Inhibitors of cyclin-dependent kinase 7 and their uses

Abstract

The present disclosure provides compounds of Formula (I), as well as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The compounds of the present disclosure are inhibitors of kinases, e.g., cyclin-dependent kinases (CDKs), e.g., CDK7. The compounds may be selective for inhibiting the activity of kinases, e.g., CDK7, over certain other kinases, e.g., CDK2, CDK9, and CDK12. Also provided are pharmaceutical compositions, kits, methods of use, and uses involving the compounds. The compounds may be useful in inhibiting kinase activity, downregulating MYC or MCL-1 transcription, inhibiting cell growth, inducing cellular apoptosis, treating disease, and / or preventing disease, 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 / 786,328, filed December 28, 2018, which is incorporated herein by reference.

[0002] Government support This invention was made with government support under Grant No. W81XWH-16-1-0252 awarded by the Department of Defense. The government has certain rights in this invention. [Background technology]

[0003] Background of the Disclosure Members of the cyclin-dependent kinase (CDK) family play critical regulatory roles in cell proliferation. 20 mammalian CDKs are known. CDK7 to CDK13 are 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). Therefore, phosphorylation by CDK7 of conserved residues in CDK1 / 2 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)).Nuclear CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (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 two functions of CDK7, CAK and CTD phosphorylation, can support critical aspects of cell proliferation, cell cycle, and transcription.

[0004] Disruption of RNAP II CTD phosphorylation is known to preferentially affect short-lived 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)). Therefore, inhibition of human CDK7 kinase activity is likely to result in antiproliferative activity, and pharmacological inhibition is believed to be useful for treating proliferative disorders, including cancer.Flavopiridol, a nonselective pan-CDK inhibitor that targets 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 CDK inhibitors to treat CLL and other cancers. Summary of the Invention

[0005] Summary of the Disclosure In one aspect, the present disclosure provides a compound of formula (I): [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, wherein R 1 , m, R 2 , n, ring A, L, R 3 , ring B, R 4 , R 5a , R 5b , R 6 , R 7 , R 8 , R 9 , R 10 , p, ring D, R 11, and q are as defined herein. Compounds of the present disclosure may inhibit the activity of a kinase. In some embodiments, the kinase is a cyclin-dependent kinase (CDK) (e.g., CDK7). Compounds of the present disclosure may be useful for inhibiting the activity of a kinase, inhibiting cell growth, and / or inducing apoptosis of a cell. In some embodiments, the cell (e.g., a 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 implicated in a wide range of diseases in subjects (e.g., proliferative diseases, cystic fibrosis). Compounds of the present disclosure may also be useful for treating and / or preventing diseases in subjects in need thereof.

[0006] The compounds of the present disclosure may be more selective for inhibiting the activity of a CDK (e.g., CDK7) than other kinases (e.g., kinases other than CDKs, kinases other than CDK7). In some embodiments, the compounds of the present disclosure are more selective for inhibiting the activity of CDK7 than CDK2, CDK9, and / or CDK12. The compounds of the present disclosure may be more advantageous than non-selective kinase inhibitors or less selective kinase inhibitors for treating and / or preventing diseases 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) than other kinases (e.g., kinases other than CDKs, 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 diseases in subjects in need thereof, and / or may reduce the frequency and severity of side effects, increase subject compliance, and / or reduce tolerance. Furthermore, the compounds of the present disclosure may be more soluble, more permeable, more stable in microsomes, and / or more bioavailable, and / or exhibit improved pharmacokinetic properties compared to other compounds. The compounds of the present disclosure include a carbocyclyl or heterocyclyl as Ring D. While not wishing to be bound by any particular theory, Ring D may contribute to one or more of the above advantages of the compounds of the present disclosure over certain other compounds. Furthermore, certain compounds of the present disclosure may be capable of covalently modifying the cysteine ​​residue Cys312 of CDK7. Cys312 of CDK7 is unique compared to other CDKs and certain other kinases. Without wishing to be bound by any particular theory, the ability of certain compounds to covalently modify Cys312 of CDK7 may contribute to one or more of the above advantages of these compounds over certain other compounds.

[0007] Exemplary compounds of the present disclosure include the following: [ka] [ka] and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0008] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure and, optionally, a pharmaceutically 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. In another aspect, the present disclosure provides a kit comprising a compound or pharmaceutical composition of the present disclosure; and instructions for using the compound or pharmaceutical composition. In some embodiments, the instructions include prescribing information.

[0009] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of the present disclosure.

[0010] In another aspect, the present 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 present disclosure.

[0011] In some 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, an angiogenesis-related disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease).

[0012] In another aspect, the present disclosure provides a method for 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 activity of the entire kinase inhibited by the compounds and pharmaceutical compositions) is a CDK (e.g., CDK7).

[0013] In another aspect, the present disclosure provides a method of inhibiting cell growth, comprising contacting a cell with an effective amount of a compound or pharmaceutical composition of the present disclosure.

[0014] In another aspect, the present 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 present disclosure.

[0015] In another aspect, the present disclosure provides a method for 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 present disclosure.

[0016] In some embodiments, the cell is an abnormally proliferative cell (eg, a malignant or pre-cancerous cell).

[0017] In another aspect, the present disclosure provides uses of the disclosed compounds and pharmaceutical compositions, including, for example, in the disclosed methods.

