncogenesis: give and take in the BCL-2 family." Curr. Opin. Genet. Dev., 21, 12-20 (2011)). Thus, inhibition of human CDK7 kinase activity is likely to result in anti-proliferative activity, and pharmacological inhibition may be useful for treating proliferative disorders, including cancer.Flavopiridol, a nonselective pan-CDK inhibitor targeting CTD kinases, has demonstrated efficacy in the treatment of chronic lymphocytic leukemia (CLL) but suffers from a poor toxicity profile (Lin et al., "Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease." J. Clin. Oncol., 27, 6012-6018 (2009); Christian et al., "Flavopiridol in chronic lymphocytic leukemia: a concise review." Clin. Lymphoma Myeloma, 9 Suppl. 3, S179-S185 (2009)). There remains a need for the treatment of CLL and other cancers with CDK inhibitors. Summary of the Invention

[0005] Summary of the Disclosure The present disclosure provides, in one aspect, a compound of formula (I), (II-1), (II-2), (II-3), or (II-4): [ka] The present invention provides compounds represented by the formula: and their pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs. The compounds of the present disclosure may inhibit the activity of kinases. In some embodiments, the kinase is a cyclin-dependent kinase (CDK) (e.g., CDK7). In some embodiments, the compounds of the present disclosure are useful for inhibiting the activity of kinases, inhibiting cell growth, and / or inducing apoptosis of cells. In some embodiments, the cell (e.g., the cell affected by or contacted with the compound) is a malignant cell or a precancerous cell. In some embodiments, the cell is in vivo or in vitro. Kinases are involved in a wide range of diseases in subjects (e.g., proliferative diseases, cystic fibrosis). The compounds of the present disclosure may also be useful for treating and / or preventing diseases in subjects in need thereof.

[0006] In some embodiments, the compounds of the present disclosure are more selective than other kinases (e.g., kinases other than CDK, kinases other than CDK7) for inhibiting the activity of CDK (e.g., CDK7). In some embodiments, the compounds of the present disclosure are more selective than CDK2, CDK9, and / or CDK12 for inhibiting the activity of CDK7. In some embodiments, the compounds of the present disclosure are more advantageous than non-selective kinase inhibitors or less selective kinase inhibitors for treating and / or preventing disease in subjects in need thereof. In some embodiments, the compounds of the present disclosure are more selective than other compounds (e.g., non-selective kinase inhibitors, less selective kinase inhibitors) for inhibiting the activity of CDK (e.g., CDK7) than other kinases (e.g., kinases other than CDK, kinases other than CDK7). Compared to other compounds, the compounds of the present disclosure may also be more potent, more effective, and / or less toxic when used to treat and / or prevent disease in a subject in need thereof, and / or may reduce the frequency of side effects, reduce the severity of side effects, increase subject compliance, and / or reduce resistance. Moreover, in some embodiments, the compounds of the present disclosure may be more soluble, more permeable, more stable in microsomes, and / or more bioavailable, and / or may exhibit improved pharmacokinetic properties compared to other compounds. In some embodiments, the compounds of the present disclosure may covalently modify a cysteine ​​residue (e.g., Cys312) of CDK7. Cys312 of CDK7 is unique compared to other CDKs and certain other kinases. In some embodiments, the moiety of the compounds of the present disclosure may be more soluble, more permeable, more stable in microsomes, and / or more bioavailable, and / or may exhibit improved pharmacokinetic properties compared to other compounds. In some embodiments, the compounds of the present disclosure may be covalently modified with a cysteine ​​residue (e.g., Cys312) of CDK7. Cys312 of CDK7 is unique compared to other CDKs and certain other kinases. In some embodiments, the moiety of the compounds of the present disclosure may be more soluble, more permeable, more stable in microsomes, and / or more bioavailable, and / or may exhibit improved pharmacokinetic properties compared to other compounds. [ka] reacts with cysteine ​​residues. Without wishing to be bound by any particular theory, the inventors hypothesize that the ability of certain compounds to covalently modify Cys312 of CDK7 contributes to one or more of the above advantages of these compounds over certain other compounds.

[0007] In some embodiments, the compounds do not bind to or inhibit 5-hydroxytryptamine (5-HT) receptors. The 5-HT receptor may be an unwanted off-target.

[0008] Exemplary compounds of the present disclosure include the following: [ka] [ka] [ka] [ka] [ka] [ka] and pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0009] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and, optionally, a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound. In some embodiments, the pharmaceutical composition comprises an additional pharmaceutical agent.

[0010] In another aspect, the disclosure provides a kit comprising a compound or pharmaceutical composition of the disclosure; and instructions for using the compound or pharmaceutical composition. In some embodiments, the instructions include prescribing information.

[0011] In another aspect, the disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the disclosure.

[0012] In another aspect, the disclosure provides a method of preventing a disease in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the disclosure.

[0013] In certain embodiments, the disease (e.g., a disease treated and / or prevented by the methods of the present disclosure) is a proliferative disease (e.g., a cancer, a benign neoplasm, a disease associated with angiogenesis, an inflammatory disease, an autoinflammatory disease, an autoimmune disease).

[0014] In another aspect, the present disclosure provides a method of inhibiting the activity of a kinase in a subject, biological sample, tissue, or cell, comprising administering to the subject or contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition of the present disclosure. In some embodiments, the kinase (e.g., the overall kinase activity inhibited by the compounds and pharmaceutical compositions) is a CDK (e.g., CDK7).

[0015] In another aspect, the disclosure provides a method of inhibiting cell growth comprising contacting a cell with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0016] In another aspect, the disclosure provides a method of inducing apoptosis in a cell, comprising contacting the cell with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0017] In another aspect, the disclosure provides a method of downregulating transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell, comprising administering to the subject or contacting the biological sample, tissue, or cell with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0018] In some embodiments, the cell is an abnormally proliferative cell (eg, a malignant or precancerous cell).

[0019] In another aspect, the disclosure provides uses of the disclosed compounds and pharmaceutical compositions, including, for example, in the disclosed methods.

[0020] The details of one or more aspects of the disclosure are set forth herein. Other features, objects, and advantages of the disclosure will be apparent from the detailed description, examples, and claims.

[0021] 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, 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 Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd 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.

[0022] The compounds of the present disclosure may contain one or more asymmetric centers, and therefore may exist in various isomeric forms, for example enantiomers and / or diastereomers.For example, in some embodiments, the compounds of the present disclosure are in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 196); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 197). The present disclosure additionally encompasses the compounds of the present disclosure as individual isomers substantially free of other isomers, or alternatively as mixtures of various isomers.

[0023] 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 , C6 , C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 It is intended to cover alkyl of the formula:

[0024] The term "aliphatic" includes both saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, substituted or unsubstituted with one or more functional groups. As will be appreciated by those skilled in the art, "aliphatic" is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes straight-chain, branched, and cyclic alkyl groups. Similar rules apply to other general terms such as "alkenyl," "alkynyl," and the like. Furthermore, the terms "alkyl," "alkenyl," "alkynyl," and the like encompass both substituted and unsubstituted groups.

[0025] In some embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-20 aliphatic carbon atoms. In some other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-10 aliphatic carbon atoms. In another other embodiment, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-8 aliphatic carbon atoms. In yet another embodiment, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-6 aliphatic carbon atoms. In another other embodiment, the alkyl, alkenyl, and alkynyl groups employed in the present disclosure contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -Cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -Cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -Cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties, etc., which again may bear one or more substituents. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl, etc.

[0026] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 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 1~7In 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, propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary 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. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogens such as F). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (unsubstituted C 1~6 Alkyl, e.g., -CH 3 In some embodiments, the alkyl group is a substituted C 1~10 Alkyl (substituted C 1~6 Alkyl, e.g., -CF 3) "Me" refers to unsubstituted methyl. "Et" refers to unsubstituted ethyl. "Pr" refers to unsubstituted propyl. "Bu" refers to unsubstituted butyl. "Bn" refers to unsubstituted benzyl.

[0027] "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 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 ("C 2~6 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 two carbon atoms ("C 2 In some embodiments, the one or more carbon-carbon double bonds are internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2~4 Examples of alkenyl groups are ethenyl (C, 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 above-mentioned C2~4 Alkenyl and pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 An additional example of an alkenyl is heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently substituted or unsubstituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In some embodiments, the alkenyl group is a substituted C 2~10 Alkenyl. In an alkenyl group, there is a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH 3 or [ka] may be an (E)-double bond or a (Z)-double bond.

[0028] "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 ("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 2~6In 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, the one or more carbon-carbon triple bonds are internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2~4 Examples of alkynyl groups include, without limitation, ethynyl (C, 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 above-mentioned C 2~4 Alkynyl and pentynyl (C 5 ), Hexynyl (C 6 An additional example of an alkynyl is heptynyl (C 7 ), Octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently substituted or unsubstituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In some embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0029] "Carbocyclyl" or "carbocyclic" means a ring structure having from 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8In 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 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). 3~6 Carbocyclyl groups include, but are not limited to, 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 may be any of the above-mentioned C 3~6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), 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. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused ring system, such as a bicyclic, bridged, or spiro ring system ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also encompasses ring systems in which a carbocyclic ring is fused with one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the carbocyclic ring, and in such instances the number of carbons is designated through the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently substituted or unsubstituted, 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 It is a carbocyclyl.

[0030] 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 3~8 In 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 5 ) 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 It is cycloalkyl.

[0031] "Heterocyclyl" or "heterocyclic" refers to the 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 nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In some embodiments, the point of attachment in a heterocyclyl group containing one or more nitrogen atoms is a carbon or nitrogen atom, where valence permits. In some embodiments, a heterocyclyl group is monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl"), saturated or partially unsaturated. A heterocyclyl bicyclic ring system can include one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclic ring is fused to one or more carbocyclyl groups as defined above (where the point of attachment is on either the carbocyclyl ring or the heterocyclic ring), or to one or more aryl or heteroaryl groups as defined above (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 heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently substituted or unsubstituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0032] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] 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 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, 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 6 Exemplary 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.

[0034] "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 ("C 6 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 substituted or unsubstituted, 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 Aryl. "Ph" refers to unsubstituted phenyl.

[0035] "Aralkyl" refers to an alkyl group substituted or unsubstituted with a substituted or unsubstituted aryl group. In some embodiments, the aralkyl is substituted or unsubstituted benzyl. In some embodiments, the aralkyl is benzyl. In some embodiments, the aralkyl is substituted or unsubstituted phenethyl. In some embodiments, the aralkyl is phenethyl.

[0036] "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 the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, in heteroaryl groups containing one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" encompasses ring systems in which a heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the point of attachment is on the heteroaryl ring. In such instances, the number of ring members is designated through the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring is fused with one or more aryl groups, as defined above, but where the point of attachment is on either the aryl or heteroaryl ring. In such instances, the number of ring members is designated as the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In some embodiments, in bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment is on either ring, i.e., either the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0037] 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 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 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 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 substituted or unsubstituted, 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.

[0038] 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.

[0039] "Heteroaralkyl" is a subset of alkyl and heteroaryl, and refers to a substituted or unsubstituted alkyl group substituted by a substituted or unsubstituted heteroaryl group.

[0040] "Unsaturated" or "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 having multiple sites of unsaturation, but are not intended to encompass aromatic groups (e.g., aryl or heteroaryl groups). Similarly, "saturated" refers to a group that contains no double or triple bonds, i.e., all single bonds.

[0041] When the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are divalent linking groups, the suffix -ene is used and they are further referred to as, for example, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

[0042] Unless expressly provided otherwise, any atom, moiety, or group described herein may be unsubstituted or substituted, where valences permit.

[0043] Groups are substituted or unsubstituted unless expressly provided otherwise. The terms "substituted, unsubstituted" refer to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are 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" 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 that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent (e.g., a substituent that upon substitution results in a stable compound (e.g., a compound that does not spontaneously transform, such as by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position in any given structure, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations to arrive at a stable compound. For purposes of this disclosure, 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. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

[0044] Exemplary carbon atom substituents are halogen, -CN, -NO 2 , -N3 、-SO 2 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 bb SO 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) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(R bb ) 2 、-P(=O)(NR bb ) 2 、-OP(=O)(NR bb ) 2 、-NR bb P(=O)(OR cc ) 2 、-NR bb P(=O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -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, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group; or the two geminal hydrogens on the carbon atom are substituted with the groups =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb 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, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aaThe groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, 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 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, 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 bbThe groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc each occurrence independently represents hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, 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 cc The groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, 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) 2 R ee 、-P(=O)(R ee ) 2 、-OP(=O)(R ee ) 2 、-OP(=O)(OR ee ) 2 、C 1~6Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, 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, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg group or two geminal R dd the substituents combine to form =O or =S; R ee In each case, independently, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, 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, 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, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R gg 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) 2 (C 1~6 alkyl), -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, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R gg The substituents combine to form =O or =S; where X - is the counter ion.

[0045] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions are halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , 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.), and carboxylate ions (e.g., acetic acid, ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, glyconic acid, etc.).

[0046] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0047] "Acyl" is -C(=O)Raa , -CHO, -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 , -C(=O)NR bb SO 2 R aa , -C(=S)N(R bb ) 2 , -C(=O)SR aa , or -C(=S)SR aa where R aa and R bb is as defined herein.

[0048] Nitrogen atoms may be substituted or unsubstituted, where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. In some embodiments, each nitrogen atom substituent is selected from 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) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, 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 attached to the nitrogen atom cc 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, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc , and R dd is as defined above.

[0049] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). In some embodiments, each nitrogen protecting group is -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(Rcc ) 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 , 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 comprises 0, 1, 2, 3, 4, or 5 R dd group, where 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 PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0050] For example, in some embodiments, the at least one nitrogen protecting group is 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, an amide group (e.g., —C(═O)R ) independently selected from cetoamide, 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-nitrocinnamic acid amide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide; aa ).

[0051] In some embodiments, the at least one nitrogen protecting group is methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl 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 (Tro c), 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 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 (Noc), 1-hydroxy-1-methyl-1-pyridyl carbamate (Noc), 1-hydroxy-1-methyl ... esters, alkyl dithiocarbamates, benzyl carbamates (Cbz), p-methoxybenzyl carbamates (Moz), p-nitrobenzyl carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-dichlorobenzyl carbamates, 4-methylsulfinylbenzyl carbamates (Msz), 9-anthrylmethyl carbamates, diphenylmethyl carbamates, 2-methylthioethyl carbamates, 2-methylsulfonylethyl carbamates, 2-(p-toluenesulfonyl)ethyl carbamates, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (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-benzoisoxazolylmethyl 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,A carbamate group (e.g., -C(=O)OR, aa ) selected independently from 6-trimethylbenzylcarbamate.

[0052] In some embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., -S(=O) 2 R aa ) selected independently 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-trimethylbenzenesulfonamide (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.

[0053] In some embodiments, the at least one nitrogen protecting group is 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-dimethylpyrrole, N-1,1,4,4-tetramethylphenylphenylamine, N-phenylpropanediol ... Trimethyldisilylazacyclopentane 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-pyrrolidine) N-phenyl-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-dimethylamine 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-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).

[0054] In some embodiments, each oxygen atom substituent is -R aa , -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 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb )2 , and -P(=O)(NR bb ) 2 where R aa , R bb , and R cc is as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a "hydroxyl protecting group"). Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Hut, 3 rdedition, John Wiley & Son, 1999, incorporated herein by reference. In some embodiments, the at least one oxygen protecting group is methyl, t-butyloxycarbonyl (BOC or Boc), 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 (PO M), 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]-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-trichloroethyl, 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-(dibromo methyl)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). ,

[0055] In some embodiments, at least one sulfur atom substituent is -R aa , -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 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 where R aa , R bb , and R cc is as defined herein. In certain embodiments, the sulfur atom substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wut, 3 rd edition, John Wiley & Son, 1999, incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0056] The term "leaving group" is given its ordinary meaning in the art of organic chemical synthesis and refers to an atom or group that can be displaced by a nucleophile. In some embodiments, the at least one leaving group is independently selected from 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 haloformate. In some embodiments, the at least one leaving group is independently selected from toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O) 2 (CF 3 CF 3 (nonaflate, -ONf), or sulfonic acid ester, such as trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the at least one leaving group is independently selected from a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the at least one leaving group is independently selected from a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the at least one leaving group is independently selected from a phosphine oxide (e.g., formed during the Mitsunobu reaction), or an internal leaving group, such as an epoxide or a cyclic sulfate. In some embodiments, the at least one leaving group is independently selected from water, ammonia, alcohol, an ether moiety, a thioether moiety, a zinc halide, a magnesium moiety, a diazonium salt, and a copper moiety.

[0057] The term "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the bounds of sound medical wisdom, without excessive toxicity, irritation, allergic responses, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutical 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.

[0058] The term "solvate" refers to a form of a compound associated with a solvent, usually through a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared in crystalline form, for example, and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some instances, a 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.

[0059] The term "hydrate" refers to a compound that is associated with water. Typically, a hydrate of a compound contains a fixed ratio of the number of water molecules to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may have 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)) Contains.

[0060] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal shift of a hydrogen atom and at least one change in valence (by way of example, single bond to double bond, triple bond to single bond, or vice versa). The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a pair of tautomers) may be catalyzed by an acid or a base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different) enamine tautomerizations.