[0018] 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, drawings, and claims.

[0019] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in accordance with the Handbook of Chemistry and Physics, 75 th The elements are identified in accordance with the CAS version of the Periodic Table of the Elements, inside cover Ed., and specific functional groups are generally defined as described 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, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary recitation of substituents set forth herein.

[0020] The compounds of the present disclosure may contain one or more asymmetric centers, and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers.For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched 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, 1966); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1977). 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.

[0021] 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 C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C5~6 It is intended to cover alkyls of the formula:

[0022] The term "aliphatic" encompasses both saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, optionally substituted with one or more functional groups. As will be appreciated by those skilled in the art, "aliphatic" herein is intended to encompass alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" encompasses straight-chain, branched, and cyclic alkyl groups. Similar rules apply to other general terms, such as "alkenyl," "alkynyl," etc. Furthermore, the terms "alkyl," "alkenyl," "alkynyl," etc., encompass both substituted and unsubstituted groups.

[0023] In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in this disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in this disclosure contain 1-10 aliphatic carbon atoms. In another embodiment, the alkyl, alkenyl, and alkynyl groups employed in this disclosure contain 1-8 aliphatic carbon atoms. In yet another embodiment, the alkyl, alkenyl, and alkynyl groups employed in this disclosure contain 1-6 aliphatic carbon atoms. In another embodiment, the alkyl, alkenyl, and alkynyl groups employed in this disclosure contain 1-4 carbon atoms. Thus, illustrative aliphatic groups include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH-cyclohexyl moieties, and the like, again, which may bear one or more substituents. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

[0024] The term "alkyl" refers to the radical of a straight-chain 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, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6In 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, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., a halogen such as F). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (unsubstituted C 1~6 In some embodiments, the alkyl group is a substituted C 1~10 Alkyl (substituted C 1~6 alkyl, for example, -CF3).

[0025] "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 2~10In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C), 1-propenyl (C), 2-propenyl (C), 1-butenyl (C), 2-butenyl (C), butadienyl (C), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "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 In alkenyl groups, the C=C double bond does not specify the stereochemistry (e.g., -CH=CHCH3 or [ka] may be an (E)-double bond or a (Z)-double bond.

[0026] "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, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C), 1-propynyl (C), 2-propynyl (C), 1-butynyl (C), 2-butynyl (C), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "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.

[0027] "Carbocyclyl" or "carbocyclic" means a ring structure having from 3 to 10 ring carbon atoms ("C 3~10 refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3~8 The carbocyclyl group may be any of the aforementioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3~10 The carbocyclyl group may be any of the aforementioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also refers to a ring system in which a carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclic ring, and in such instances the number of carbon atoms is designated through the number of carbon atoms in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In some embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0028] 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 5~6In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups are the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups are the aforementioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In some embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0029] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). The point of attachment in a heterocyclyl group containing one or more nitrogen atoms can be a carbon atom or a nitrogen atom, valence permitting. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and can be 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 such instances, the number of ring members is designated via the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0030] 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- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0031] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. 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, etc.

[0032] "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 ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracyl). "Aryl" also encompasses ring systems in which the aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, but where the radical or point of attachment is on the aryl ring. In such instances, the number of carbon atoms is designated through the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In some embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0033] "Aralkyl" refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In some embodiments, the aralkyl is optionally substituted benzyl. In some embodiments, the aralkyl is benzyl. In some embodiments, the aralkyl is optionally substituted phenethyl. In some embodiments, the aralkyl is phenethyl.

[0034] "Heteroaryl" refers to a radical of a 5-10-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared among 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 heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" 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 encompasses ring systems in which a heteroaryl ring is fused to 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 bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0035] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems 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, heteroaryl groups are 5-8 membered aromatic ring systems 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, heteroaryl groups are 5-6 membered aromatic ring systems 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, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0036] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0037] "Heteroaralkyl" is a subset of alkyl and heteroaryl, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0038] "Unsaturated" or "partially unsaturated" refers to a group that includes at least one double or triple bond. "Partially unsaturated" ring systems are also intended to encompass rings with multiple sites of unsaturation, but are not intended to include 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.

[0039] When 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.

[0040] Unless expressly provided otherwise, atoms, moieties, or groups described herein can be unsubstituted or substituted, where valence allows. The term "optionally substituted" refers to substituted or unsubstituted.

[0041] Groups are optionally substituted unless expressly provided otherwise. The term "optionally substituted / optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on a group (e.g., a carbon atom or a 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 specified, a "substituted" group has a substituent at one or more substitutable positions of the group; 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 in order to arrive at stable compounds. 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.

[0042] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(Raa )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)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(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 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogens on a carbon atom are substituted with groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa, =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by; R aa 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 aa 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 contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb In each case, independently, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10Alkyl, 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 bb 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 contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc In each case, independently, 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 contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd In each case, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee, -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2,-NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may be combined 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, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff In each case, independently, 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 contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and R gg In each case, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)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, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be joined to form =O or =S; where X - is the counter ion.

[0043] 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 - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 -, sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), and carboxylate ions (e.g., acetic acid, ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, glyconic acid, etc.).

[0044] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0045] "Acyl" is -C(=O)R aa ,-CHO,-CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R 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.

[0046] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa, -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(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- to 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 has 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc , and R dd is as defined above.

[0047] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa, -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 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 contains 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.

[0048] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa) include formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamic acid amide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0049] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) are 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-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Troc), Bamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl carbamate, Dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrile benzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 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 2,4,6-trimethylbenzylcarbamate.

[0050] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) are 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.

[0051] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacyclo Pentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorsalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0052] Exemplary oxygen atom substituents are -R aa , -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, where R aa , R bb , and R ccis 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, T.W. Greene and P.G.M.Wut, 3 rdedition, John Wiley & Son, 1999 (incorporated herein by reference). Exemplary oxygen protecting groups include 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 (POM), siloxymethyl, 2- Methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)- 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trimethyl-4-phenyl-2-methyl-4-oxo-2-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-trimethyl-4-oxo-2-yl, 1-methyl-1-benzyloxy-2-fluoroethyl ... Lithoethyl, 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(4',4''-diphenyl)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 (levuriate), 4,4-(ethylenedithio)pentanoate (levurinoyl dithioacetal), pivalic acid, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitoic acid), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoic acid, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(di bromomethyl)benzoic acid, 2-formylbenzenesulfonic acid, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, chlorodiphenylacetic acid, isobutyric acid, monosuccinic acid, (E)-2-methyl-2-butenoic acid, o-(methoxyacyl)benzoic acid, α-naphthoate, nitric acid, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, boric acid, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfuric acid, methanesulfonic acid (mesylate), benzylsulfonic acid, and tosylic acid (Ts).

[0053] Exemplary sulfur atom substituents are -R aa , -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(Rbb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(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, which is incorporated herein by reference.

[0054] A "hydrocarbon chain" refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group. The hydrocarbon chain includes: (1) one or more chains of carbon atoms immediately between the two radicals of the hydrocarbon chain; (optionally, one or more hydrogen atoms on the chain(s) of carbon atoms; and (3) optionally, one or more substituents ("non-chain substituents" that are not hydrogen) on the chain(s) of carbon atoms. A chain of carbon atoms consists of consecutively connected carbon atoms ("chain atoms" or "carbon units") and does not include hydrogen atoms or heteroatoms. However, the non-chain substituents of the hydrocarbon chain may include any atom, including hydrogen atoms, carbon atoms, and heteroatoms. For example, the hydrocarbon chain -C A H(C B H2C C H3)- is one chain atom CA , C A one hydrogen atom on the chain, and a non-chain substituent -(C B H2C C H3). x "Hydrocarbon chain" (where x is a positive integer) refers to a hydrocarbon chain that includes x number of chain atoms (single or multiple) between two radicals of the hydrocarbon chain. If the possible values ​​of x are greater than 1, the smallest possible value of x is used to define the hydrocarbon chain. For example, -CH(C2H5)- is a C1 hydrocarbon chain; [ka] is a C hydrocarbon chain. When a range of values ​​is used, the meaning of the range is as described herein. For example, C 3~10 A hydrocarbon chain refers to a hydrocarbon chain in which the shortest chain of carbon atoms immediately adjacent between two radicals of the hydrocarbon chain has 3, 4, 5, 6, 7, 8, 9, or 10 chain atoms. The hydrocarbon chain may be saturated (e.g., -(CH4-). The hydrocarbon chain may also be unsaturated and may contain one or more C=C and / or C≡C bonds anywhere in the hydrocarbon chain. Illustratively, -CH=CH-(CH2-, -CH2-C≡C-CH2-, and -C≡C-CH=CH- are all examples of unsubstituted, unsaturated hydrocarbon chains. In some embodiments, the hydrocarbon chain is unsubstituted (e.g., -C≡C- or -(CH4-). In some embodiments, the hydrocarbon chain is substituted (e.g., -CH(C2H5)- and -CF2-). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl ring. Illustratively, [ka] and [ka] are all examples of hydrocarbon chains. In contrast, in some embodiments, [ka] is not within the scope of the hydrocarbon chains described herein. x When a chain atom of a hydrocarbon chain is replaced by a heteroatom, the resulting group is C x-1 In contrast to hydrocarbon chains, C chain atoms are replaced by heteroatoms x These are called hydrocarbon chains. For example, [ka] is a C3 hydrocarbon chain in which one chain atom has been replaced by an oxygen atom.

[0055] The term "leaving group" is given its ordinary meaning in the art of organic chemical synthesis and refers to an atom or group capable of being displaced by a nucleophile. Examples of suitable leaving groups include halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate ester such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF3CF3) (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphine oxide (formed, for example, during the Mitsunobu reaction) or an internal leaving group such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0056] The term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the bounds of sound medical wisdom, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic responses, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically 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.

[0057] The term "solvate" refers to a form of a compound associated with a solvent, usually through a solvolysis reaction. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharmaceutically 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.

[0058] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R·xH2O (where R is the compound and x is a number greater than 0). A given compound may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0059] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., reactions that provide tautomeric pairs) may be catalyzed by acid or base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different)enamine tautomerizations.