[0061] It will also be understood that compounds having the same molecular formula but differing in the nature or order of bonding of their atoms, or the arrangement of those atoms in space, are called "isomers". Isomers that differ in the arrangement of those atoms in space are called "stereoisomers".

[0062] Stereoisomers that are not mutual mirror images 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 can be characterized by the absolute configuration of their asymmetric center and are described by the Cahn and Prelog R and S ranking rules, or by the manner in which the molecule rotates the plane of polarization, and are designated as dextrorotatory or levorotatory (i.e., as the (+) or (-) isomers, respectively). A chiral compound can exist as either individual enantiomers or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0063] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) in a specific crystal packing arrangement. 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.

[0064] The term "co-crystal" refers to a crystal structure composed of at least two components. In some embodiments, the co-crystal may contain a compound of the present disclosure and one or more other components, including atoms, ions, molecules, or solvent molecules. In some embodiments, the co-crystal may contain a compound of the present disclosure and one or more components related to the compound, including isomers, tautomers, salts, solvates, hydrates, synthetic precursors, synthetic derivatives, fragments, or impurities of the compound.

[0065] The term "isotopically labeled derivative" or "isotopically labeled" refers to a compound in which one or more atoms in the compound (or in the associated ions or molecules of a salt, hydrate, or solvate) are replaced with an isotope of the same element. For a given element or position in a molecule, the isotope will be enriched or present in a higher percentage of the total atoms of the element in the molecule in a sample, or in a higher percentage of the total atoms at that position, compared to an unlabeled variant. In some embodiments, the enriched isotope will be a stable isotope. In some embodiments, the enriched isotope will be an unstable or radioactive isotope (e.g., a radionuclide). In some embodiments, the enriched isotope may be detected by measurement techniques, including nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, or techniques that measure radioactive decay. An isotopically labeled derivative may be an isotope-labeled compound. Examples of isotopes are deuterium and 13 Contains C.

[0066] The term "prodrug" refers to a compound having a cleavable group that becomes the compounds described herein (which are pharmacologic in vivo) by solvolysis or under physiological conditions. Such examples include choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid derivative forms, but the acid-sensitive form often offers the advantage of solubility, tissue compatibility, or delayed release to mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid 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, C 2 ~C 8 Alkynyl, Aryl, C 6 ~C 12 Substituted aryl, and C 7 ~C 12 Arylalkyl esters are sometimes preferred.

[0067] 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 in a cell (e.g., activity of a cyclin-dependent kinase) relative to a vehicle.

[0068] When a compound, pharmaceutical composition, method, use, or kit is referred to as binding "selectively," "specifically," or "competitively" to a first protein or first chromatin, the compound, pharmaceutical composition, method, use, or kit binds to the first protein or first chromatin with a higher binding affinity (e.g., about 2-fold or more, about 5-fold or more, about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold or more) than it binds to a second protein or second chromatin that is different from the first protein and first chromatin. When a compound, pharmaceutical composition, method, use, or kit is referred to as one that "selectively," "specifically," or "competitively" modulates (e.g., increases or inhibits) the activity of a cyclin-dependent kinase, the compound, pharmaceutical composition, method, use, or kit modulates the activity of a cyclin-dependent kinase to a greater extent (e.g., by about 2-fold or more, about 5-fold or more, about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold or more) than the activity of at least one protein that is different from the cyclin-dependent kinase.

[0069] The term "abnormal activity" refers to an activity that deviates from normal activity, i.e., is not normal. The term "increased activity" refers to an activity that is higher than normal activity.

[0070] The terms "composition" and "formulation" are used interchangeably.

[0071] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., a minor, a child, or an adolescent), or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)), or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey), a commercially relevant mammal (e.g., a cattle, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, such as a chicken, a duck, a goose, or a turkey)). In some embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic animal or a genetically modified animal. A "patient" refers to a human subject in need of treatment for a disease. The subject may also be a plant. In some embodiments, the plant is a terrestrial plant. In some embodiments, the plant is a non-vascular terrestrial plant. In some embodiments, the plant is a vascular terrestrial plant. In some embodiments, the plant is a seed plant. In some embodiments, the plant is a cultivated plant. In some embodiments, the plant is a dicotyledonous plant. In some embodiments, the plant is a monocotyledonous plant. In some embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, such as maize, corn, wheat, rice, oats, barley, rye, or millet. In some embodiments, the plant is a legume, such as a bean plant, such as a soybean plant. In some embodiments, the plant is a tree or shrub.

[0072] 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, or 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 another biological sample.

[0073] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into, into, or onto a subject.

[0074] The terms "treatment", "treat" and "treating" refer to arresting, alleviating, delaying the onset or inhibiting the progression of a disease as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay and / or prevent recurrence.

[0075] The terms "disease," "disease," and "disorder" are used interchangeably.

[0076] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response, i.e., to treat a disease. An effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the subject. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is a prophylactic treatment. In some embodiments, an effective amount is the amount of a compound described herein in a single dose. In some embodiments, an effective amount is the combined amount of a compound described herein in multiple doses.

[0077] A "therapeutically effective amount" of a compound described herein 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 avoids symptoms, signs, or causes of a disease, and / or an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0078] 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 therapeutic agent alone, or in combination with other agents, that 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.

[0079] "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; 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, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases.

[0080] The term "angiogenesis" refers to the physiological process by which new blood vessels are formed from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesodermal cell precursors. The first blood vessels in the developing embryo are formed through vasculogenesis, and angiogenesis is subsequently responsible for most blood vessel growth during normal and abnormal development. Angiogenesis is an essential process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign to a malignant state, which has led to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis can also be chemically stimulated by angiogenic proteins such as growth factors (e.g., VEGF). "Pathological angiogenesis" refers to abnormal (e.g., excessive or insufficient) angiogenesis that results in and / or is associated with disease.

[0081] 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 lipomas, chondromas, adenomas, acrochordons, senile hemangiomas, seborrheic keratosis, lentigines, and sebaceous hyperplasias. 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 a primary or 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 or 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.

[0082] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to invade and destroy normal body tissue. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include hematological malignancies. Additional exemplary cancers include 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, triple-negative breast cancer (TNBC)); 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. stomach adenocarcinoma) 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));heavy chain disease (e.g. alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma;hypopharyngeal cancer;inflammatory myofibroblastic tumor;immunocytic amyloidosis;kidney cancer (e.g. nephroblastoma, also known as Wilms tumor, renal cell carcinoma);liver cancer (e.g. hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma);Lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic 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 leukocytosis ... myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, ductal internal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasm; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendix 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 cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva);

[0083] The term "hematological malignancies" refers to tumors that affect the blood, bone marrow, and / or lymph nodes. Exemplary hematological malignancies include 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., These include diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL)), B-cell NHL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosal intralymphoid tissue (MALT) lymphoma, muscular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary Lymphomas, such as primary mediastinal B-cell lymphoma, Burkitt's lymphoma, Van derström's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, central nervous system (CNS) lymphomas (e.g., primary CNS lymphoma and secondary CNS lymphoma); and precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) lymphomas of immune privileged sites (e.g., cerebral lymphoma, ocular lymphoma, placental lymphoma, fetal lymphoma, testicular lymphoma); one or more mixed types of leukemia / lymphoma as described above; myelodysplasia; and multiple myeloma (MM).

[0084] 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, These include connective tissue inflammation, 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 enterocolitis.

[0085] "Autoimmune disease" refers to a disease resulting from an abnormal immune response of the subject's body to substances and tissues that are 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 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-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0086] The term "kinase" is a type of enzyme that transfers a phosphate group from a high-energy donor molecule, such as ATP, to a specific substrate (a process called phosphorylation). Kinases are part of a larger family of phosphotransferases. One of the largest groups of kinases are protein kinases, which act on specific proteins to modify their activity. Kinases are used to transmit signals widely in cells to control complex processes. Various other kinases act on small molecules, such as lipids, carbohydrates, amino acids, and nucleotides, either to signal or to prime those involved in metabolic pathways. Kinases are often named after their substrates. Over 500 different protein kinases have been identified in humans. Exemplary human protein kinases include AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1, CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3, C DK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, C DKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1, CLK2, CLK2ps,CLK3、CLK3ps、CLK4、COT、CRIK、CRK7、CSK、CTK、CYGD、CYGF、DAPK1、DAPK2、DAPK3、DCAMKL1、DCAMKL2、DCAMKL3、DDR1、DDR2、DLK、DMPK1、DMPK2、DRAK1、DRAK2、DYRK1A、DYRK1B、DYRK2、DYRK3、DYRK4、EGFR、EphA1、EphA10、EphA2、EphA3、EphA4、EphA5、EphA6、EphA7、EphA8、EphB1、EphB2、EphB3、EphB4、EphB6、Erk1、Erk2、Erk3、Erk3ps1、Erk3ps2、Erk3ps3、Erk3ps4、Erk4、Erk5、Erk7、FAK、FER、FERps、FES、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1、FLT1ps、FLT3、FLT4、FMS、FRK、Fused、FYN、GAK、GCK、GCN2、GCN22、GPRK4、GPRK5、GPRK6、GPRK6ps、GPRK7、GSK3A、GSK3B、Haspin、HCK、HER2 / ErbB2、HER3 / ErbB3、HER4 / ErbB4、HH498、HIPK1、HIPK2、HIPK3、HIPK4、HPK1、HRI、HRIps、HSER、HUNK、ICK、IGF1R、IKKa、IKKb、IKKe、ILK、INSR、IRAK1、IRAK2、IRAK3、IRAK4、IRE1、IRE2、IRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR、KHS1、KHS2、KIS、KIT、KSGCps、KSR1、KSR2、LATS1、LATS2、LCK、LIMK1、LIMK2、LIMK2ps、LKB1、LMR1、LMR2、LMR3、LOK、LRRK1、LRRK2、LTK、LYN、LZK、MAK、MAP2K1、MAP2K1ps、MAP2K2、MAP2K2ps、MAP2K3、MAP2K4、MAP2K5、MAP2K6、MAP2K7、MAP3K1、MAP3K2、MAP3K3、MAP3K4、MAP3K5、MAP3K6、MAP3K7、MAP3K8、MAPKAPK2、MAPKAPK3、MAPKAPK5、MAPKAPKps1、MARK1、MARK2、MARK3、MARK4、MARKps01、MARKps02、MARKps03、MARKps04、MARKps05、MARKps07、MARKps08、MARKps09、MARKps10、MARKps11、MARKps12、MARKps13、MARKps15、MARKps16、MARKps17、MARKps1 8、MARKps19、MARKps20、MARKps21、MARKps22、MARKps23、MARKps24、MARKps25、MARKps26、MARKps27、MARKps28、MARKps29、MARKps30、MAST1、MAST2、MA ST3、MAST4、MASTL、MELK、MER、MET、MISR2、MLK1、MLK2、MLK3、MLK4、MLKL、MNK1、MNK1ps、MNK2、MOK、MOS、MPSK1、MPSK1ps、MRCKa、MRCKb、MRCKps、MSK1、MNK1 SK12、MSK2、MSK22、MSSK1、MST1、MST2、MST3、MST3ps、MST4、MUSK、MYO3A、MYO3B、MYT1、NDR1、NDR2、NEK1、NEK10、NEK11、NEK2、NEK2ps1、NEK2ps2、NEK2ps 3、NEK3、NEK4、NEK4ps、NEK5、NEK6、NEK7、NEK8、NEK9、NIK、NIM1、NLK、NRBP1、NRBP2、NuaK1、NuaK2、Obscn、Obscn2、OSR1、p38a、p38b、p38d、p38g、p70S6 K、p70S6Kb、p70S6Kps1、p70S6Kps2、PAK1、PAK2、PAK2ps、PAK3、PAK4、PAK5、PAK6、PASK、PBK、PCTAIRE1、PCTAIRE2、PCTAIRE3、PDGFRa、PDGFRb、PDK1、PEK 、PFTAIRE1、PFTAIRE2、PHKg1、PHKg1ps1、PHKg1ps2、PHKg1ps3、PHKg2、PIK3R4、PIM1、PIM2、PIM3、PINK1、PITSLRE、PKACa、PKACb、PKACg、PKCa、PKCb、PK Cd、PKCe、PKCg、PKCh、PKCi、PKCips、PKCt、PKCz、PKD1、PKD2、PKD3、PKG1、PKG2、PKN1、PKN2、PKN3、PKR、PLK1、PLK1ps1、PLK1ps2、PLK2、PLK3、PLK4、PRKXPRKXps, PRKY, PRP4, PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK (for example, SIK1, SIK, skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, img src, SRM, SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1 / HGK, ZC2 / TNIK, ZC3 / MINK, and ZC4 / NRK are included.,

[0087] The term "CDK" refers to cyclin-dependent kinases. CDKs bind to regulatory proteins, cyclins (e.g., cyclin H). CDKs phosphorylate their substrates at serine and threonine. The consensus sequence for phosphorylation sites in the amino acid sequence of CDK substrates is [S / T * ]PX[K / R] (SEQ ID NO: 1), where S / T * is a phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, and R is arginine. CDKs include CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19, and CDK20.

[0088] "CDK7" or "cyclin-dependent kinase 7" is a CDK whose substrates are cyclin H, MAT1 (e.g., MNAT1), or cyclin H and MAT1. CDK7 is alternatively referred to as CAK1, HCAK, MO15, STK1, CDKN7, and p39MO15. Non-limiting examples of the nucleotide and protein sequences of human CDK7 are set forth in GenBank Accession No. NP_001790, which is incorporated herein by reference. The amino acid sequence of this CDK7 is as follows: MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTALREIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLMTLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRAPELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDMCSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPGPTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF (SEQ ID NO: 2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0089] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE Kinases are implicated in a wide range of diseases. In particular, CDKs are master regulators of the cell cycle. Their sequential activation and inactivation drive the cycle forward. CDK activity is regulated by multiple mechanisms, including positive and negative phosphorylation, binding of regulatory proteins such as cyclins, and CDK inhibitors. CDK7 plays a critical role in regulating RNA polymerase II-mediated transcription of protein-coding genes. Disruption of CDK7 signaling can also cause transcriptional defects. The absence of selective inhibitors of CDK7 hampers investigation of the transcriptional and functional consequences of acute and long-term inhibition of CDK7 activity under normal and pathological conditions.

[0090] In one aspect, the present disclosure provides compounds represented by formula (I), (II-1), (II-2), (II-3) or (II-4), and pharma- ceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Compounds of the present disclosure may inhibit the activity of a kinase. In some embodiments, the kinase is CDK. In some embodiments, the kinase is CDK7. In some embodiments, the kinase is CDK2, CDK9, or CDK12. Compounds of the present disclosure may be selective in inhibiting the activity of a kinase (e.g., CDK7) over certain other kinases (e.g., CDK2, CDK9, CDK12). Also provided are pharmaceutical compositions, kits, methods of use, and uses involving compounds of the present disclosure. The compounds, pharmaceutical compositions, kits, methods of use, and uses of the present disclosure may be useful for inhibiting the activity of kinases, inhibiting cell growth, and / or inducing cell apoptosis.The compounds, pharmaceutical compositions, kits, methods of use, and uses of the present disclosure may also be useful for treating and / or preventing disease.In some embodiments, the disease is a proliferative disease (e.g., cancer, benign neoplasm, pathological angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease) or cystic fibrosis.

[0091] 5-hydroxytryptamine (5-HT) receptors modulate the release of many neurotransmitters and affect a variety of biological and neurological processes.Kinase inhibitors may be advantageous in that they do not inhibit 5-HT receptors.The compounds described herein will also have this advantage.

[0092] compound In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R 3 and R 4 Each of is independently hydrogen, halogen, substituted or unsubstituted C 1 ~C 6 alkyl, substituted or unsubstituted phenyl, or R 3 and R 4 combine to form a substituted or unsubstituted, monocyclic, 3- to 6-membered carbocyclyl; R 5 is a substituted or unsubstituted C 1 ~C 6 is an alkyl or substituted or unsubstituted carbocyclyl; [ka] -NR L1 C(=O)-, -C(=O)NR L1 -, -NR L1 -, -O-, -S-, -NR L1 -C(=O)-C(R L4 ) 2 -, -C(=O)-NR L1 -C(R L4 ) 2 -, -C(R L4 ) 2 -NR L1 -C(=O)-, -C(R L4 ) 2 -C(=O)-NR L1 -, -NR L1 -C(=O)-O-, -OC(=O)-NR L1 -,-NR L1 -C(=O)-NR L1 - or not present, where R L1 each occurrence independently represents hydrogen, substituted or unsubstituted C 1 ~C 6 alkyl, or a nitrogen protecting group, and R L4 Each occurrence of is independently hydrogen, halogen, or substituted or unsubstituted C1~6 or R L4 two of the above may be joined to form a substituted or unsubstituted, monocyclic, 3- to 6-membered carbocyclyl; Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 2 each occurrence independently represents halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR a , -N(R a ) 2 , -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a ) 2 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , -NO 2 , -NR a C(=O)Ra, -NR a C(=O)OR a , -NR a C(=O)N(R a ) 2 , -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2 is; R ais independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R a when two of the following are joined together to form a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valence permits; [ka] does not exist, -C(=O)-, -NR L2 -, -C(=O)NR L2 -, -NR L2 C(=O)-, -O-, or -S-, where R L2 is hydrogen, substituted or unsubstituted C 1 ~C 6 alkyl, or nitrogen protecting groups; Ring B is absent, carbocyclyl, heterocyclyl, aryl, or heteroaryl, provided that when Ring B is absent, L 2 does not exist; R 1 each occurrence independently represents halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR a , -N(R a ) 2 , -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a, -C(=NR a )N(R a ) 2 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , -NO 2 , -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a ) 2 , -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2 is; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, valence permitting; L 3 is absent or -NR L3a - where R L3a is hydrogen, substituted or unsubstituted C 1~6 is an alkyl, or nitrogen protecting group; R E1 is hydrogen or substituted or unsubstituted C 1~6 is alkyl; R E2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -CH 2 OR EE , -CH 2 N(R EE ) 2 , or -CH 2 S.R. EE is; R E3is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -CH 2 OR EE , -CH 2 N(R EE ) 2 , or -CH 2 S.R. EE is; R EE each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R EE the groups are joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; Ring C is a substituted or unsubstituted phenyl, or a substituted or unsubstituted, monocyclic, 5- or 6-membered heteroaryl; R 7 is hydrogen, halogen, or substituted or unsubstituted C 1~6 is alkyl; R 8 Each occurrence of is independently hydrogen, halogen, or substituted or unsubstituted C 1~6 alkyl or R 8 are joined together to form a substituted or unsubstituted, monocyclic, 3- to 6-membered carbocyclyl; and R 1N and R 2N Each of is independently hydrogen, substituted or unsubstituted C 1 ~C 6 alkyl, or a nitrogen protecting group, or R 1N and R 2N combine to form a substituted or unsubstituted, monocyclic, heterocyclyl or heteroaryl; provided that the compound has the formula: [ka] It is not expressed as:

[0093] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0094] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0095] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0096] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0097] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0098] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0099] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0100] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0101] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0102] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0103] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0104] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0105] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0106] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0107] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0108] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0109] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0110] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0111] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0112] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0113] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0114] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0115] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0116] In one embodiment, R 3 is hydrogen. In some embodiments, R 3 is a substituted or unsubstituted C 1~6 In some embodiments, R 3 is Me. In some embodiments, R 3 is a substituted methyl (e.g., methyl substituted with 1 to 3 halogens). 3 is -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 3 is Et. In some embodiments, R 3 is a substituted ethyl (e.g., ethyl substituted with one or more halogens). 3 is Pr or Bu. 3 is a substituted propyl (e.g., propyl substituted with one or more halogens) or a substituted butyl (e.g., butyl substituted with one or more halogens). In some embodiments, R 3 In some embodiments, R 3 is substituted phenyl. In some embodiments, R 3 is halogen, substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Et), -OH, -O(substituted or unsubstituted C 1~6 Alkyl) (e.g., -OMe, -OCF 3 , -OEt), or -CN.

[0117] In one embodiment, R 4 is hydrogen. In some embodiments, R 4 is a substituted or unsubstituted C1~6 In some embodiments, R 4 In some embodiments, R 4 is a substituted methyl (e.g., methyl substituted with 1 to 3 halogens). 4 is -CH 2 F, -CHF 2 , or -CF 3 In some embodiments, R 4 is Et. In some embodiments, R 4 is a substituted ethyl (e.g., ethyl substituted with one or more halogens). 4 is Pr or Bu. 4 is a substituted propyl (e.g., propyl substituted with one or more halogens) or a substituted butyl (e.g., butyl substituted with one or more halogens). In some embodiments, R 4 is Ph. In some embodiments, R 4 is substituted phenyl. In some embodiments, R 4 is halogen, substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Et), -OH, -O(substituted or unsubstituted C 1~6 Alkyl) (e.g., -OMe, -OCF 3 , -OEt), or -CN.

[0118] In one embodiment, R 3 and R 4 Each of 3 It is.

[0119] In one embodiment, R 3 and R 4 are bonded to substituted or unsubstituted (e.g., halogen, substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Et), -OH, -O(substituted or unsubstituted C1~6 Alkyl) (e.g., -OMe, -OCF 3 In one embodiment, R forms a monocyclic, 3-6 membered carbocyclyl, substituted or unsubstituted with one or more (e.g., 1 or 2) substituents independently selected from the group consisting of -OEt, -OCH ... 3 and R 4 are joined to form an unsubstituted, monocyclic, 3- to 6-membered carbocyclyl. 3 and R 4 are linked to form a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cyclohexyl. 3 and R 4 are linked to form a substituted or unsubstituted cyclopropyl. 3 and R 4 combine to form an unsubstituted cyclopropyl.

[0120] In one embodiment, R 5 is the unsubstituted C 1 ~C 6 In some embodiments, R 5 is the replaced C 1 ~C 6 In some embodiments, R 5 is a substituted or unsubstituted C in the case of halogen (e.g., one or more fluoro groups). 1~3 In some embodiments, R 5 is -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -C 2 H 5 In some embodiments, R 5 is -CH 3 In some embodiments, R 5 is a substituted methyl (e.g., methyl substituted with 1 to 3 halogens). In some embodiments, R 5 is -CH2 In some embodiments, R 5 -CHF 2 In some embodiments, R 5 -CF 3 In some embodiments, R 5 is Et. In some embodiments, R 5 is a substituted ethyl (e.g., ethyl substituted with one or more halogens). In some embodiments, R 5 is Pr or Bu. 5 is a substituted propyl (e.g., propyl substituted with one or more halogens) or a substituted butyl (e.g., butyl substituted with one or more halogens). In some embodiments, R 5 is unsubstituted pentyl or unsubstituted hexyl. In some embodiments, R 5 is a substituted pentyl (eg, pentyl substituted with one or more halogens) or a substituted hexyl (eg, hexyl substituted with one or more halogens).

[0121] In one embodiment, R 5 is a substituted or unsubstituted (e.g., halogen, substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Et), -OH, -O(substituted or unsubstituted C 1~6 Alkyl) (e.g., -OMe, -OCF 3 , -OEt), or -CN. In some embodiments, R 5 is unsubstituted, monocyclic, 3-6 membered carbocyclyl. 5 is a substituted, monocyclic, 3- to 6-membered carbocyclyl. 5 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. 5is substituted or unsubstituted cyclopropyl. In some embodiments, R 5 is unsubstituted cyclopropyl.

[0122] In one embodiment, R 3 , R 4 , and R 5 Each of is Me.

[0123] In some embodiments, the compounds disclosed herein include R 5 For example, in some embodiments, R 5 is enriched with respect to at least one isotope. In certain embodiments, the at least one isotope comprises deuterium.

[0124] In some embodiments, the compound has the formula: [ka] It is expressed as:

[0125] In one embodiment, [ka] -NR L1 In some embodiments, [ka] is -NHC(=O)-. In some embodiments, [ka] -NR L1 -OR-NR L1 -C(=O)-C(R L4 ) 2 In one embodiment, [ka] -NR L1 - (for example, -NH-). In some embodiments, [ka] -NR L1 -C(=O)-C(R L4 ) 2 In one embodiment, [ka] is -NH-C(=O)-CH 2 In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] is -C(=O)NR L1 - (for example, -C(=O)NH-). In some embodiments, [ka] is -O- or -S-. [ka] is -C(=O)-NR L1 -C(R L4 ) 2 -(For example, -C(=O)-NH-CH 2 -), -C(R L4 ) 2 -NR L1 -C(=O)-(for example, -CH 2-NH-C(=O)-), -C(R L4 ) 2 -C(=O)-NR L1 -(For example, -CH 2 -C(=O)-NH-), -NR L1 -C(=O)-O- (e.g., -NH-C(=O)-O-), -OC(=O)-NR L1 - (for example, -OC(=O)-NH-), or -NR L1 -C(=O)-NR L1 - (for example, -NH-C(=O)-NH-). In some embodiments, L 1 does not exist.

[0126] When the formulae described herein encompass more than one instance of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from one another.

[0127] In one embodiment, R L1 is hydrogen. L1 is hydrogen. L1 is not hydrogen. L1 In at least one of the cases, substituted or unsubstituted C 1 ~C 6 In some embodiments, R L1 At least one of the following is unsubstituted C 1 ~C 6 Alkyl (e.g., Me, Et). In some embodiments, R L1 At least one instance of R is Me. L1 In at least one of the cases, is a nitrogen protecting group (eg, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0128] In one embodiment, R L4 is hydrogen. L4is hydrogen. L4 is not hydrogen. L4 At least one of R is halogen (e.g., F, Cl, Br). L4 is F. In some embodiments, R L4 is F. In some embodiments, R L4 In at least one of the cases, substituted or unsubstituted C 1 ~C 6 In some embodiments, R L4 At least one of the following is unsubstituted C 1 ~C 6 Alkyl (e.g., Me, Et). In some embodiments, R L4 At least one instance of R is Me. L4 In at least one instance of R is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts). L4 Each instance of is independently hydrogen or halogen.

[0129] In one embodiment, R L4 In the two cases, they are linked together to form substituted or unsubstituted (e.g., halogen, substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Et), -OH, -O(substituted or unsubstituted C 1~6 Alkyl) (e.g., -OMe, -OCF 3 In one embodiment, R forms a monocyclic, 3- to 6-membered carbocyclyl, substituted or unsubstituted with one or more (e.g., 1 or 2) substituents independently selected from the group consisting of -OEt, -OCH ... L4 In some embodiments, R L4In the case of two of them, they combine to form a substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl. In certain embodiments, R L4 In the case of two of them, they combine to form a substituted or unsubstituted cyclopropyl. In certain embodiments, R L4 In the case of two of them, they combine to form an unsubstituted cyclopropyl.

[0130] In certain embodiments, ring A is carbocyclic. In certain embodiments, ring A is a monocyclic, 3- to 7-membered carbocyclic ring containing 0, 1, or 2 double bonds as allowed by valency in a carbocyclic ring system. In certain embodiments, ring A is a bicyclic, 5- to 13-membered carbocyclic ring containing 0, 1, 2, or 3 double bonds as allowed by valency in a carbocyclic ring system. In certain embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0131] In certain embodiments, ring A is heterocyclic. In certain embodiments, ring A is a monocyclic heterocyclic ring. In certain embodiments, ring A is a 3- to 7-membered monocyclic heterocyclic ring. In certain embodiments, ring A is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

[0132] In certain embodiments,

Chem.

Chem.

Chem.

[0133] In some embodiments, ring A is a 5-13 membered bicyclic heterocyclyl. In some embodiments, ring A is a heterocyclyl in which the heteroatom in the heterocyclic ring system is oxygen and / or nitrogen. In some embodiments, ring A is a heterocyclyl in which the heteroatom in the heterocyclic ring system is oxygen. In some embodiments, ring A is a heterocyclyl in which the heteroatom in the heterocyclic ring system is nitrogen.

[0134] In some embodiments, ring A is aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is naphthyl. In some embodiments, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0135] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0136] In some embodiments, ring A is heteroaryl. In some embodiments, ring A is monocyclic or bicyclic heteroaryl. In some embodiments, ring A is monocyclic, 5- or 6-membered heteroaryl. In some embodiments, ring A is furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyrazinyl or pyridazinyl. In some embodiments, ring A is bicyclic, 9- or 10-membered (e.g., 5,6-fused, 6,5-fused, or 6,6-fused) heteroaryl. In some embodiments, ring A is benzofuranyl, aza-benzofuranyl, diaza-benzofuranyl, benzothienyl, aza-benzothienyl, diaza-benzothienyl, indolyl, aza-indolyl, diaza-indolyl, isoindolyl, aza-isoindolyl, diaza-isoindolyl, benzoxazolyl, aza-benzoxazolyl, diaza-benzoxazolyl, benzothiazolyl, aza-benzothiazolyl, diaza-benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, or diaza-benzimidazolyl. In some embodiments, ring A is thieno[2,3-d]pyrimidinyl or thieno[3,2-d]pyrimidinyl. In some embodiments, ring A is isoquinolyl. In certain embodiments, Ring A is aza-isoquinolinyl, diaza-isoquinolinyl, quinolinyl, aza-quinolinyl, or diaza-quinolinyl. [ka] In one embodiment, [ka] In one embodiment, [ka] [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0137] In some embodiments, ring A is a phenyl fused to a monocyclic, 4-7 membered ring. In some embodiments, ring A is a phenyl fused to a monocyclic, 4-7 membered (e.g., monocyclic, 5 membered) carbocyclyl. In some embodiments, ring A is a phenyl fused to a monocyclic, 5- or 6-membered heterocyclyl. In some embodiments, ring A is a phenyl fused to a monocyclic, 5-membered heterocyclyl. In some embodiments, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0138] In one embodiment, R 2 At least one of R is halogen (e.g., F, Cl, Br, I). 2 is F. In some embodiments, R 2 At least one instance of R is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). 2 At least one instance of R is unsubstituted alkyl. 2 At least one of the following is unsubstituted C 1~6 In some embodiments, R 2 At least one instance of R is Me. 2 At least one instance of R is Et, Pr, or Bu.2 If at least one of 1~6 In some embodiments, R 2 At least one of the following is a substituted methyl (e.g., -CF 3 , -CF 2 H, -CFH 2 In some embodiments, R 2 If at least one of the following is true, then -CF 3 In some embodiments, R 2 At least one instance of R is a substituted ethyl, a substituted propyl, or a substituted butyl. 2 At least one instance of R is substituted or unsubstituted alkenyl. 2 At least one of the following may be a substituted or unsubstituted C 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). 2 At least one instance of R is substituted or unsubstituted alkynyl. 2 At least one of the following may be a substituted or unsubstituted C 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 2 At least one of R is substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system, as valences permit). 2 At least one instance of R is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 2 At least one of R is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 2At least one instance of R is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. 2 is substituted or unsubstituted aryl. 2 is substituted or unsubstituted phenyl. 2 At least one instance of R is substituted or unsubstituted naphthyl. 2 At least one instance of R is substituted or unsubstituted heteroaryl. 2 At least one of R is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. 2 At least one instance of R is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. 2 At least one instance of R is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 2 At least one of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. 2 If at least one of a (Examples include -OH, -O(substituted or unsubstituted, C 1~6 Alkyl) (e.g., -OMe, -OCF 3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 2 In one embodiment, at least one of R 2 If at least one of the following is true, then -SR a (Examples include -SH, -S(substituted or unsubstituted, C 1~6 Alkyl) (e.g., -SMe, -SCF 3 , -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 2 If at least one of -N(R a ) 2 (For example, -NH 2 , -NH(substituted or unsubstituted, C 1~6 alkyl) (e.g., -NHMe), or -N(substituted or unsubstituted, C 1~6 Alkyl)-(substituted or unsubstituted, C 1~6 alkyl) (e.g., -NMe 2 In some embodiments, R 2 In some embodiments, at least one of R 2 If at least one of the following is true, then -NO 2 In some embodiments, R 2 If at least one of the following is present, -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a ) 2 In some embodiments, R 2 If at least one of the following is true, then -C(=O)R a (e.g., -C(=O)(substituted or unsubstituted alkyl) (e.g., -C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In some embodiments, R 2 If at least one of the following is true, then -C(=O)OR a(e.g., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (e.g., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In some embodiments, R 2 If at least one of the following is true, then -C(=O)N(R a ) 2 (For example, -C(=O)NH 2 , -C(=O)NH(substituted or unsubstituted alkyl) (e.g., -C(=O)NHMe), -C(=O)NH(substituted or unsubstituted phenyl), -C(=O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or -C(=O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). 2 If at least one of the following is true, then -NR a C(=O)R a (For example, -NHC(=O)(substituted or unsubstituted C 1~6 alkyl) (e.g., -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). 2 If at least one of the following is true, then -NR a C(=O)OR a In some embodiments, R 2 If at least one of the following is true, then -NR a C(=O)N(R a ) 2 (For example, -NHC(=O)NH 2 , -NHC(=O)NH(substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 2 If at least one of the following is true, then -OC(=O)R a (Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (For example, -OC(=O)O (substituted or unsubstituted alkyl) or -OC(=O)O (substituted or unsubstituted phenyl)), or -OC(=O)N(R a )2 (For example, -OC(=O)NH 2 , -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH(substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or -OC(=O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).

[0139] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3, 4, or 5. In some embodiments, n is 5. In some embodiments, n is 6, 7, 8, 9, 10, or 11.

[0140] In one embodiment, R 2 At least one of the following is halogen, substituted or unsubstituted alkyl, -OR a , -N(R a ) 2 , -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a ) 2 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , -NO 2 , -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a ) 2 , -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2and n, where valence permits, is 1 or 2. In some embodiments, R 2 At least one of the following is halogen, substituted or unsubstituted C 1~6 Alkyl, or -O(substituted or unsubstituted C 1~6 In some embodiments, R 2 In at least one of the cases, halogen, one or more halogen-substituted or unsubstituted C 1~6 Alkyl, or -O(C substituted or unsubstituted with one or more halogens 1~6 alkyl).