[0060] It will also be understood that compounds that have the same molecular formula but that differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0061] Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center (e.g., it is bonded to four different groups), a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0062] 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, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0063] The term "co-crystal" refers to a crystal structure composed of at least two components. In certain embodiments, a co-crystal may contain a compound of the present disclosure and one or more other components (including atoms, ions, molecules, or solvent molecules). In certain embodiments, a 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).

[0064] 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) have been replaced with an isotope of the same element. For a given element or position in a molecule, the isotope will be enriched or present at a higher percentage of the total atoms of that element in the molecule in a sample, or at 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.

[0065] The term "prodrug" refers to a compound having a cleavable group that becomes a compound described herein (which is pharmaceutically active in vivo) upon solvolysis or under physiological conditions. 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-labile form often offers advantages 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 esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from pendant acidic groups on the compounds described herein are specific prodrugs. In some cases, it may be desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The compounds described herein may be used in combination with C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C6-C 12 Substituted aryl and C7-C 12 Aryl alkyl esters are sometimes preferred.

[0066] The terms "inhibition," "inhibiting," "inhibit," or "inhibitor" refer to the ability of a compound to reduce, slow, stop, or prevent the activity of a specific biological process in a cell (e.g., the activity of a cyclin-dependent kinase) relative to a vehicle.

[0067] 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 the 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.

[0068] 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.

[0069] The terms "composition" and "formulation" are used interchangeably.

[0070] A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., a minor, child, or 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, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic animal or a genetically modified animal. "Patient" refers to a human subject in need of disease treatment. 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.

[0071] 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 biomolecules derived from another biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0072] 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.

[0073] The terms "treatment," "treat," and "treating" refer to halting, alleviating, delaying the onset of, or inhibiting the progression of a disease 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 or condition. 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, e.g., to delay and / or prevent recurrence.

[0074] The terms "disease," "disease," and "disorder" are used interchangeably.

[0075] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response, i.e., 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.

[0076] 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 the amount of 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.

[0077] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a disease, or one or more symptoms associated with a disease, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of therapeutic agent alone, or in combination with other agents, that provides a prophylactic benefit in terms of disease prevention. 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.

[0078] "Proliferative disease" refers to a disease caused by abnormal growth or expansion of cells by doubling (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with: 1) pathological proliferation of normally quiescent cells; pathological migration of cells from their normal location (e.g., neoplastic cell metastasis); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as that seen in proliferative retinopathies and tumor metastasis. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis-related diseases, inflammatory diseases, and autoimmune diseases.

[0079] The term "angiogenesis" refers to the physiological process by which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, 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 granulation tissue formation. However, angiogenesis is also a fundamental step in the transition of tumors from benign to malignant states, leading to the use of angiogenesis inhibitors in cancer treatment. Angiogenesis can 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.

[0080] 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 grow slower than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not possess the propensity to infiltrate, invasive, or metastasize to distant sites. Exemplary benign neoplasms include lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, lentigo, and sebaceous hyperplasia. In some cases, a "benign" tumor can later give rise to a malignant neoplasm, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells; these tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characterized by rapid growth accompanied by 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 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.

[0081] 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); muscle cancer; myelodysplastic syndrome (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 myeloid leukemia, etc.) leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, ductal carcinoma, 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 neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (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; synovioma; 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);

[0082] The term "hematological malignancy" refers to a tumor affecting 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., B-cell NHL, such as diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), 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 lymphoma, and thyroid cancer. Lymphomas, such as mediastinal B-cell lymphoma, Burkitt's lymphoma, Van der Ström's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and 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 leukemia / lymphomas as described above; myelodysplasia; and multiple myeloma (MM).

[0083] The term "inflammatory disease" refers to a disease caused by or resulting in inflammation. The term "inflammatory disease" can 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 1), 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, lymphocytic 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 hypertension 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, oophoritis, 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.

[0084] "Autoimmune disease" refers to a disease resulting from an abnormal immune response of a subject's body against substances and tissues normally present in the body. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This may be restricted to a certain 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., medications that reduce the immune response. Exemplary autoimmune diseases include glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, 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.

[0085] The term "kinase" refers to 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 is the protein kinases, which act on specific proteins to modify their activity. Kinases are used extensively in cells to transmit signals and control complex processes. Various other kinases act on small molecules, such as lipids, carbohydrates, amino acids, and nucleotides, either to signal or to prime metabolic pathways. Kinases are often named after their substrates. More than 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、PRKXComprising PRKXps, 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, 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.,

[0086] The term "Src family kinase" refers to a family of non-receptor tyrosine protein kinases that includes nine members: the SrcA subfamily, which includes c-Src (proto-oncogene tyrosine-protein kinase Src), YES (proto-oncogene tyrosine-protein kinase Yes), FYN (proto-oncogene tyrosine-protein kinase FYN), and FGR (Gardner-Rasheed feline sarcoma virus (v-FGR) oncogene homolog); the SrcB subfamily, which includes LCK (lymphocyte-specific protein tyrosine kinase), HCK (tyrosine-protein kinase HCK, hematopoietic cell kinase), BLK (tyrosine-protein kinase BLK), and LYN (tyrosine-protein kinase LYN); and FRK (Fyn-related kinase).

[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 a CDK substrate is [S / T * ]PX[K / R] (SEQ ID NO: 1), where S / T * is 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 (incorporated herein by reference). The amino acid sequence of this CDK7 is as follows: MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTALREIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLMTLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRAPELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDMCSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPGPTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF (SEQ ID NO: 2). [Brief explanation of the drawings]

[0089] Brief description of the drawings The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects of the present disclosure and together with the description, serve to explain the principles of the disclosure.