[0141] In one embodiment, R a is hydrogen. a is hydrogen. a At least one of R a In some embodiments, R a At least one instance of R is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). a At least one instance of R is unsubstituted alkyl. a At least one of the following is unsubstituted C 1~6 In some embodiments, R a At least one instance of R is Me. a At least one instance of R is Et, Pr, or Bu. a If at least one of 1~6 In some embodiments, R a is substituted methyl. a At least one instance of R is a substituted ethyl, a substituted propyl, or a substituted butyl. aAt least one instance of R is substituted or unsubstituted alkenyl. a At least one of the following may be a substituted or unsubstituted C: 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). a At least one instance of R is substituted or unsubstituted alkynyl. a At least one of the following may be a substituted or unsubstituted C: 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R a At least one of R is substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system, as valences permit). a At least one instance of R is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. a At least one of R is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). a At least one instance of R is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. a is substituted or unsubstituted aryl. a is substituted or unsubstituted phenyl. a At least one instance of R is substituted or unsubstituted naphthyl.a At least one instance of R is substituted or unsubstituted heteroaryl. a At least one of R is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. a At least one instance of R is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. a At least one instance of R is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. a At least one of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. a At least one of R is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. a At least one of R, when attached to an oxygen atom, is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). a In some embodiments, R a In the two cases, they are combined to form a substituted or unsubstituted heteroaryl (eg, a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl).

[0142] In one embodiment, L 2 In one embodiment, L 2is -C(=O)- or -NR L2 In one embodiment, L 2 In some embodiments, L 2 -NR L2 - (for example, -NH-). In some embodiments, [ka] is -C(=O)NR L2 - (for example, -C(=O)NH-) or -NR L2 In some embodiments, L is -NHC(=O)- (for example, -NHC(=O)-). 2 is -O- or -S-.

[0143] In one embodiment, R L2 is hydrogen. In some embodiments, R L2 is a substituted or unsubstituted C 1~6 In some embodiments, R L2 is Me. In some embodiments, R L2 is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. L2 is a nitrogen protecting group (e.g., Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0144] In one embodiment, L 2 and Ring B are absent. In some embodiments, Ring B is carbocyclyl. In some embodiments, Ring B is a monocyclic, 3-7 membered carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system, as valences permit. In some embodiments, Ring B is a bicyclic, 5-13 membered carbocyclyl containing zero, one, two, or three double bonds in the carbocyclic ring system, as valences permit. In some embodiments, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0145] In some embodiments, ring B is heterocyclyl. In some embodiments, ring B is monocyclic heterocyclyl. In some embodiments, ring B is 3-7 membered monocyclic heterocyclyl. In some embodiments, ring B is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

[0146] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0147] In some embodiments, ring B is a 5-13 membered bicyclic heterocyclyl. In some embodiments, ring B is a heterocyclyl in which the heteroatom in the heterocyclic ring system is oxygen and / or nitrogen. In some embodiments, ring B is a heterocyclyl in which the heteroatom in the heterocyclic ring system is oxygen. In some embodiments, ring B is a heterocyclyl in which the heteroatom in the heterocyclic ring system is nitrogen.

[0148] In some embodiments, Ring B is aryl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is naphthyl. In some embodiments, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0149] In one aspect [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0150] In some embodiments, ring B is heteroaryl. In some embodiments, ring B is monocyclic or bicyclic heteroaryl. In some embodiments, ring B is monocyclic, 5- or 6-membered heteroaryl. In some embodiments, ring B is furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. In some embodiments, ring B is pyridinyl. In some embodiments, ring B is pyrimidinyl. In some embodiments, ring B is pyrazinyl or pyridazinyl. In some embodiments, ring B is bicyclic, 9- or 10-membered (e.g., 5,6-fused, 6,5-fused, or 6,6-fused) heteroaryl. In some embodiments, ring B is benzofuranyl, aza-benzofuranyl, diaza-benzofuranyl, benzothienyl, aza-benzothienyl, diaza-benzothienyl, indolyl, aza-indolyl, diaza-indolyl, isoindolyl, aza-isoindolyl, diaza-isoindolyl, benzoxazolyl, aza-benzoxazolyl, diaza-benzoxazolyl, benzothiazolyl, aza-benzothiazolyl, diaza-benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, or diaza-benzimidazolyl. In some embodiments, ring B is thieno[2,3-d]pyrimidinyl or thieno[3,2-d]pyrimidinyl. In some embodiments, ring B is isoquinolinyl. In certain embodiments, Ring B is aza-isoquinolinyl, diaza-isoquinolinyl, quinolinyl, aza-quinolinyl, or diaza-quinolinyl. [ka] In one embodiment, [ka] In one embodiment, [ka] [ka] In one embodiment, [ka] It is.

[0151] In some embodiments, ring B is phenyl fused to a monocyclic, 4-7 membered ring. In some embodiments, ring B is phenyl fused to a monocyclic, 4-7 membered (e.g., monocyclic, 5 membered) carbocyclyl. In some embodiments, ring B is phenyl fused to a monocyclic, 5- or 6-membered heterocyclyl. In some embodiments, ring B is phenyl fused to a monocyclic, 5-membered heterocyclyl.

[0152] In one embodiment, R 1 At least one of R is halogen (e.g., F, Cl, Br, I). 1 At least one instance of R is substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In some embodiments, R 1 At least one instance of R is unsubstituted alkyl. 1 At least one of the following is unsubstituted C 1~6 In some embodiments, R 1 At least one instance of R is Me. 1 is Et, Pr, or Bu. 1 If at least one of 1~6 In some embodiments, R 1 At least one of the following is a substituted methyl (e.g., -CF 3 , -CF2 H, -CFH 2 In some embodiments, R 1 is a substituted ethyl, a substituted propyl, or a substituted butyl. 1 In some embodiments, at least one of R 1 In at least one of the cases, substituted or unsubstituted C 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). 1 At least one instance of R is substituted or unsubstituted alkynyl. 1 In at least one of the cases, substituted or unsubstituted C 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 1 At least one of R is substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system, as valences permit). 1 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 1 At least one of R is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 1 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. 1is substituted or unsubstituted aryl. 1 is substituted or unsubstituted phenyl. 1 is substituted or unsubstituted naphthyl. 1 is substituted or unsubstituted heteroaryl. 1 At least one of R is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. 1 At least one instance of R is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 1 At least one instance of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. 1 -OR if at least one of a (Examples include -OH, -O(substituted or unsubstituted C 1~6 Alkyl) (e.g., -OMe, -OCF 3 , -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 1 In one embodiment, at least one of R 1 -SR if at least one of a (Examples include -SH, -S(substituted or unsubstituted C 1~6 Alkyl) (e.g., -SMe, -SCF 3, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 1 If at least one of -N(R a ) 2 (For example, -NH 2 , -NH(substituted or unsubstituted C 1~6 alkyl) (e.g., -NHMe), or -N(substituted or unsubstituted C 1~6 Alkyl)-(substituted or unsubstituted C 1~6 alkyl) (e.g., -NMe 2 In some embodiments, R 1 In one embodiment, at least one of R 1 -NO if at least one of 2 In some embodiments, R 1 In at least one of the cases, -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a ) 2 In some embodiments, R 1 In at least one of the cases, -C(=O)R a (e.g., -C(=O)(substituted or unsubstituted alkyl) (e.g., -C(=O)Me) or -C(=O)(substituted or unsubstituted phenyl)). In some embodiments, R 1 If at least one of the following is true, then -C(=O)OR a (e.g., -C(=O)OH, -C(=O)O(substituted or unsubstituted alkyl) (e.g., -C(=O)OMe), or -C(=O)O(substituted or unsubstituted phenyl)). In some embodiments, R 1 In at least one of the cases, -C(=O)N(R a ) 2 (For example, -C(=O)NH 2, -C(=O)NH(substituted or unsubstituted alkyl) (for example, -C(=O)NHMe), -C(=O)NH(substituted or unsubstituted phenyl), -C(=O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or -C(=O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)). In certain embodiments, R 1 In at least one of the cases, -NR a C(=O)R a (for example, -NHC(=O)(substituted or unsubstituted C 1~6 alkyl) (for example, -NHC(=O)Me) or -NHC(=O)(substituted or unsubstituted phenyl)). In certain embodiments, R 1 In at least one of the cases, -NR a C(=O)OR a In certain embodiments, R 1 In at least one of the cases, -NR a C(=O)N(R a ) 2 (for example, -NHC(=O)NH 2 , -NHC(=O)NH(substituted or unsubstituted C 1~6 alkyl) (for example, -NHC(=O)NHMe)). In certain embodiments, R 1 In at least one of the cases, -OC(=O)R a (for example, -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (for example, -OC(=O)O(substituted or unsubstituted alkyl) or -OC(=O)O(substituted or unsubstituted phenyl)), or -OC(=O)N(R a ) 2 (for example, -OC(=O)NH 2 , -OC(=O)NH(substituted or unsubstituted alkyl), -OC(=O)NH(substituted or unsubstituted phenyl), -OC(=O)N(substituted or unsubstituted alkyl)-(substituted or unsubstituted alkyl), or -OC(=O)N(substituted or unsubstituted phenyl)-(substituted or unsubstituted alkyl)).

[0153] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3, 4, or 5. In some embodiments, m is 5. In some embodiments, m is 6, 7, 8, 9, 10, or 11.

[0154] In one embodiment, R 1 At least one of the following is halogen, substituted or unsubstituted alkyl, -OR a , -N(R a ) 2 , -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a ) 2 , -C(=O)R a , -C(=O)OR a , -C(=O)N(R a ) 2 , -NO 2 , -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a ) 2 , -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2 and m is 1 or 2, as valence permits. 1 At least one of the following is halogen, substituted or unsubstituted C 1~6 Alkyl, or -O(substituted or unsubstituted C 1~6 In some embodiments, R 1 In at least one of the cases, halogen, one or more halogen-substituted or unsubstituted C 1~6Alkyl, or -O(C substituted or unsubstituted with one or more halogens 1~6 alkyl).

[0155] In one embodiment, L 3 In one embodiment, L 3 -NR L3a In one embodiment, L 3 In some embodiments, L 3 is -NMe-.

[0156] In one embodiment, R L3a is hydrogen. In some embodiments, R L3a is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R L3a is the unsubstituted C 1 ~C 6 Alkyl (e.g., Me, Et). In some embodiments, R L3a is Me. In some embodiments, R L3a is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0157] In one embodiment, R E1 is hydrogen. In some embodiments, R E1 is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R E1 is the unsubstituted C 1 ~C 6 Alkyl (e.g., Me, Et). In some embodiments, R E1 is Me.

[0158] In one embodiment, R E2 is hydrogen. In some embodiments, R E2 is a substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R E2is a substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R E2 is a substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R E2 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system, as valences permit). E2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). E2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl). In some embodiments, R E2 is a substituted or unsubstituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl). E2 In some embodiments, R E2 is -CH 2 OR EE (For example, -CH 2 O(substituted or unsubstituted C 1~6 Alkyl)) or -CH 2 S.R. EE (For example, -CH 2 S(substituted or unsubstituted C 1~6 In some embodiments, R E2 is -CH 2 N(R EE ) 2 In some embodiments, R E2 is -CH 2 N(substituted or unsubstituted C 1~6 Alkyl) 2 In some embodiments, R E2 is -CH 2 N(unsubstituted C 1~3 Alkyl) 2 In some embodiments, RE2 is -CH 2 N(CH 3 ) 2 It is.

[0159] In one embodiment, R E3 is hydrogen. In some embodiments, R E3 is a substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R E3 is a substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2~6 alkenyl). In some embodiments, R E3 is a substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2~6 alkynyl). In some embodiments, R E3 is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system, as valences permit). E3 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). E3 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl). In some embodiments, R E3 is a substituted or unsubstituted heteroaryl (e.g., a substituted or unsubstituted 5-6 membered monocyclic heteroaryl or a substituted or unsubstituted 9-10 membered bicyclic heteroaryl). E3 In some embodiments, R E3 is -CH 2 OR EE (For example, -CH 2 O(substituted or unsubstituted C 1~6 Alkyl)) or -CH 2 S.R. EE (For example, -CH 2 S(substituted or unsubstituted C 1~6 In some embodiments, R E3 is -CH2 N(R EE ) 2 In some embodiments, R E3 is -CH 2 N(substituted or unsubstituted C 1~6 Alkyl) 2 In some embodiments, R E3 is -CH 2 N(unsubstituted C 1~3 Alkyl) 2 In some embodiments, R E3 is -CH 2 N(CH 3 ) 2 It is.

[0160] In one embodiment, R E1 , R E2 , and R E3 Each of R is hydrogen. E1 is hydrogen and R E2 and R E3 is hydrogen, and R E2 and R E3 The other of the two is -CH 2 N(R EE ) 2 In some embodiments, R E1 is hydrogen and R E2 and R E3 is hydrogen, and R E2 and R E3 The other of the two is -CH 2 NMe 2 In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] It is.

[0161] In one embodiment, R EE is hydrogen. EE is hydrogen. EE In one embodiment, R EE In at least one of the cases, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R EE At least one of the following is unsubstituted C 1~3 In some embodiments, R EE Each instance of is substituted or unsubstituted alkyl. In some embodiments, R EE In each case, the unsubstituted C 1~3 In some embodiments, R EE At least one instance of R is substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl. EE At least one instance of R is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. EE In some embodiments, R EE The two cases combine to form a substituted or unsubstituted heteroaryl (eg, substituted or unsubstituted pyrrolyl).

[0162] In some embodiments, ring C is substituted or unsubstituted phenyl. In some embodiments, ring C is substituted (e.g., monosubstituted) phenyl. In some embodiments, ring C is unsubstituted phenyl. In some embodiments, ring C is substituted or unsubstituted, monocyclic, 5- or 6-membered heteroaryl. In some embodiments, ring C is substituted (e.g., monosubstituted), monocyclic, 5- or 6-membered heteroaryl. In some embodiments, ring C is unsubstituted, monocyclic, 5- or 6-membered heteroaryl. In some embodiments, ring C is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In some embodiments, ring C is substituted or unsubstituted pyrrolyl. In some embodiments, ring C is substituted or unsubstituted imidazolyl. In some embodiments, ring C is substituted or unsubstituted pyridinyl. In some embodiments, ring C is substituted or unsubstituted pyrimidinyl. In some embodiments, ring C is substituted or unsubstituted pyrazinyl. In some embodiments, ring C is substituted or unsubstituted pyridazinyl.

[0163] In one embodiment, [ka] or [ka] or [ka] In one embodiment, [ka] or [ka] or [ka] It is.

[0164] In one embodiment, R 7 is hydrogen. In some embodiments, R 7 is halogen (e.g., F, Cl). In some embodiments, R 7 is F. In some embodiments, R 7 is a substituted or unsubstituted C 1~6 In some embodiments, R 7 is C substituted with one or more halogens (e.g., one or more F). 1~6 In some embodiments, R 7 is the unsubstituted C 1~6 Alkyl (e.g., Me, Et). In some embodiments, R 7 is Me.

[0165] In one embodiment, R 8 is hydrogen. 8 is hydrogen. 8 At least one of R is halogen (e.g., F, Cl). 8 is F. In some embodiments, R 8 In at least one of the cases, substituted or unsubstituted C 1~6 In some embodiments, R 8 In at least one of the cases, C is substituted with one or more halogens (e.g., one or more F). 1~6 In some embodiments, R 8 At least one of the following is unsubstituted C 1~6 Alkyl (e.g., Me, Et). In some embodiments, R 8In at least one of the cases, it is Me.

[0166] In one embodiment, R 8 In the two cases, they are linked together to form substituted or unsubstituted (e.g., halogen, substituted or unsubstituted C 1~6 Alkyl (e.g., Me, -CF 3 , Et), -OH, -O(substituted or unsubstituted C 1~6 Alkyl) (e.g., -OMe, -OCF 3 In one embodiment, R forms a monocyclic, 3- to 6-membered carbocyclyl, which may be substituted or unsubstituted with one or more (e.g., 1 or 2) substituents independently selected from the group consisting of -OEt, -OCl ... 8 In some embodiments, R 8 may be joined to form a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cyclohexyl. 8 are joined to form a substituted or unsubstituted cyclopropyl. 8 The two cases combine to form an unsubstituted cyclopropyl.

[0167] In one embodiment, R 1N is hydrogen. In some embodiments, R 1N is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 1N is the unsubstituted C 1 ~C 6 In some embodiments, R 1N is Me. In some embodiments, R 1N is Et. In some embodiments, R 1N In some embodiments, R 1N In some embodiments, R 1N is the replaced C 1 ~C6 Alkyl (e.g., C substituted with one or more halogens (e.g., one or more F) 1 ~C 6 In some embodiments, R 1N is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0168] In one embodiment, R 2N is hydrogen. In some embodiments, R 2N is a substituted or unsubstituted C 1 ~C 6 In some embodiments, R 2N is the unsubstituted C 1 ~C 6 In some embodiments, R 2N is Me. In some embodiments, R 2N is Et. In some embodiments, R 2N In some embodiments, R 2N In some embodiments, R 2N is the replaced C 1 ~C 6 Alkyl (e.g., C substituted with one or more halogens (e.g., one or more F) 1 ~C 6 In some embodiments, R 2N is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0169] In one embodiment, R 1N and R 2N Each of 1 ~C 6 In some embodiments, R 1N and R 2N Each of 1 ~C 3 In some embodiments, R 1N and R 2N Each of 3In some embodiments, R 1N and R 2N are joined to form a substituted or unsubstituted, monocyclic heterocyclyl. In some embodiments, R EE are joined to form a substituted or unsubstituted pyrrolidinyl, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted morpholinyl, or a substituted or unsubstituted piperazinyl. 1N and R 2N are joined to form a substituted or unsubstituted, monocyclic heteroaryl (eg, substituted or unsubstituted pyrrolyl).