[0090] [Figure 1] Figure 1 shows exemplary results of pull-down assays of compounds 205, 200, and 207 at 1 μM and 2.5 μM. Experimental details are described elsewhere. Western blotting with cyclin H identifies the CDK7-cyclin H complex (CDK7), whereas Western blotting with cyclin K identifies the CDK12-cyclin K complex and the CDK13-cyclin K complex.

[0091] [Figure 2] Figure 2 shows exemplary results of pull-down assays of compounds 200, 201, and 206 at 1 μM and 2.5 μM. Experimental details are described elsewhere. Western blotting with cyclin H identifies the CDK7-cyclin H complex (CDK7), whereas Western blotting with cyclin K identifies the CDK12-cyclin K complex and the CDK13-cyclin K complex.

[0092] [Figure 3] Figure 3 shows exemplary results of pull-down assays of compounds 202 and 203 at 1 μM. Experimental details are described elsewhere. Western blotting with cyclin H identifies the CDK7-cyclin H complex (CDK7), whereas Western blotting with cyclin K identifies the CDK12-cyclin K complex and the CDK13-cyclin K complex.

[0093] [Figure 4] Figure 4 shows exemplary results of pull-down assays of compounds 200 and 204 at 1 μM. Experimental details are described elsewhere. Western blotting with cyclin H identifies the CDK7-cyclin H complex (CDK7), whereas Western blotting with cyclin K identifies the CDK12-cyclin K complex and the CDK13-cyclin K complex.

[0094] [Figure 5] Figure 5 shows exemplary results of pull-down assays of compounds 207, 208, and 209 at 1 μM and 2.5 μM. Experimental details are described elsewhere. Western blotting with cyclin H identifies the CDK7-cyclin H complex (CDK7), whereas Western blotting with cyclin K identifies the CDK12-cyclin K complex and the CDK13-cyclin K complex.

[0095] [Figure 6] Figure 6 shows exemplary results of pull-down assays of compounds 065 and 079 at 1 μM. Experimental details are described elsewhere. Western blotting with cyclin H identifies the CDK7-cyclin H complex (CDK7), whereas western blotting with cyclin K identifies the CDK12-cyclin K complex and the CDK13-cyclin K complex. DETAILED DESCRIPTION OF THE INVENTION

[0096] Detailed Description of Certain Aspects of the Disclosure Kinases are implicated in a wide range of diseases. CDKs, in particular, 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. Disruptions in CDK7 signaling can also cause transcriptional defects. The lack of selective inhibitors of CDK7 has hindered investigation of the transcriptional and functional consequences of acute and long-term inhibition of CDK7 activity under normal and pathological conditions.

[0097] In one aspect, the present disclosure provides compounds represented by Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. The compounds of the present disclosure may inhibit the activity of a kinase. In some embodiments, the kinase is a CDK. In some embodiments, the kinase is CDK7. In some embodiments, the kinase is CDK2, CDK9, or CDK12. The 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 the 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 a kinase, inhibiting cell growth, and / or inducing apoptosis in cells. The compounds, pharmaceutical compositions, kits, methods of use, and uses of the present disclosure may also be useful for treating and / or preventing diseases. 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.

[0098] compound In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 1 is the expression: [ka] [ka] [ka] wherein: L 3 is a bond or a substituted or unsubstituted C 1~4 a hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently —C═O—, —O—, —S—, —NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L3a -, or -NR L3a S(=O)2-, where R L3a is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting group, and where R L3b is independently hydrogen, 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, or substituted or unsubstituted heteroaryl, or R L3b when two of the following are joined to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; L 4 is a bond or a substituted or unsubstituted, branched or unbranched C 1~6It is a hydrocarbon chain; R E1 , R E2 , and R E3 each independently represents hydrogen, 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, -CN, -CHOR EE , -CHN(R EE )2, -CH2SR EE , -OR EE , -N(R EE )2, -Si(R EE )3, or -SR EE where R EE 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 R EE when two of the following are joined to form a substituted or unsubstituted heterocyclyl; Alternatively, R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; R E4 is a leaving group; R E5 is a halogen; R E6 is hydrogen, substituted or unsubstituted C 1~6 alkyl, or nitrogen protecting groups; Each instance of Y is independently O, S, or NR E7 where R E7 is hydrogen, substituted or unsubstituted, C 1~6 alkyl, or nitrogen protecting groups; a is 1 or 2; and each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, valence permitting; m is 0 or 1; R 2 each occurrence of 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, -NO2, -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; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valence permits; L is a single bond or -C(=O)-; R 3 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 4 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 5a and R 5beach independently represents hydrogen, 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, -NO2, -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 or R 5a and R 5b are joined to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; R 6 and R 7 each occurrence of is independently hydrogen, 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(Ra )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -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 or R 6 and R 7 are joined to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; R 8 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 9 and R 10 each occurrence of is independently hydrogen, 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, -NO2, -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 or R 9 and R 10 are joined to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; p is 0, 1, 2, 3, or 4; Ring D is carbocyclyl or heterocyclyl; R 11 and each occurrence of each independently represents a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted aryl, a 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, -NO2, -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 ,-OC(=O)N(R a )2, or when attached to a nitrogen atom is a nitrogen protecting group; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valence permits; and 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 to form a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl; provided that the compound has the formula: [ka] But it is not expressed.

[0099] Formula (I) is a ring A [ka] In some embodiments, ring A is carbocyclyl. In some embodiments, ring A is a monocyclic, 3- to 7-membered carbocyclyl containing zero, one, or two double bonds in the carbocyclic ring system, as valence permits. In some embodiments, ring A is a bicyclic, 5- to 13-membered carbocyclyl containing zero, one, two, or three double bonds in the carbocyclic ring system, as valence permits. In some embodiments, ring A is cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, ring A is cyclobutyl. In some embodiments, ring A is not cyclobutyl.

[0100] In some embodiments, ring A is heterocyclyl. In some embodiments, ring A is a 3- to 7-membered monocyclic heterocyclyl. In some embodiments, ring A is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl. In some embodiments, ring A is a 5- to 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.

[0101] In some embodiments, ring A is aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is naphthyl.

[0102] In some embodiments, ring A is 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 [ka] wherein the attachment point is attached to L. In some embodiments, ring A is [ka] wherein the point of attachment is attached to L. In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is [ka] wherein the attachment point is attached to L. In some embodiments, ring A is [ka] wherein the attachment point is attached to L. In some embodiments, ring A is [ka] wherein the point of attachment is attached to L. In some embodiments, ring A is pyrazinyl or pyridazinyl. In some embodiments, ring A is a bicyclic 9- or 10-membered (e.g., 5,6-fused, 6,5-fused, or 6,6-fused) heteroaryl. In some embodiments, when ring A is a bicyclic 9- or 10-membered heteroaryl, the monocyclic ring attached to L is a monocyclic heteroaryl. In some embodiments, when ring A is a bicyclic 9- or 10-membered heteroaryl, the monocyclic ring attached to L is phenyl. 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 [ka] wherein the attachment point is attached to L. In some embodiments, ring A is [ka] wherein the point of attachment is attached to L. In some embodiments, ring A is isoquinolinyl. In some embodiments, ring A is [ka] wherein the point of attachment is attached to L. In some embodiments, ring A is aza-isoquinolinyl, diaza-isoquinolinyl, quinolinyl, aza-quinolinyl, or diaza-quinolinyl.

[0103] Ring A is a substituent R 1 In some embodiments, [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] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] In one embodiment, [ka] is.

[0104] 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] In one embodiment, [ka] In one embodiment, [ka] is.

[0105] In some embodiments, R 1 In some embodiments, R 1comprises a Michael acceptor moiety. In some embodiments, the electrophilic moiety or Michael acceptor moiety reacts with a cysteine ​​residue of a kinase (e.g., a CDK (e.g., CDK7)). In some embodiments, the electrophilic moiety or Michael acceptor moiety may react with residue Cys312 of CDK7. In some embodiments, the compounds of the present disclosure can be covalently or irreversibly attached to a kinase. In some embodiments, the compounds of the present disclosure can be covalently or irreversibly attached to CDK7. In some embodiments, the compounds of the present disclosure can be non-covalently or reversibly bound to a kinase. Non-covalent or reversible binding to a kinase may involve non-covalent interactions (e.g., electrostatic interactions, hydrophobic interactions, hydrogen bonding, van der Waals interactions, pi-pi stacking, or a combination thereof).