[0170] In some embodiments, the compound contains no more than four hydrogen bond donors. In some embodiments, the compound contains no more than five hydrogen bond donors. In some embodiments, the compound contains no more than six hydrogen bond donors. In some embodiments, the compound contains no more than four hydrogen bond acceptors. In some embodiments, the compound contains no more than five hydrogen bond acceptors. In some embodiments, the compound contains no more than six hydrogen bond acceptors.

[0171] In some embodiments, the compound has the formula: [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the compound is represented by any one of formulas (I-1) to (I-33), or a pharma- ceutically acceptable salt thereof.

[0172] In some embodiments, the compound has the formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the compound is represented by formula (I-1) or a pharma- ceutically acceptable salt thereof.

[0173] In another aspect, the present disclosure provides a compound of formula: [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In one embodiment, the compound is represented by any one of formulas (II-1) to (II-4), or a pharma- ceutically acceptable salt thereof.

[0174] In some embodiments, the provided compound (compounds described herein, compounds of the present disclosure) is a compound represented by formula (I), (II-1), (II-2), (II-3), or (II-4), (II-1), (II-2), (II-3), or (II-4), or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In some embodiments, the provided compound is a compound represented by formula (I), (II-1), (II-2), (II-3), or (II-4), or a pharma-ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the provided compound is a compound represented by formula (I), (II-1), (II-2), (II-3), or (II-4), or a pharma-ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound provided is a compound represented by formula (I), (II-1), (II-2), (II-3), or (II-4), or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound provided is a mixture of tautomers. In some embodiments, the compound provided is a mixture of enantiomers and / or diastereomers (e.g., a racemic mixture).

[0175] In some embodiments, the molecular weight of the provided compound, when not in the form of a salt, solvate, hydrate, co-crystal, or prodrug, is less than 2,000 g / mol, less than 1,500 g / mol, less than 1,200 g / mol, less than 1,000 g / mol, less than 800 g / mol, less than 700 g / mol, or less than 600 g / mol. In some embodiments, the molecular weight of the provided compound, when not in the form of a salt, solvate, hydrate, co-crystal, or prodrug, is less than 1000 g / mol. In some embodiments, the molecular weight of the provided compound, when not in the form of a salt, solvate, hydrate, co-crystal, or prodrug, is less than 600 g / mol.

[0176] In some embodiments, provided compounds inhibit the activity of a kinase (e.g., abnormal activity (e.g., increased activity, greater than normal activity)). In some embodiments, the kinase is a CDK (e.g., wild-type or mutant CDK). In some embodiments, the kinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19, or CDK20. In some embodiments, the kinase is CDK7 (e.g., wild-type or mutant CDK7). In some embodiments, the kinase is CDK2. In some embodiments, the kinase is CDK9. In some embodiments, the kinase is CDK12. In some embodiments, the kinase is a human kinase. In some embodiments, the kinase is a non-human mammalian kinase. In some embodiments, the kinase is a wild-type kinase. In some embodiments, the kinase is a mutant kinase. In some embodiments, the compounds provided inhibit the activity of the kinase as measured in an assay described herein or known in the art. In some embodiments, the compounds provided inhibit the activity of the kinase with an IC of less than or equal to 30 μM. 50 , IC less than or equal to 10 μM 50 , IC less than or equal to 3 μM 50 , IC less than or equal to 1 μM 50 , IC less than or equal to 0.3 μM 50 , or an IC of less than or equal to 0.1 μM 50 It is inhibited by.

[0177] It has been reported that certain CDK7 inhibitors also inhibit the activity of CDK12 and / or CDK13 (Kwiatowski et al., Nature, 511, 616-620 (2014)). The compounds of the present disclosure may be selective for inhibiting the activity of a first kinase over a second kinase, where the first and second kinases are different from each other. In some embodiments, the first kinase is a CDK. In some embodiments, the first kinase is CDK7. In some embodiments, the second kinase is a kinase that is not a CDK (e.g., a kinase that is not CDK7). In some embodiments, the second kinase is CDK2, CDK9, or CDK12. The selectivity of a compound or pharmaceutical composition of the present disclosure for inhibiting the activity of a first kinase over a second kinase can be determined by the IC of the compound or pharmaceutical composition that inhibits the activity of the first kinase. 50 IC of a compound or pharmaceutical composition that inhibits the activity of the second kinase 50The selectivity of a compound or pharmaceutical composition of the present disclosure for inhibiting the activity of a first kinase over a second kinase may also be measured by the quotient of the Kd value of an adduct of the compound or pharmaceutical composition and a second kinase over the Kd value of the adduct of the compound or pharmaceutical composition and the first kinase. In some embodiments, provided compounds are at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 300-fold, or at least 1,000-fold selective for inhibiting the activity of a first kinase over a second kinase (e.g., in an in vitro assay or an assay described herein). In some embodiments, the compounds provided are at most 3-fold, at most 4-fold, at most 5-fold, at most 7-fold, at most 10-fold, at most 20-fold, at most 50-fold, at most 100-fold, at most 300-fold, or at most 1,000-fold selective for inhibiting the activity of a first kinase over a second kinase (e.g., in an in vitro assay or an assay described herein). The compounds of the present disclosure may be advantageous over non-selective or less selective kinase inhibitors for treating and / or preventing in subjects in need thereof. The compounds of the present disclosure may be more selective than other compounds (e.g., non-selective kinase inhibitors, less selective kinase inhibitors) for inhibiting the activity of a CDK (e.g., CDK7) over other kinases (e.g., kinases other than CDK, kinases other than CDK7, CDKs other than CDK7). In certain embodiments, provided compounds are more selective for inhibiting the activity of CDK7 over CDK2 (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 300-fold, or at least 1,000-fold).In some embodiments, provided compounds are more selective for inhibiting the activity of CDK7 than CDK9 (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 300-fold, or at least 1,000-fold). In some embodiments, provided compounds are more selective for inhibiting the activity of CDK7 than CDK12 (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 7-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 300-fold, or at least 1,000-fold). In some embodiments, provided compounds bind reversibly (e.g., non-covalently) to the kinase. In some embodiments, provided compounds bind irreversibly (e.g., covalently) to the kinase. Certain compounds of the present disclosure may be capable of covalently modifying a cysteine ​​residue located outside the canonical kinase domain of CDK7 (e.g., Cys312). Cys312 is found exclusively in CDK7. Without wishing to be bound by any particular theory, the ability of certain compounds disclosed herein to covalently modify Cys312 of CDK7 may contribute to one or more of the advantages of these compounds over certain other compounds (e.g., selectivity for inhibiting the activity of CDK7 over certain other kinases (e.g., CDKs other than CDK7). Irreversible binding of certain compounds of the present disclosure to CDK7 may result in persistent disruption of transcription and induction of apoptosis in certain malignant and / or precancerous cells. Genome-wide transcript analysis following inhibitor treatment portrays CDK7-responsive genes, particularly MYC and MCL-1 genes, as important genes in maintaining a malignant or precancerous state of cells. Selective inhibition of CDK7 may be useful for treating or preventing proliferative diseases.

[0178] Compared with other compounds, the compounds of the present disclosure may also be more potent, more effective, and / or less toxic when used to treat and / or prevent disease in a subject in need thereof.Compared with other compounds, the compounds of the present disclosure may also reduce the frequency of side effects, reduce the severity of side effects, increase the compliance of subjects, and / or reduce resistance when used to treat and / or prevent disease in a subject in need thereof.In addition, the compounds of the present disclosure may be more soluble, more permeable, more stable in microsomes, and / or more bioavailable, and / or show improved pharmacokinetic properties compared with other compounds.

[0179] In some embodiments, the compounds described herein do not inhibit (the activity of) 5-hydroxytryptamine (5-HT) receptors. 5-HT receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. 5-HT receptors affect a variety of biological and neurological processes, such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. 5-HT receptors are the target of a variety of medicinal and recreational drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens. 5-HT may be an unwanted off-target of the compounds described herein.

[0180] In some embodiments, the 5-HT receptor is 5-HT 1 In some embodiments, the 5-HT receptor is a 5-HT 2 In some embodiments, the 5-HT receptor is a 5-HT 3In some embodiments, the 5-HT receptor is a 5-HT 4 In some embodiments, the 5-HT receptor is a 5-HT 5 In some embodiments, the 5-HT receptor is a 5-HT 6 In some embodiments, the 5-HT receptor is a 5-HT 7 In some embodiments, the compounds described herein do not bind to the 5-HT receptor. In some embodiments, the compounds provided bind to the 5-HT receptor with an IC of less than 3 μM. 50 , IC lower than 10 μM 50 , IC lower than 30 μM 50 , IC lower than 100 μM 50 , IC lower than 300 μM 50 , or IC lower than 1 mM 50 In some embodiments, provided compounds do not inhibit 5-HT receptors by at least 1%, at least 3%, at least 10%, or at least 30% at 1 μM of the compound. In some embodiments, provided compounds do not inhibit 5-HT receptors by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% at 10 μM of the compound.

[0181] In another aspect, the disclosure provides a method of preparing a compound described herein. In some embodiments, the method of preparation is a method described herein.

[0182] Pharmaceutical Compositions, Kits, and Administration In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure, or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, and optionally, a pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition of the present disclosure comprises an effective amount (for example, where effective amount is effective for treating disease) of the compound of the present disclosure, or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug, and optionally, a pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition comprises the compound of formula (I-1), or its pharmaceutically acceptable salt; and optionally, a pharmaceutically acceptable excipient.

[0183] The pharmaceutical compositions of the present disclosure may be useful for treating and / or preventing a disease (e.g., a proliferative disease (e.g., cancer, benign neoplasm, inflammatory disease, autoimmune disease, pathological angiogenesis), cystic fibrosis) in a subject in need thereof. The compositions of the present disclosure may also be useful for inhibiting the activity of a kinase (e.g., a CDK) in a subject, biological sample, tissue, or cell. The compositions of the present disclosure are useful for treating and / or preventing a disease associated with overexpression or aberrant activity of a kinase (e.g., a cyclin-dependent kinase (CDK)). The compositions of the present disclosure may also be useful for inducing apoptosis in a cell (e.g., a malignant or precancerous cell).

[0184] In some embodiments, the effective amount is a therapeutically effective amount (e.g., an amount effective to treat a disease in a subject in need thereof). In some embodiments, the effective amount is an amount effective to inhibit the activity of a kinase (e.g., a CDK (e.g., CDK7)) in a subject in need thereof. In some embodiments, the effective amount is an amount effective to inhibit the activity of a kinase (e.g., a CDK (e.g., CDK7)) in a subject, biological sample, tissue, or cell. In some embodiments, the effective amount is an amount effective to induce apoptosis in a cell. In some embodiments, the effective amount is a prophylactically effective amount (e.g., an amount effective to prevent a disease in a subject in need thereof and / or maintain remission of a disease in a subject in need thereof).

[0185] In some embodiments, an effective amount is an amount effective to inhibit the activity of a kinase (e.g., a CDK (e.g., CDK7)) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In some embodiments, an effective amount is an amount effective to inhibit the activity of a kinase (e.g., a CDK (e.g., CDK7)) by 10% or less, 20% or less, 30% or less, 40% or less, 50% or less, 60% or less, 70% or less, 80% or less, 90% or less, 95% or less, or 98% or less. In some embodiments, an effective amount is an amount effective to inhibit the activity of a kinase (e.g., a CDK (e.g., CDK7)) by a difference in the range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0186] In some embodiments, an effective amount is an amount that is ineffective to inhibit 5-hydroxytryptamine (5-HT) receptors. In some embodiments, an effective amount is an amount that is ineffective to inhibit 5-HT receptors by at least 1%, at least 3%, at least 10%, at least 20%, at least about 30%, or at least 50%.

[0187] In some embodiments, the effective amount is effective to treat a disease (e.g., cancer) and to inhibit the activity of a kinase (e.g., CDK (e.g., CDK7)) but is not effective to inhibit the 5-HT receptor. In some embodiments, the effective amount is effective to treat a disease (e.g., cancer) but is not effective to inhibit the 5-HT receptor. In some embodiments, the effective amount is effective to inhibit the activity of a kinase (e.g., CDK (e.g., CDK7)) but is not effective to inhibit the 5-HT receptor.

[0188] In some embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In some embodiments, the subject described herein is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a dog. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate animal. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the subject is a transgenic animal (e.g., a transgenic mouse, a transgenic pig). In some embodiments, the subject is a fish or reptile.

[0189] In some embodiments, the biological sample, tissue, or cell (e.g., the biological sample, tissue, or cell that is contacted with a compound or pharmaceutical composition described herein) is in vitro. In some embodiments, the biological sample, tissue, or cell is in vivo or ex vivo. In some embodiments, the cell is a malignant cell or a precancerous cell. In some embodiments, the biological sample is tissue from a tumor (e.g., a malignant or benign tumor).

[0190] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology.In general, such preparation methods include bringing the compound described herein (i.e., "active ingredient") into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single-dose or multi-dose unit.

[0191] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as single unit doses, and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0192] The relative amounts of the active ingredient, pharma- ceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein may vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is to be administered. The compositions may contain between 0.1% and 100% (w / w) of the active ingredient.

[0193] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

[0194] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0195] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0196] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ... sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80) ), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate,Triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer® P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0197] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0198] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0199] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0200] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malate and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0201] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0202] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0203] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0204] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0205] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0206] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0207] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, loofah, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon. Exemplary synthetic oils include butyl stearate, caprylic / capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecyl ester, oleyl alcohol, silicone oil, and mixtures thereof.

[0208] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0209] In some embodiments, in the injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension is formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation is a sterile injectable solution, suspension, or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. In some embodiments, the vehicle and solvent employed in the injectable preparation according to the present disclosure is water, Ringer's solution (USP), isotonic sodium chloride solution, and mixtures thereof. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or di-glycerides, can be employed. In some embodiments, fatty acids such as oleic acid are used in the preparation of the injectable preparation of the present disclosure.

[0210] In some embodiments, the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0211] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the drug depends on its dissolution rate at that time, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0212] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing a conjugate described herein with a suitable nonirritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active ingredient.

[0213] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or with (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders, such as paraffin. (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0214] Solid compositions of a similar type may be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings known in the art of pharmacology. They may optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0215] In some embodiments, the active ingredient is provided in microencapsulated form with one or more excipients as mentioned above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release controlling coatings, and other coatings known in the pharmaceutical formulating art. In such solid dosage forms, the active ingredient can be admixed with at least one inert diluent, such as sucrose, lactose, or starch. Such solid dosage forms may contain additional substances other than the inert diluent, as is normal practice, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes.

[0216] Dosage forms for topical and / or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. In general, the active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier or excipient, and / or any preservatives and / or buffers as necessary. In addition, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in a proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0217] Suitable devices for use in the delivery of the intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices that limit the effective penetration length of the needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical Mantoux method of intradermal administration. Jet injection devices are suitable that deliver liquid formulations to the dermis via liquid jet injectants and / or via needles that generate a jet that penetrates the stratum corneum and reaches the dermis. Ballistic powder / particle delivery devices are suitable that use compressed gas to accelerate powder-formed compounds through the outer layer of the skin into the dermis.

[0218] Formulations suitable for topical administration include liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may contain, for example, from about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient is increased up to the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more additional ingredients as described herein.

[0219] The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles comprising the active ingredient and having a diameter ranging from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of a dry powder for administration using a device comprising a dry powder reservoir (to which a continuous stream of propellant can be directed to disperse the powder) and / or using a self-propelling solvent / powder dispensing vessel (such as a device comprising the active ingredient dissolved and / or suspended in a low boiling propellant in a closed vessel). Such powders comprise particles in which at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0220] Low boiling propellants generally include liquid propellants having a boiling point below 65° F. at atmospheric pressure. Generally, the propellant may comprise 50-99.9% (w / w) of the composition and the active ingredient may comprise 0.1-20% (w / w) of the composition. The propellant may further comprise additional ingredients such as liquid non-ionic and / or solid anionic surfactants, and / or solid diluents (which may have a particle size similar to that of the particles containing the active ingredient).

[0221] The pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, containing the active ingredient, and may be conveniently administered using either a nebulizer and / or atomizer device. Such formulations may further include one or more additional ingredients, including flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter ranging from about 0.1 to about 200 nanometers.

[0222] The formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions described herein.Another formulation suitable for intranasal administration is a coarse powder that contains the active ingredient and has an average particle size of about 0.2 micrometers to 500 micrometers.Such formulations are administered by rapid inhalation through the nasal passages from a container of powder held close to the nostrils.

[0223] Formulations for nasal administration may, for example, contain as little as about 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may include one or more additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations may be, for example, in the form of tablets, and / or lozenges made using conventional methods, and may contain, for example, 0.1-20% (w / w) of the active ingredient, the remainder comprising an orally dissolvable and / or degradable composition, and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range of from about 0.1 to about 200 nanometers and may further comprise one or more additional ingredients described herein.

[0224] The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in a formulation for administration to the eye. Such formulations may be in the form of, for example, eye drops comprising, for example, a 0.1 to 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other useful ophthalmically administrable formulations include those comprising the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0225] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to any and all animals. Modifications of pharmaceutical compositions suitable for administration to humans to make compositions suitable for administration to a variety of animals are well understood, and the ordinarily skilled veterinary pharmacologist may design and / or perform such modifications using routine experimentation.

[0226] The compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage.However, it will be understood that the total daily use amount of the compositions described herein will be determined by physicians within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism will depend on a variety of factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient being adopted; the specific composition being adopted; the age, weight, general health, sex and dietary habits of the subject; the time of administration, route of administration and the excretion rate of the specific active ingredient being adopted; the duration of treatment; the drugs that are used in combination with or simultaneously with the specific active ingredient being adopted; and the like factors well known in the medical field.

[0227] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powder, ointment, cream, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as oral spray, nasal spray, and / or aerosol. Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via blood and / or lymphatic supply, and / or direct administration to the affected area. In general, the most appropriate route of administration will depend on a variety of factors, including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the eye of a subject.

[0228] The exact amount of compound required to achieve an effective amount will vary from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of side effects or disorders, the identity of the particular compound, the mode of administration, etc. An effective amount may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amount of the compound described herein. In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administering the multiple doses to a subject or applying the multiple doses to a biological sample, tissue, or cell is 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every other day, 1 dose every 2 days, 1 dose every week, 1 dose every 2 weeks, 1 dose every 3 weeks, or 1 dose every 4 weeks. In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a biological sample, tissue or cell is 1 dose per day.In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a biological sample, tissue or cell is 2 doses per day.In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a biological sample, tissue or cell is 3 doses per day.In some embodiments, when administering multiple doses to a subject or applying multiple doses to a biological sample, tissue or cell, the period between the first dose and the last dose of the multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifespan of a subject or cell. In some embodiments, the period between the first and last dose of the multiple doses is 3 months, 6 months, or 1 year. In some embodiments, the period between the first and last dose of the multiple doses is the lifespan of the subject or cell.In some embodiments, the doses described herein (e.g., either a single dose or multiple doses) independently include between 0.1 μg and 1 μg, inclusive, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g of a compound described herein. In some embodiments, the doses described herein independently include between 1 mg and 3 mg, inclusive, of a compound described herein. In some embodiments, the doses described herein independently include between 3 mg and 10 mg, inclusive, of a compound described herein. In some embodiments, the doses described herein independently include between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, the doses described herein independently encompass between 30 mg and 100 mg, inclusive, of a compound described herein.

[0229] The dosage ranges as described herein provide guidelines for administering provided pharmaceutical compositions to adults.For example, the amount to be administered to children or adolescents can be determined by a physician or person skilled in the art, and can be less than or the same as that administered to adults.In some embodiments, the dosages described herein are for adults with a body weight of about 70 kg.

[0230] The compound or composition may be administered in combination with one or more additional pharmaceutical agents different from the compounds of the present disclosure, as described herein. In some embodiments, the additional pharmaceutical agent is an additional therapeutically active agent, an additional prophylactically active agent, or a combination thereof. The compound or composition may be administered in combination with an additional pharmaceutical agent that improves its activity (e.g., efficacy and / or effectiveness) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the activity of a kinase (e.g., CDK) in a subject, biological sample, tissue, or cell), improves bioavailability, improves safety, reduces drug resistance, reduces and / or modifies metabolism, inhibits excretion, and / or modifies distribution in a subject, biological sample, tissue, or cell. It will also be understood that the treatment employed may achieve the desired effect for the same disorder and / or it may achieve a different effect. In certain embodiments, a pharmaceutical composition described herein that includes a compound described herein and an additional pharmaceutical agent exhibits a synergistic effect not present in a pharmaceutical composition that includes either the compound or the additional pharmaceutical agent, but not both.

[0231] The compound or composition may be administered simultaneously with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration, as provided in the U.S. Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells, and other small organic molecules. In some embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., a proliferative disease, a cancer, an inflammatory disease, an autoimmune disease, a genetic disease, a blood disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder) or a precancerous condition. Each additional pharmaceutical agent may be administered at a dose and / or schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered in a single dose, together with each other and / or with the compounds or compositions described herein, or may be administered separately in different doses. The particular combination employed in the regimen will take into consideration the compatibility of the compounds described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in the combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in the combination will be lower than the levels utilized individually.

[0232] Additional pharmaceutical agents include cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, antiinflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol lowering agents, antidiabetic agents, antiallergic agents, contraceptive agents, analgesics, and combinations thereof. In some embodiments, the additional pharmaceutical agent is an antiproliferative agent (e.g., an anticancer agent). In some embodiments, the additional pharmaceutical agent is abiraterone acetate (e.g., ZYTIGA), ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, adotrastuzumab emtansine (e.g., KADCYLA), afatinib dimaleate (e.g., GILOTRIF), aldesleukin (e.g., PROLEUKIN), alemtuzumab (e.g., CAMPATH), anastrozole (e.g., ARIMIDEX), arsenic trioxide (e.g., TRISENOX), asparaginase from Erwinia chrysanthemi (asparaginase erwinia chrysanthemi) (e.g., ERWINAZE), axitinib (e.g., INLYTA), azacitidine (e.g., MYLOSAR, VIDAZA), BEACOPP, belinostat (e.g., BELEODAQ), bendamustine hydrochloride (e.g., TREANDA), BEP, bevacizumab (e.g., AVASTIN), bicalutamide (e.g., CASODEX), bleomycin (e.g., BLENOXANE), blinatumomab (e.g., BLINCYTO), bortezomib (e.g., VELCADE), bosutinib (e.g., BOSULIF), Lentuximab vedotin (e.g., ADCETRIS), busulfan (e.g., BUSULFEX, MYLERAN), cabazitaxel (e.g., JEVTANA), cabozantinib-s-malate (e.g., COMETRIQ), CAF, capecitabine (e.g., XELODA), CAPOX, carboplatin (e.g., PARAPLAT, PARAPLATIN), carboplatin-taxol, carfilzomib (e.g., KYPROLIS), carmustine (e.g., BECENUM, BICNU, CARMUBRIS), carmustine implant (e.g.,GLIADEL WAFER, GLIADEL), ceritinib (e.g., ZYKADIA), cetuximab (e.g., ERBITUX), chlorambucil (e.g., AMBOCHLORIN, AMBOCLORIN, LEUKERAN, LINFOLIZIN), chlorambucil-prednisone, CHOP, cisplatin (e.g., PLATINOL, PLATINOL-AQ), clofarabine (e.g., CLOFAREX, CLOLAR), CMF, COPP, COPP-ABV, crizotinib (e.g., XALKORI), CVP, cyclophosphamide (e.g., CLAFEN, CYTOXAN, NEOSAR), cytarabine (e.g., CYTOSAR-U, TARABINE PFS), dabrafenib (e.g., TAFINLAR), dacarbazine (e.g., DTIC-DOME), dactinomycin (e.g., COSMEGEN), dasatinib (e.g., SPRYCEL), daunorubicin hydrochloride (e.g., CERUBIDINE), decitabine (e.g., DACOGEN), degarelix, denileukin diftitox (e.g., ONTAK), denosumab (e.g., PROLIA, XGEVA), dinutuximab (e.g., UNITUXIN), docetaxel (e.g., TAXOTERE), doxorubicin hydrochloride (e.g., ADRIAMYCIN PFS, ADRIAMYCIN RDF), doxorubicin hydrochloride liposomal (e.g., DOXIL, DOX-SL, EVACET, LIPODOX), enzalutamide (e.g., XTANDI), epirubicin hydrochloride (e.g., ELLENCE), EPOCH, erlotinib hydrochloride (e.g., TARCEVA), etoposide (e.g., TOPOSAR, VEPESID), etoposide phosphate (e.g., ETOPOPHOS), everolimus (e.g., AFINITOR DISPERZ, AFINITOR), exemestane (e.g., AROMASIN), FEC, fludarabine phosphate (e.g., FLUDARA), fluorouracil (e.g., ADRUCIL, EFUDEX, FLUOROPLEX), FOLFIRI, FOLFIRI-bevacizumab, FOLFIRI-cetuximab, Folfirinox, FOLFOX, FU-LV, fulvestrant (e.g.,FASLODEX), gefitinib (e.g., IRESSA), gemcitabine hydrochloride (e.g., GEMZAR), gemcitabine-cisplatin, gemcitabine-oxaliplatin, goserelin acetate (e.g., ZOLADEX), Hyper-CVAD, ibritumomab tiuxetan (e.g., ZEVALIN), ibrutinib (e.g., IMBRUVICA), ICE, idelalisib (e.g., ZYDELIG), ifosfamide (e.g., CYFOS, IFEX, IFOSFAMIDUM), imatinib mesylate (e.g., GLEEVEC), imiquimod (e.g., Aldara), ipilimumab (e.g., YERVOY), irinotecan hydrochloride (e.g., CAMPTOSAR), ixabepilone (e.g., IXEMPRA), lanreotide acetate (e.g., SOMATULINE DEPOT), lapatinib ditosylate (e.g., TYKERB), lenalidomide (e.g., REVLIMID), lenvatinib (e.g., LENVIMA), letrozole (e.g., FEMARA), leucovorin calcium (e.g., WELLCOVORIN), leuprolide acetate (e.g., LUPRON DEPOT, LUPRON DEPOT-3 MONTH, LUPRON DEPOT-4 MONTH, LUPRON DEPOT-PED, LUPRON, VIADUR), liposomal cytarabine (e.g., DEPOCYT), lomustine (e.g., CEENU), mechlorethamine hydrochloride (e.g., MUSTARGEN), megestrol acetate (e.g., MEGACE), mercaptopurine (e.g., PURINETHOL, PURIXAN), methotrexate (e.g., ABITREXATE, FOLEX PFS, FOLEX, METHOTREXATE LPF, MEXATE, MEXATE-AQ), mitomycin C (e.g., MITOZYTREX, MUTAMYCIN), mitoxantrone hydrochloride, MOPP, nelarabine (e.g., ARRANON), nilotinib (e.g., TASIGNA), nivolumab (e.g., OPDIVO), obinutuzumab (e.g., GAZYVA), OEPA, ofatumumab (e.g., ARZERRA), OFF, olaparib (e.g., LYNPARZA),Omacetaxine mepescusate (e.g., SYNRIBO), OPPA, oxaliplatin (e.g., ELOXATIN), paclitaxel (e.g., TAXOL), paclitaxel albumin-stabilized nanoparticle formulation (e.g., ABRAXANE), PAD, palbociclib (e.g., IBRANCE), disodium pamidronate (e.g., AREDIA), panitumumab (e.g., Vectibix), panobinostat (e.g., FARYDAK), pazopanib hydrochloride (e.g., VOTRIENT), pegaspargase (e.g., ONCASPAR), peginterferon alpha-2b (e.g., PEG-INTRON), peginterferon alpha-2b (e.g., SYLATRON), pembrolizumab (e.g., KEYTRUDA), pemetrexed disodium (e.g., ALIMTA), pertuzumab (e.g., PERJETA), plerixafor (e.g., MOZOBIL), pomalidomide (e.g., POMALYST), ponatinib hydrochloride (e.g., ICLUSIG), pralatrexate (e.g., FOLOTYN), prednisone, procarbazine hydrochloride (e.g., MATULANE), radium-223 dichloride (e.g., XOFIGO), raloxifene hydrochloride (e.g., EVISTA, KEOXIFENE), ramucirumab (e.g., CYRAMZA), R-CHOP, recombinant HPV bivalent vaccine (e.g., CERVARIX), recombinant human papillomavirus (e.g., HPV) nonavalent vaccine (e.g., GARDASIL), 9), recombinant human papillomavirus (e.g., HPV) quadrivalent vaccine (e.g., GARDASIL), recombinant interferon alpha-2b (e.g., INTRON A), regorafenib (e.g., STIVARGA), rituximab (e.g., RITUXAN), romidepsin (e.g., ISTODAX), ruxolitinib phosphate (e.g., JAKAFI), siltuximab (e.g., SYLVANT), sipuleucel-t (e.g., PROVENGE), sorafenib tosylate (e.g., NEXAVAR), STANFORD V, sunitinib malate (e.g., SUTENT), TAC, tamoxifen citrate (e.g., NOLVADEX, NOVALDEX),Temozolomide (e.g., METHAZOLASTONE, TEMODAR), temsirolimus (e.g., TORISEL), thalidomide (e.g., SYNOVIR, THALOMID), thiotepa, topotecan hydrochloride (e.g., HYCAMTIN), toremifene (e.g., FARESTON), tositumomab and iodine I131 tositumomab (e.g., BEXAR), TPF, trametinib (e.g., MEKINIST), trastuzumab (e.g., HERCEPTIN), VAMP, vandetanib (e.g., CAPRELSA), VEIP, vemurafenib (e.g., ZELBORAF), vinblastine sulfate (e.g., VELBAN, VELSAR), vincristine sulfate (e.g., VINCASAR PFS), vincristine sulfate liposome (e.g., MARQIBO), vinorelbine tartrate (e.g., NAVELBINE), vismodegib (e.g., ERIVEDGE), vorinostat (e.g., ZOLINZA), XELIRI, XELOX, ziv-aflibercept (e.g., ZALTRAP), or zoledronic acid (e.g., ZOMETA). In some embodiments, the additional pharmaceutical agent is ENMD-2076, PCI-32765, AC220, dovitinib lactate (e.g., TKI258, CHIR-258), BIBW 2992 (e.g., TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (e.g., VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (e.g., AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (e.g., Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (e.g., CCI-779), everolimus (e.g., RAD-001), ridaforolimus, AP23573 (e.g., Ariad), AZD8055, BEZ235, BGT226, XL765, PF-4691502,GDC0980, SF1126, and OSI-027), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurocidin, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine, or combinations thereof. In some embodiments, the additional pharmaceutical agent is a cytotoxic chemotherapy (e.g., a cytotoxic chemotherapy agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, l-asparaginase, cyclophosphamide, or etoposide)). In some embodiments, the additional pharmaceutical agent is an epigenetic modifier, such as azacitidine or romidepsin. In some embodiments, the additional pharmaceutical agent is ruxolitinib, BBT594, CHZ868, CYT387, or BMS911543. In some embodiments, the additional pharmaceutical agent is a tyrosine kinase inhibitor. In some embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, MCL1 inhibitor, BCL-2 inhibitor, BCL-xL inhibitor, BRD4 inhibitor, BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, CDK9 inhibitor, Jumonji histone demethylase inhibitor, or DNA damage inducer. In some embodiments, the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1, 4-(((5'-chloro-2'-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin. In some embodiments, the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., a CDK). In some embodiments, the additional pharmaceutical agent is an antibody or fragment thereof (e.g.,In some embodiments, the additional pharmaceutical agent is a tyrosine kinase inhibitor. In some embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic agents (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation ... The pharmaceutical agent is a glucocorticoid (e.g., cortisol, cortisone, prednisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, or deoxycorticosterone acetate). In some embodiments, the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody). In some embodiments, the additional pharmaceutical agent is an immune modulator. In some embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In some embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor. In some embodiments, the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In some embodiments, the additional pharmaceutical agent is a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor. In some embodiments, the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte-activation gene 3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B- and T-lymphocyte attenuator (BTLA) inhibitor, galectin 9 (GAL9) inhibitor, checkpoint kinase 1 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T-cell activation (VISTA) inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810, or AMP-224. In some embodiments, the PD-L1 inhibitor is atezolizumab, durvalumab, BMS-936559, avelumab, or CA-170. In some embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In some embodiments, the additional pharmaceutical agent is an aromatase inhibitor. In some embodiments, the additional pharmaceutical agent is a PI3K inhibitor.In some embodiments, the additional pharmaceutical agent is an mTOR inhibitor. In some embodiments, the additional pharmaceutical agent is an endocrine therapy. In some embodiments, the compound or pharmaceutical composition is administered in combination with surgery, radiation therapy, and / or transplantation (e.g., stem cell transplantation, bone marrow transplantation). In some embodiments, the compound or pharmaceutical composition disclosed herein is administered in combination with radiation therapy.

[0233] Also covered by the present disclosure are kits (e.g., pharmaceutical packs). In some embodiments, the kits include a compound or pharmaceutical composition described herein and instructions for using the compound or pharmaceutical composition. In some embodiments, the kits include a first container, where the first container includes the compound or pharmaceutical composition. In some embodiments, the kits further include a second container. In some embodiments, the second container includes an excipient (e.g., an excipient for diluting or suspending the compound or pharmaceutical composition). In some embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kits further include a third container. In some embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form a unit dosage form. In some embodiments, the compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form a unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, an ampoule, a bottle, a syringe, a dispenser package, a tube, or an inhaler.

[0234] In some embodiments, the instructions are for administering the compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In some embodiments, the instructions are for contacting a biological sample, tissue, or cell with the compound or pharmaceutical composition. In some embodiments, the instructions include information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). In some embodiments, the instructions include prescribing information.

[0235] Method and use of use The present disclosure also provides methods of using the disclosed compounds and pharmaceutical compositions. In another aspect, the present disclosure provides a method of inhibiting activity of a kinase in a subject, the method comprising administering to the subject an effective amount of a disclosed compound or pharmaceutical composition.