[0106] In some embodiments, R 1 is the formula (i-1): [ka] In some embodiments, R 1 is the expression: [ka] and m is 1. In some embodiments, R 1 is expressed as equation (i-2): [ka] In some embodiments, R 1 is expressed by the formula (i-3): [ka] In some embodiments, R 1 is expressed by the formula (i-4): [ka] In some embodiments, R 1 is expressed as equation (i-5): [ka] In some embodiments, R 1 is expressed as equation (i-6): [ka] In some embodiments, R 1 is expressed as equation (i-7): [ka] In some embodiments, R 1 is expressed as equation (i-8): [ka] In some embodiments, R 1 is expressed as equation (i-9): [ka] In some embodiments, R 1 is expressed as equation (i-10): [ka] In some embodiments, R 1 is expressed as equation (i-11): [ka] In some embodiments, R 1 is expressed as equation (i-12): [ka] In some embodiments, R1 is expressed as equation (i-13): [ka] In some embodiments, R 1 is expressed as equation (i-14): [ka] In some embodiments, R 1 is expressed as equation (i-15): [ka] In some embodiments, R 1 is expressed as equation (i-16): [ka] In some embodiments, R 1 is expressed as equation (i-17): [ka] In some embodiments, R 1 is expressed as equation (i-18): [ka] In some embodiments, R 1 is expressed as equation (i-19): [ka] In some embodiments, R 1 is expressed as equation (i-20): [ka] In some embodiments, R 1 is expressed as equation (i-21): [ka] In some embodiments, R 1 is expressed as equation (i-22): [ka] In some embodiments, R 1 is expressed as equation (i-23): [ka] In some embodiments, R 1 is expressed as equation (i-24): [ka] In some embodiments, R 1 is expressed as equation (i-25): [ka] In some embodiments, R 1 is expressed as equation (i-26): [ka] In some embodiments, R 1 is expressed as equation (i-27): [ka] In some embodiments, R 1 is expressed as equation (i-28): [ka] In some embodiments, R 1 is expressed as equation (i-29): [ka] In some embodiments, R 1 is expressed as equation (i-30): [ka] In some embodiments, R 1 is expressed as equation (i-31): [ka] In some embodiments, R 1 is expressed as equation (i-32): [ka] In some embodiments, R 1 is expressed as equation (i-33): [ka] In some embodiments, R 1 is expressed as equation (i-34): [ka] In some embodiments, R 1 is expressed as equation (i-35): [ka] In some embodiments, R 1 is expressed as equation (i-36): [ka] In some embodiments, R 1 is expressed as equation (i-37): [ka] In some embodiments, R1 is expressed as equation (i-38): [ka] In some embodiments, R 1 is expressed as equation (i-39): [ka] In some embodiments, R 1 is expressed as equation (i-40): [ka] In some embodiments, R 1 is expressed as equation (i-41): [ka] In some embodiments, R 1 is expressed as equation (i-42): [ka] In some embodiments, R 1 is expressed by the formula (i-1a): [ka] In some embodiments, R 1 is expressed by the formula (i-1b): [ka] In some embodiments, R 1 is expressed by the formula (i-1c): [ka] In some embodiments, R 1 is expressed as equation (i-1d): [ka] In some embodiments, R 1 is expressed as equation (i-1e): [ka] In some embodiments, R 1 is expressed as (i-1f): [ka] In some embodiments, R 1 is expressed as formula (i-1g): [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is expressed as formula (i-1g): [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is the expression: [ka] and m is 1. In some embodiments, R 1 is the expression: [ka] In some embodiments, R 1 is the expression: [ka] In some embodiments, R 1 is the expression: [ka] In some embodiments, R 1 is the expression: [ka] In some embodiments, R 1 is not expressed by any of the formulas (i-35) to (i-42).

[0107] In one embodiment, L 3 is a bond. L 3 is an arbitrary permutation of C 1~4 In some embodiments, L 3 is an arbitrary permutation of C 1~4 In some embodiments, L is alkylene. 3 is the unsubstituted C 1~4 In some embodiments, L is alkylene (e.g., —CH—). 3 is an arbitrary permutation of C 2~4アル In some embodiments, L 3 is an arbitrary permutation of C 2~4 alkynylene (e.g., —C≡C—). In some embodiments, L 3 is an arbitrary permutation of C 1~4 a hydrocarbon chain, wherein one or more carbon units of the hydrocarbon chain are independently —C(═O)—, —O—, —S—, or —NR L3a -, -NR L3a C(=O)-, -C(=O)NR L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O)O-, -NR L3a C(=S)-, -C(=S)NR L3a -, trans-CR L3b =CR L3b -, cis-CR L3b =CR L3b -, -C≡C-, -S(=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR L3a -, -NR L3a S(=O)-, -S(=O)2-, -S(=O)2O-, -OS(=O)2-, -S(=O)2NR L3a -, or -NR L3a In some embodiments, L is replaced by S(=O)-. 3 is an arbitrary permutation of C 1~4 a hydrocarbon chain, wherein one carbon unit of the hydrocarbon chain is -NR L3a In some embodiments, L is replaced with - (e.g., -NH-). 3 has the formula: -(CH2) 1-4 -NR L3a-(For example, -(CH2) 1-4 -NH-) or -NR L3a -CH2) 1~4 - (for example, -NH-CH2) 1-4 In some embodiments, L 3 is -NR L3a In some embodiments, L 3 is -NR L3a (C=O)—. In some embodiments, L 3 is -(C=O)NR L3a In some embodiments, L 3 is -NH-. In some embodiments, L 3 is —(C═O)—. In some embodiments, L 3 is —NH(C═O)—. In some embodiments, L 3 is —(C═O)NH—. In some embodiments, L 3 is —O—. In some embodiments, L 3 is -S-.

[0108] In some embodiments, R L3a is hydrogen. In some embodiments, R L3a is a substituted or unsubstituted acyl (e.g., -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2). In some embodiments, R L3a is an arbitrary permutation of C 1~6 alkyl (e.g., Me). In some embodiments, R L3a is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0109] When formula (I) encompasses more than one occurrence of a moiety, any two occurrences of that moiety may be the same or different from one another, unless otherwise provided.

[0110] In some embodiments, R L3bis hydrogen. L3b is hydrogen. L3b is -Cl, -Br, or -I. L3b is -Cl, -Br, or -I. L3b is -F. In some embodiments, R L3b is -F. In some embodiments, R L3b At least one instance of R is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. L3b At least one of R is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. L3b The groups may be joined to form an optionally substituted carbocyclic ring. L3b The groups are joined to form an optionally substituted heterocyclic ring.

[0111] In one embodiment, L 4 is a bond. 4 is an arbitrary permutation of C 1~6 In some embodiments, L 4 is an arbitrary permutation of C 1~3 In some embodiments, L is alkylene. 4 is -CH-. In some embodiments, L 4 is —(CH)—. In some embodiments, L 4 is -(CH2)3-.