[0236] In another aspect, the disclosure provides a method of inhibiting activity of a kinase in a biological sample or tissue, the method comprising contacting the biological sample or tissue with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0237] In another aspect, the disclosure provides a method of inhibiting activity of a kinase in a cell, the method comprising contacting the cell with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0238] In another aspect, the disclosure provides a method of downregulating transcription of MYC or MCL-1 in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the disclosure.

[0239] In another aspect, the disclosure provides a method for downregulating transcription of MYC or MCL-1 in a biological sample or tissue, the method comprising contacting the biological sample or tissue with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0240] In another aspect, the present disclosure provides a method of downregulating the transcription of MYC or MCL-1 in a cell, the method comprising contacting the cell with an effective amount of a compound or pharmaceutical composition of the present disclosure.

[0241] Kinases are associated with a wide range of diseases. In certain embodiments, the kinase is a CDK (e.g., CDK7). The process of eukaryotic cell division may be broadly divided into a series of sequential phases referred to as G1, S, G2, and M. Accurate progression through the various phases of the cell cycle has been shown to depend critically on the spatial and temporal regulation of a family of proteins known as CDKs and a series of diverse partner proteins of these homologs (referred to as cyclins). CDKs are CDC2 (also known as CDK1)-homologous serine-threonine kinase proteins that may be able to utilize ATP as a substrate for the phosphorylation of diverse polypeptides in a sequence-dependent context. Cyclins are a family of proteins characterized by a homology region called the "cyclin box" that contains approximately 100 amino acids and is used to bind to and define selectivity for specific CDK partner proteins.

[0242] Modulation of expression levels, degradation rates, protein levels, and activity levels of various CDKs and cyclins throughout the cell cycle leads to the periodic formation of a series of CDK / cyclin complexes (wherein the CDKs are enzymatically active). The formation of these complexes controls the passage of distinct cell cycle checkpoints, thereby allowing the cell division process to continue. Failure to meet prerequisite biochemical criteria at a given cell cycle checkpoint, i.e. failure to form the required CDK / cyclin complex, can lead to cell cycle arrest and / or cellular apoptosis. Abnormal cell proliferation can often result from loss of precise cell cycle control. Thus, inhibition of CDK enzyme activity provides a means by which aberrantly dividing cells can be arrested from division and / or killed. The diversity of CDKs and CDK complexes and their critical roles in mediating the cell cycle provide a wide range of potential therapeutic targets that can be selected based on clear biochemical rationale.

[0243] CDK7, a member of the CDK family, was first isolated as the catalytic subunit of the trimeric CDK-activating kinase (CAK) complex. This complex, consisting of CDK7, cyclin H, and MAT1, is responsible for mitogen activation in vitro. The discovery that CDK7 was also a component of the basic transcription repair factor IIH (TFIIH) implied a dual role for CDK7 in transcription as part of TFIIH and in cell cycle control as a trimeric CAK complex. TFIIH, a multisubunit protein complex, was identified as a factor required for RNA polymerase II (RNAP II)-catalyzed transcription, and this complex was subsequently found to play a central role in nucleotide excision repair. CDK7 is involved in at least three complexes: a component of the trimeric CAK complex, a quaternary complex with XPD (or ERCC2, a protein involved in transcription-coupled nucleotide excision repair), and the nine-subunit TFIIH complex. The dual function of CDK7 in CAK and CTD phosphorylation supports critical aspects of cell proliferation, cell cycle, and transcription. Overexpression of CDK7 can inhibit apoptosis, promote transcription and cell proliferation, and / or interfere with DNA repair, thus causing proliferative diseases.

[0244] The diseases described herein may be associated with abnormal activity of a kinase (e.g., CDK (e.g., CDK7)). The abnormal activity of the kinase may be elevated and / or abnormal activity. Deregulation of cell cycle progression is a hallmark of proliferative diseases. Some proliferative diseases have abnormalities in kinase activity, some of which go through elevated and / or abnormal kinase activation. Inhibition of the catalytic activity of CDKs is expected to inhibit cell cycle progression by blocking phosphorylation of cell cycle CDKs, in addition to inhibiting transcription of effectors of cell division. In some embodiments, the kinase is not overexpressed and the activity of the kinase is elevated and / or abnormal. In other certain embodiments, the kinase is overexpressed and the activity of the kinase is elevated and / or abnormal. The compounds and pharmaceutical compositions of the present disclosure may inhibit the activity of CDK7 and may be useful for treating and / or preventing proliferative diseases.

[0245] The diseases described herein may also be associated with the inhibition of apoptosis of cells in a subject. Apoptosis is a process of programmed cell death. Inhibition of apoptosis may lead to uncontrolled cell proliferation and thus cause proliferative diseases. Cell cycle CDKs (e.g., CDK1, 2, 4, and 6) are activated by phosphorylation by CDK7 / cyclin H (also called CAK). Thus, inhibition of CDK7 may lead to cell cycle arrest at multiple points in the cell cycle due to failure to activate cell cycle CDKs. CDK7 activates transcription by phosphorylating the CTD of RNAP II. Inhibition of CTD phosphorylation has been shown to inhibit transcription and reduce expression of short-lived proteins, including those involved in apoptosis regulation. It is understood in the art that stalling of RNA polymerase may lead to activation of p53 (also known as protein 53 or tumor protein 53, a tumor suppressor protein encoded by the TP53 gene in humans), leading to apoptosis. Thus, inhibition of CDK7 activity is expected to cause cytotoxicity by inducing apoptosis. The compounds and pharmaceutical compositions of the present disclosure induce apoptosis and thus may be useful for treating and / or preventing diseases (e.g., proliferative diseases, cystic fibrosis).

[0246] In another aspect, the present disclosure provides a method for treating a disease in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the present disclosure. In some embodiments, the effective amount is effective for treating the disease. In some embodiments, the effective amount is effective for treating the disease and inhibiting the activity of a kinase. In some embodiments, the effective amount is effective for treating the disease and downregulating the transcription of MYC or MCL-1. In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a compound represented by formula (I-1), or a pharma- ceutically acceptable salt thereof.

[0247] In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the present disclosure. In some embodiments, the effective amount is effective for preventing the disease. In some embodiments, the effective amount is effective for preventing the disease and for inhibiting the activity of a kinase. In some embodiments, the effective amount is effective for preventing the disease and for downregulating the transcription of MYC or MCL-1.

[0248] In another aspect, the disclosure provides a method of inhibiting cell growth, the method comprising contacting a cell with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0249] In another aspect, the disclosure provides a method of inducing apoptosis in a cell, the method comprising contacting the cell with an effective amount of a compound or pharmaceutical composition of the disclosure.

[0250] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal.

[0251] In some embodiments, the biological sample or tissue is bone marrow, lymph node, spleen, or blood. In some embodiments, the biological sample or tissue is in vitro. In some embodiments, the biological sample or tissue is ex vivo.

[0252] In some embodiments, the cell is in vitro. In some embodiments, the cell is ex vivo. In some embodiments, the cell is in vivo. In some embodiments, the cell is in a subject. In some embodiments, the cell is in a biological sample or tissue. In some embodiments, the cell is a malignant cell. In some embodiments, the cell is a pre-cancerous cell.

[0253] In some embodiments, the disease (e.g., a disease treated or prevented using a compound or pharmaceutical composition of the present disclosure) is cancer. In some embodiments, the disease is associated with abnormal activity of a kinase (e.g., increased activity, undesired activity). In some embodiments, the disease is associated with abnormal activity of a CDK (e.g., CDK7). In some embodiments, the disease is associated with abnormal activity of a kinase (e.g., overexpression). In some embodiments, the disease is associated with overexpression of a CDK (e.g., CDK7). In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is cancer. In some embodiments, the disease is an adenocarcinoma, blastoma, carcinoma, hematological malignancy, myeloma, or sarcoma. In some embodiments, the disease is a precancerous condition. In some embodiments, the disease is a hematological malignancy. In some embodiments, the disease is a hematological malignancy. In some embodiments, the disease is a leukemia. In some embodiments, the disease is chronic lymphocytic leukemia (CLL). In some embodiments, the disease is acute lymphoblastic leukemia (ALL). In some embodiments, the disease is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the disease is chronic myelogenous leukemia (CML). In some embodiments, the disease is acute myelogenous leukemia (AML). In some embodiments, the disease is acute monocytic leukemia (AMoL). In some embodiments, the disease is lymphoma. In some embodiments, the disease is Burkitt's lymphoma. In some embodiments, the disease is Hodgkin's lymphoma. In some embodiments, the disease is non-Hodgkin's lymphoma. In some embodiments, the disease is multiple myeloma. In some embodiments, the disease is melanoma. In some embodiments, the disease is adrenocortical carcinoma. In some embodiments, the disease is colorectal cancer. In some embodiments, the disease is breast cancer. In some embodiments, the disease is triple negative breast cancer (TNBC). In some embodiments, the disease is esophageal cancer. In some embodiments, the disease is gastric cancer. In some embodiments, the disease is liver cancer. In some embodiments, the disease is ovarian cancer. In some embodiments, the disease is pancreatic cancer. In some embodiments, the disease is prostate cancer. In some embodiments, the disease is testicular cancer. In some embodiments, the disease is bone cancer.In some embodiments, the disease is osteosarcoma. In some embodiments, the disease is Ewing's sarcoma. In some embodiments, the disease is brain cancer. In some embodiments, the disease is neuroblastoma. In some embodiments, the disease is lung cancer. In some embodiments, the disease is small cell lung cancer (SCLC). In some embodiments, the disease is non-small cell lung cancer. In some embodiments, the disease is a benign neoplasm. In some embodiments, the disease is pathological angiogenesis. In some embodiments, the disease is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the disease is an autoinflammatory disease. In some embodiments, the disease is an autoimmune disease. In some embodiments, the disease is cystic fibrosis.

[0254] In some embodiments, the method further comprises administering an additional treatment to the subject. In some embodiments, the additional treatment is an additional pharmaceutical agent. In some embodiments, the additional treatment is an aromatase inhibitor, an HDAC inhibitor, a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a bromodomain inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a receptor tyrosine kinase (RTK) inhibitor, a Ras inhibitor, a mitogen-activated protein kinase kinase (MEK) inhibitor, a nucleoside analog (e.g., 5-fluorouracil), an endocrine therapy, a cytotoxic chemotherapy, an epigenetic modifier, a steroid (e.g., glucocorticoid), an immunotherapy, or a radiation therapy. In some embodiments, the additional treatment is aromatase inhibitor, HDAC inhibitor, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor, mammalian target of rapamycin (mTOR) inhibitor, endocrine therapy, cytotoxic chemotherapy, epigenetic modifier, glucocorticoid, immunotherapy, or radiation therapy.In some embodiments, the additional treatment is cytotoxic chemotherapy.In some embodiments, the additional treatment is immunotherapy.In some embodiments, the additional treatment is radiation therapy.

[0255] In some embodiments, the additional therapy is a bromodomain-containing protein inhibitor (e.g., a bromodomain-containing protein 2 (BRD2) inhibitor, a bromodomain-containing protein 3 (BRD3) inhibitor, a bromodomain-containing protein 4 (BRD4) inhibitor, a TBP (TATA box-binding protein)-associated factor protein (TAF) inhibitor, a CREB-binding protein (CBP) inhibitor, or an E1A-binding protein p300 (EP300) inhibitor). In some embodiments, the additional therapy is a bromodomain-containing protein 4 (BRD4) inhibitor. In some embodiments, the additional therapy is a JQ1 ( [ka] ), or a pharma- ceutically acceptable salt thereof. In some embodiments, the additional therapy is an epidermal growth factor receptor (EGFR) inhibitor, a fibroblast growth factor receptor (FGFR) inhibitor, or a platelet-derived growth factor receptor (PDGFR) inhibitor.

[0256] In some embodiments, the additional treatment is an EGFR inhibitor. In some embodiments, the additional treatment is erlotinib, lapatinib, AZD8931, WZ4002, or a pharma- ceutically acceptable salt thereof. In some embodiments, the additional treatment is panitumumab, vandetanib, icotinib, afatinib, brigatinib, CO-1688, AZD-4769, poziotinib, CUDC-101, S-222611, AC-480, imgatuzumab, sapitinib, TAS-2913, theiiatinib, XG FR-2421, HM-61713B, epitinib, NRC-2694, MLBS-42, JRP-890, cetuximab, AL-6802, TAK-285, BGB-102, AEE788, gefitinib, DMS-3008, TX-2036, KI-6783, KI-6896, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional therapy is neratinib, or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the additional treatment is an FGFR inhibitor. In some embodiments, the additional treatment is PD173074, pazopanib, masatinib, dovitinib, ponatinib, regorafenib, pirfenidone, nintedanib, brivanib, lenvatinib, cediranib, AZD4547, SU6668, BGJ398, ENMD2076, picropodophyllin, RG1507, dalotuzumab, figitumumab, cixutumumab, BIIB022, AMG479, FP1039, IMCA1, PRO001, R3Mab, MK-2461, SSR128129E, tyrophostin AG 1296, CH5183284, LY2874455, JNJ-42756493, lucitanib, orantinib, danusertib, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional treatment is BGJ398, or a pharmaceutically acceptable salt thereof.

[0258] In certain embodiments, the additional treatment is a PDGFR inhibitor (eg, imatinib, or a pharma- ceutically acceptable salt thereof).

[0259] In certain embodiments, the additional therapy is a PI3K inhibitor. In some embodiments, the additional therapy is GDC0941, tozasertib, GSK1059615, PX866, LY294002, SF1126, XL147, XL765, BGT226, BYL719, BAY80946, BAY841236, GDC-0941, GDC-0032, GDC-0980, GDC-0941, PX-866, GSK2126458, CAL-101, INK1117, ZSTK474, PWT33597, AEZS-136, PKI-587, PF-4691502, PF-05212384, wortmannin, demethoxyviridine, pictilisib, idelalisib, IPI-145, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapy is BKM120, BEZ235, or a pharma- ceutically acceptable salt thereof.

[0260] In some embodiments, the additional treatment is an mTOR inhibitor.In some embodiments, the additional treatment is GDC-0980, OSI-027, AZD8055, INK-128, sirolimus, temsirolimus, everolimus, ridaforolimus, AP23573, rapamycin, simapimod, AZD8055, PF04691502, deforolimus, intercellular protein FKBP38, wortmannin, SF1126, or a pharmaceutically acceptable salt thereof.In some embodiments, the additional treatment is Torin2, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional treatment is a MEK inhibitor. In some embodiments, the additional treatment is selumetinib, MEK162, PD325901, PD98059, XL518, CI-1040, anthroquinonol, AS-1940477, AS-703988, BI-847325, E-6201, GDC-0623, GDC-0973, RG422, RO4987655, RO5126766, SL327, WX-554, U0126, BAY869766, vemurafenib, TAK-733, pimasertib, binimetinib, YopJ polypeptide, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional treatment is trametinib or vemurafenib, or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the additional treatment is a cytotoxic chemotherapy, hi some embodiments, the additional treatment is a platinum-based cytotoxic chemotherapy.

[0262] The compounds or pharmaceutical compositions of the disclosure and the additional treatment may exhibit a synergistic effect in the methods and uses of the disclosure.

[0263] In another aspect, provided herein is the use of a compound or pharmaceutical composition of the present disclosure in the manufacture of a medicament for use in a method of the present disclosure (e.g., a method of treating a disease in a subject in need thereof; a method of preventing a disease in a subject in need thereof; a method of inhibiting the activity of a kinase in a subject, biological sample, tissue, or cell; a method of inhibiting cell growth; a method of inducing apoptosis in a cell; a method of downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell).

[0264] In another aspect, provided herein is the use of a compound or pharmaceutical composition of the disclosure in a method of the disclosure (e.g., a method of treating a disease in a subject in need thereof; a method of preventing a disease in a subject in need thereof; a method of inhibiting the activity of a kinase in a subject, biological sample, tissue, or cell; a method of inhibiting cell growth; a method of inducing apoptosis in a cell; a method of downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell).

[0265] In another aspect, provided herein is a compound or pharmaceutical composition of the disclosure for use in a method of the disclosure (e.g., a method of treating a disease in a subject in need thereof; a method of preventing a disease in a subject in need thereof; a method of inhibiting the activity of a kinase in a subject, biological sample, tissue, or cell; a method of inhibiting cell growth; a method of inducing apoptosis in a cell; a method of downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell).

[0266] example In order that the disclosure described herein may be more fully understood, the following examples are set forth: The synthetic and biological examples described in this application are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0267] Example 1. Synthesis of a compound The compounds provided herein can be prepared from readily available starting materials using methods known in the art, such as those described in U.S. Patent Application Publication US 2019 / 0055248, which is incorporated herein by reference.

[0268] Example 1.1. Synthesis of (S)-3-(4-acrylamidobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-1) Compound I-1 was synthesized according to the method shown in Scheme 1. Scheme 1. Exemplary synthesis of compound I-1. [ka]

[0269] 5-(tert-butyl) 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate [ka] To a solution of tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (4 g, 16 mmol) and DIEA (5.2 mL, 32 mmol) in THF (160 mL) was added ethyl chloroformate (1.5 mL, 16 mmol, dissolved in 40 mL THF) dropwise at 0° C. for 30 min, then the mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was then concentrated and water was added. The resulting mixture was then extracted with ethyl acetate (EA). The EA layer was collected and concentrated under reduced pressure, then purified by column chromatography on silica gel (EA / Hexane, 40%) to give the desired compound (1.6 g, 33%) as a white solid. LCMS: 325 [M+H] + .

[0270] 5-(tert-butyl) 1-ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate [ka] To a solution of 5-(tert-butyl) 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (972 mg, 3 mmol) and DIEA (1.5 mL, 9 mmol) in DCM (30 mL) was added 4-nitrobenzoyl chloride (666 mg, 3.6 mmol) at 0° C. The mixture was then stirred at room temperature overnight. After completion, the reaction mixture was concentrated under reduced pressure and the residue was then purified by column chromatography on silica gel (EA / Hexane, 30%) to give the desired compound (1.1 g, 78%). LCMS: 474 [M+H] + .

[0271] tert-Butyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ka] To a solution of 5-(tert-butyl) 1-ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (1.1 g, 2.34 mmol) in isopropanol (3 mL) was added LiOH (1 Maq., 3 mL). The resulting mixture was stirred at room temperature for 30 min and water was added. The resulting mixture was then extracted three times with isopropanol / chloroform (v / v=1 / 3). The organic layer was collected and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (MeOH / DCM, 6%) to give the desired compound (715 mg, 76%). LCMS: 402 [M+H] + .

[0272] tert-Butyl 1,6,6-trimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ka] To a solution of tert-butyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (715 mg, 1.78 mmol) in THF (10 mL) was added iodomethane (406 mL, 4.27 mmol). The mixture was then stirred at 80° C. overnight. After completion, the mixture was then concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA / Hexane, 45%-70%) to give the desired compound (230 mg, 31%). 1 H NMR (500MHz, chloroform-d) δ10.05(d,J=16.1Hz,1H),8.30-8.14(m,2H),8.04(dd,J=13.1,8.7Hz,2H ),4.62(d,J=4.3Hz,2H),3.50(d,J=19.6Hz,3H),1.69(d,J=31.9Hz,6H),1.49(d,J=17.7Hz,9H). LCMS:416[M+H] + .

[0273] 4-Nitro-N-(1,6,6-trimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide [ka] To a solution of tert-butyl 1,6,6-trimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (230 mg, 0.55 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give the desired compound (225 mg, 95%) as a TFA salt, which was used directly in the next step.1 H NMR (500MHz, methanol-d 4 )δ8.35(d,J=8.8Hz,2H),8.13(d,J=8.8Hz,2H),4.65(s,2H),3.82(s,3H),1.86(s,6H). LCMS:316[M+H] + .

[0274] (S)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide [ka] (S)-N in dioxane (4 mL) 1 ,N 1 To a solution of -dimethyl-2-phenylethane-1,2-diamine (86 mg, 0.52 mmol) and DIEA (430 uL, 2.6 mmol) was added phosgene (420 uL, 15% wt in toluene, 0.62 mmol). After stirring for 0.5 h, 4-nitro-N-(1,6,6-trimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzamide from the previous step was added and the mixture was then stirred again until the reaction was complete. The mixture was then concentrated and purified by column chromatography on silica gel (MeOH / DCM=10%) to give the desired compound (96 mg, 37%). LCMS: 506 [M+H] + .

[0275] (S)-3-(4-aminobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide [ka] To a solution of (S)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (96 mg, 0.19 mmol) in MeOH (10 mL) was added Pd / C (10% loaded, 10 mg). The mixture was then heated under H until the reaction was complete. 2 The mixture was stirred at ambient temperature for 3 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give the desired compound (76 mg, 85%), which was used in the next step without purification. LCMS: 476 [M+H] + .

[0276] (S)-3-(4-acrylamidobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-1) [ka] To a solution of (S)-3-(4-aminobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (76 mg, 0.16 mmol) and DIEA (53 microliters, 0.32 mmol) in dry acetonitrile (2 mL) was added acryloyl chloride (17 mg, 0.19 mmol, dissolved in 1 mL acetonitrile) at 0° C. After completion, the mixture was diluted with isopropanol / chloroform (v / v=1 / 3) and washed with saturated NaHCO 3 The organic layer was washed with Na 2 SO 4 The mixture was dried over ice and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1.75N NH 3 , 10%) to give the desired compound (50 mg, 60%) as a white solid. 1 H NMR (500MHz, DMSO-d 6)δ10.77(s,1H),10.40(s,1H),8.01(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7.45-7.35(m,2 H),7.30(dd,J=8.4,6.9Hz,2H),7.23-7.15(m,1H),6.47(dd,J=16.9,10.1Hz,1H),6.35-6.2 3(m,2H),5.82(dd,J=10.1,1.9Hz,1H),4.92-4.83(m,1H),4.57-4.45(m,2H),3.73(s,3H),2 .67(t,J=10.9Hz,1H),2.39(dd,J=12.3,6.3Hz,1H),2.20(s,6H),1.71(s,3H),1.64(s,3H). LCMS:530[M+H] + .

[0277] Example 1.2. Synthesis of (S)-3-(4-acrylamidobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1-ethyl-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-4) [ka]

[0278] Scheme 2. Synthesis of compound I-4. [ka]

[0279] tert-Butyl 1-ethyl-6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ka]

[0280] To a solution of tert-butyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (109 mg, 0.27 mmol) in DMF (2 mL) was added sodium hydride (22 mg, 60% loaded, 0.54 mmol) in an ice bath. After stirring for 10 min, iodoethane (43 uL, 0.54 mmol) was then added and the resulting mixture was stirred at room temperature for 1 h until the reaction was complete. The mixture was then purified by HPLC to give the desired compound (94 mg, 64%) as a TFA salt. LCMS: 430 [M+H] + .

[0281] N-(1-ethyl-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-nitrobenzamide [ka]

[0282] To a solution of tert-butyl 1-ethyl-6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (94 mg, 0.17 mmol) from the previous step in MeOH (2 mL) was added HCl (4N in dioxane, 1 mL) and the mixture was stirred at 40° C. for 0.5 h. Upon completion, the mixture was concentrated and then purified by column chromatography on silica gel (1.75N NH in MeOH / DCM). 3 , 10%) to give the desired compound as the HCl salt (48 mg, 77%). LCMS: 330 [M+H] + .

[0283] (S)-N-(2-(dimethylamino)-1-phenylethyl)-1-ethyl-6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide [ka]

[0284] (S)-N in THF (2 mL) 1 ,N 1 To a solution of 1,2-dimethyl-2-phenylethane-1,2-diamine (32 mg, 0.2 mmol) and DIEA (85 uL, 0.52 mmol) was added phenyl 4-nitrochloroformate (47 mg, 0.23 mmol). The mixture was stirred at room temperature for 1 h, then N-(1-ethyl-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-nitrobenzamide (48 mg, 0.13 mmol) from the previous step was added, and the resulting mixture was stirred at 50° C. for 4 h. After cooling, the mixture was concentrated and then purified by column chromatography on silica gel (MeOH / DCM, 6%) to give the desired compound (38 mg, 57%) as a yellow solid. LCMS: 520 [M+H] + .

[0285] (S)-3-(4-aminobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1-ethyl-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide [ka]

[0286] The compound from the previous step (38 mg, 0.073 mmol) was dissolved in MeOH (10 mL), then Pd / C (4 mg, 10% loaded) was added, and the mixture was then rinsed with H 2 Stirred at ambient temperature for 1 h. Upon completion, the mixture was filtered, and then the filtrate was concentrated under reduced pressure to give the desired compound, which was used in the next step without purification. LCMS: 490 [M+H] + .

[0287] (S)-3-(4-acrylamidobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1-ethyl-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide [ka] To a solution of (S)-3-(4-aminobenzamido)-N-(2-(dimethylamino)-1-phenylethyl)-1-ethyl-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (0.073 mmol) from the previous step and DIEA (24 uL, 0.15 mmol) in DMF (1 mL) was carefully added acryloyl chloride (0.5 M in DMF) at 0° C. until the reaction was complete. The mixture was then purified by HPLC to give the desired compound (20.7 mg, 43% for two steps) as a TFA salt. 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.42(s,1H),8.02(d,J=8.9Hz,2H),7.78(d,J=8.9Hz,2H),7.48-7.35(m,4H),7.34-7.25(m,1H),6. 78(d,J=9.1Hz,1H),6.47(dd,J=17.0,10.2Hz,1H),6.30(dd,J=17.0,1.9Hz,1H),5.81(dd,J=10.1,1.9Hz,1H),5.35(m ,1H),4.74(d,J=11.9Hz,1H),4.53(d,J=11.8Hz,1H),4.03(q,J=7.1Hz,2H),3.55(td,J=12.5,2.7Hz,1H),3.35(ddd,J =13.0,8.9,4.0Hz,1H),2.88(d,J=4.8Hz,3H),2.84(d,J=4.8Hz,3H),1.75(s,3H),1.67(s,3H),1.36(t,J=7.1Hz,3H). LCMS:544[M+H] + .

[0288] Example 1.3. Synthesis of (S)-3-(4-acrylamidobenzamido)-1-(difluoromethyl)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-5) [ka] Compound I-5 was obtained by following the synthetic route of compound I-4 using difluoromethyl trifluoromethanesulfonate in the first step.

[0289] tert-Butyl 1-(difluoromethyl)-6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ka] To a solution of tert-butyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (80 mg, 0.2 mmol) in DMF (2 mL) was added sodium hydride (16 mg, 60% loaded) at 0° C. After 10 min, difluoromethyl trifluoromethanesulfonate (60 mg, 0.3 mmol) was added and the mixture was then stirred at room temperature for 3 h. After completion, the mixture was washed with water, extracted with EA, concentrated and then purified by column chromatography on silica gel (EA / Hexane, 20%) to give the desired compound (20 mg, 22%). LCMS: 452 [M+H] + .

[0290] (S)-3-(4-acrylamidobenzamido)-1-(difluoromethyl)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-5) [ka] 1 H NMR (500MHz, DMSO-d 6 )δ11.22(s,1H),10.46(s,1H),8.03(d,J=8.9Hz,2H),7.92-7.65(m,3H),7.48-7.43(m,2H),7.39( dd,J=8.5,6.8Hz,2H),7.34-7.25(m,1H),6.86(d,J=9.1Hz,1H),6.47(dd,J=17.0,10.1Hz,1H),6.3 1(dd,J=17.0,1.9Hz,1H),5.82(dd,J=10.1,1.9Hz,1H),5.35(m,1H),4.86-4.72(m,1H),4.65-4.52 (m,1H),3.60-3.30(m,2H),2.88(d,J=4.8Hz,3H),2.84(d,J=4.9Hz,3H),1.80(s,3H),1.72(s,3H). LCMS:566[M+H] + .

[0291] Example 1.4. Synthesis of (S)-3-(5-acrylamidopicolinamido)-N-(2-(dimethylamino)-1-phenylethyl)-1,6,6-trimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-8) [ka] Compound I-8 (6.6 mg, 15%) was obtained by following the synthetic route of compound I-1 using 5-nitropicolinic acid. 1 H NMR (500MHz, DMSO-d 6)δ10.76(s,1H),10.34(s,1H),9.00(s,1H),8.93(dd,J=2.5,0.7Hz,1H),8.38(dd,J=8.5,2.4 Hz,1H),8.17-7.96(m,1H),7.42(d,J=7.6Hz,2H),7.35(s,2H),7.26(s,1H),6.49(dd,J=17.0, 10.1Hz,1H),6.35(dd,J=17.0,1.8Hz,1H),5.88(dd,J=10.1,1.8Hz,1H),4.68(s,1H),4.57(d, J=11.9Hz,2H),3.73(s,3H),3.32(s,6H),2.63(m,1H),2.36(m,1H),1.73(s,3H),1.65(s,3H). LCMS:531[M+H] + .

[0292] Example 1.5. Synthesis of (S)-3-(5-acrylamidopicolinamido)-1-(difluoromethyl)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound I-33) [ka] Compound I-33 (9.3 mg, 35%) was obtained by following the synthetic route of compounds I-1 and I-5 using difluoromethyl trifluoromethanesulfonate and 5-nitropicolinic acid. 1 H NMR (500MHz, DMSO-d 6)δ10.76(d,J=11.1Hz,2H),8.95(dd,J=2.5,0.7Hz,1H),8.38(dd,J=8.6,2.5Hz,1H),8.21-8.10(m, 1H),7.76(t,J=58.3Hz,1H),7.42-7.35(m,2H),7.30(dd,J=8.4,6.9Hz,2H),7.25-7.07(m,1H),6.51 -6.45(m,1H),6.45-6.30(m,2H),5.88(dd,J=10.1,1.8Hz,1H),4.92-4.85(m,1H),4.67-4.58(m,2H) ,2.67(dd,J=12.3,9.1Hz,1H),2.40(dd,J=12.3,6.2Hz,1H),2.19(s,6H),1.77(s,3H),1.69(s,3H). LCMS:567[M+H] + .

[0293] Example 2. Biological assay of compounds Compounds were assayed against various kinases using the Invitrogen CDK7 assay. Exemplary results are shown in Table 1 below with IC values ​​for compounds of the present disclosure. 50 values ​​and for the comparator compounds in Table 2. 50 In Tables 1 and 2, "A" indicates an IC value of less than 100 nM. 50 "B" represents IC values ​​that are ≥ 100 nM and < 1 μM 50 represents IC value, and "C" is IC above 1 µM 50 Values ​​are expressed as percentiles. Cofactors used for each kinase in the assay were as follows: CDK7: cyclin H and MNAT1; CDK2: cyclin A; CDK9: cyclin T1.

[0294] 5-HT inhibition assays were performed according to the Cerep SET Human Serotonin Transporter Binding (Antagonist Radioligand) Assay, such as the assay described at www.eurofinsdiscoveryservices.com / catalogmanagement / viewitem / / 439, accessed on July 22, 2019. In some experiments, the assay information is as shown below: Ligand: [3H]Imipramine; Ligand Kd(nM):1.7; Ligand concentration: 2 nM; Nonspecific: imipramine (10 μM); Incubation: 60 min at RT; Control inhibitor: imipramine; and Test compound concentration: 10 μM. Exemplary results are presented in Table 1 as 5-HT% inhibition at 10 μM compound for the disclosed compounds, and in Table 2 as 5-HT% inhibition at 10 μM compound for the comparative compounds. The results demonstrate that the disclosed compounds (see Table 1) are more selective for CDK7, as they have lower 5-HT% inhibition while maintaining CDK7 inhibition.

[0295] Table 1. IC against CDK7 50 Value and 5-HT% inhibition [Table 1]

[0296] Table 2. IC against CDK7 for comparative compounds 50 Value and 5-HT% inhibition [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0297] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless otherwise indicated to the contrary or otherwise clear from the context. A claim or description including "or" between one or more members of a group is considered to satisfy that one, more than one, or all of the members of the group are present in, employed in, or otherwise related to a given product or process, unless otherwise indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise related to a given product or process. The present disclosure includes embodiments in which more than one or all of the members of the group are present in, employed in, or otherwise related to a given product or process.

[0298] Moreover, the disclosure covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as enumerated in Markush group format, for example, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, when the disclosure, or aspects of the disclosure, are described as including certain elements and / or features, it should be understood that certain embodiments or aspects of the disclosure consist of or consist essentially of such elements and / or features. For the sake of brevity, those embodiments have not been specifically stated in haec verba herein. It is also noted that the terms "comprising," "including," and "containing" are intended to be open and permit the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Moreover, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value, or subrange within the ranges set forth in different embodiments of this disclosure, up to ten times the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0299] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular aspect of the present disclosure that is within the prior art may be expressly excluded from any one or more of the claims. Because such aspects would be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not expressly stated herein. Any particular aspect of the present disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0300] Those skilled in the art will recognize, or at most be able to ascertain using routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: R 5 is -CH3 or -CHF2; Ring A is aryl or heteroaryl; and R 1N and R 2N Each of the above may be independently C 1 ~C 3 is alkyl; provided that the compound has the formula: 【Chemistry 2】 It is not expressed by The compound, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 【Request 2】 【Chemistry 3】 2. The compound of claim 1, wherein:

3. R 1N and R 2N 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each of is methyl.

4. 4. The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein Ring A is phenyl.

5. 5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein Ring A is pyridinyl.

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

7. 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof; and Pharmaceutically acceptable excipients 23. A pharmaceutical composition comprising:

9. 9. The pharmaceutical composition of claim 8 for treating a disease in a subject in need thereof.

10. The pharmaceutical composition according to claim 9, for preventing a disease in a subject in need thereof.

11. The pharmaceutical composition of claim 10, for inhibiting the activity of a kinase in a subject, for downregulating the transcription of MYC or MCL-1 in a subject, for inhibiting cell growth, or for inducing apoptosis of a cell.

12. 1. An in vitro method of inhibiting kinase activity in a biological sample, tissue or cell, downregulating transcription of MYC or MCL-1 in a biological sample, tissue or cell, inhibiting cell growth or inducing apoptosis in a cell, comprising:

10. An in vitro method comprising contacting a biological sample, tissue or cell with an effective amount of a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition according to claim 8.

13. A compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition according to claim 8; and Instructions for using the compound, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition Including the kit.

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