[0112] In some embodiments, R E1 is hydrogen. In some embodiments, R E1 is -Cl, -Br, or -I. In some embodiments, R E1 is -F. In some embodiments, R E1 is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6In some embodiments, R E1 is optionally substituted alkenyl or optionally substituted alkynyl. In some embodiments, R E1 is an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl. E1 -CN, -CH2OR EE , -CHN(R EE )2, -CH2SR EE , -OR EE , -N(R EE )2, -Si(R EE )3, or -SR EE In some embodiments, R E1 is -CH2N(R EE )2. In some embodiments, R E1 is —CHN(optionally substituted alkyl) (e.g., —CHN(CH)). In some embodiments, R E1 In some embodiments, R E1 is -OH, -SH, or -NHR EE But it's not -NH2 either.

[0113] In some embodiments, R E2 is hydrogen. In some embodiments, R E2 is -Cl, -Br, or -I. In some embodiments, R E2 is -F. In some embodiments, R E2 is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R E2 is optionally substituted alkenyl or optionally substituted alkynyl. In some embodiments, R E2 is an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl. E2 -CN, -CH2OR EE , -CHN(R EE )2, -CH2SR EE , -OR EE , -N(R EE)2, -Si(R EE )3, or -SR EE In some embodiments, R E2 is -CH2N(R EE )2. In some embodiments, R E2 is —CHN(optionally substituted alkyl) (e.g., —CHN(CH)). In some embodiments, R E2 In some embodiments, R E2 is -OH, -SH, or -NHR EE But it's not -NH2 either.

[0114] In some embodiments, R E3 is hydrogen. In some embodiments, R E3 is -Cl, -Br, or -I. In some embodiments, R E3 is -F. In some embodiments, R E3 is an optionally substituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R E3 is optionally substituted alkenyl or optionally substituted alkynyl. In some embodiments, R E3 is an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl. E3 -CN, -CH2OR EE , -CHN(R EE )2, -CH2SR EE , -OR EE , -N(R EE )2, -Si(R EE )3, or -SR EE In some embodiments, R E3 is -CH2N(R EE )2. In some embodiments, R E3 is —CHN(optionally substituted alkyl) (e.g., —CHN(CH)). In some embodiments, R E3 In some embodiments, R E3 is -OH, -SH, or -NHR EE But it's not -NH2 either.

[0115] In some embodiments, R E1 and R E3 are joined to form an optionally substituted carbocyclic ring. E1 and R E3 are joined to form an optionally substituted heterocyclic ring. E2 and R E3 are joined to form an optionally substituted carbocyclic ring. E2 and R E3 are joined to form an optionally substituted heterocyclic ring. E1 and R E2 are joined to form an optionally substituted carbocyclic ring. E1 and R E2 are joined to form an optionally substituted heterocyclic ring.

[0116] In some embodiments, R EE is hydrogen. EE is hydrogen. EE Each instance of R is not hydrogen. EE In the case of at least one of 1~6 In some embodiments, R EE If at least one of 1~3 alkyl (e.g., Me). In some embodiments, R EE Each instance of R is optionally substituted alkyl. EE In each case, the unsubstituted C 1~3 alkyl (e.g., Me). In some embodiments, R EE At least one instance of R is optionally substituted alkenyl or optionally substituted alkynyl. EEAt least one instance of R is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. EE When two of these are joined together, they form a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). EE each occurrence of is independently hydrogen, or substituted or unsubstituted alkyl, or R EE two instances of are joined to form a substituted or unsubstituted heterocyclyl; and m is 1.

[0117] In some embodiments, R E4 is -Cl, -Br, or -I. In some embodiments, R E4 is -F. In some embodiments, R E4 is -OS(=O)R E4a or -OS(=O)2R E4a where R E4a is 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. E4 -OR E4a In some embodiments, R E4 is -OMs, -OTf, -OTs, -OBs, or 2-nitrobenzenesulfonyloxy. E4 is -OMe, -OCF, or -OPh. E4 is -OC(=O)R E4a In some embodiments, R E4 is -OC(=O)Me, -OC(=O)CF, -OC(=O)Ph, or -OC(=O)Cl. In some embodiments, R E4 is -OC(=O)OR E4a In some embodiments, R E4 is -OC(=O)OMe or -OC(=O)O(t-Bu).

[0118] In some embodiments, R E5 is -Cl, -Br, or -I. In some embodiments, R E5 is -F.

[0119] In some embodiments, R E6 is hydrogen. In some embodiments, R E6 is a substituted or unsubstituted C 1~ C alkyl (e.g., Me). In some embodiments, R E6 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0120] In some embodiments, a is 1. In some embodiments, a is 2.

[0121] In some embodiments, z is 0 at least once. In some embodiments, z is 1 at least once. In some embodiments, z is 2 at least once. In some embodiments, z is 3, 4, 5, or 6 at least once.

[0122] In some embodiments, at least one instance of Y is O. In some embodiments, each instance of Y is O. In some embodiments, at least one instance of Y is S. In some embodiments, at least one instance of Y is NR E7 In some embodiments, at least one instance of Y is NH.

[0123] In some embodiments, R E7 is hydrogen. In some embodiments, R E7 is a substituted or unsubstituted C 1~ C alkyl (e.g., Me). In some embodiments, R E7 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0124] In some embodiments, m is 0. In some embodiments, m is 1.

[0125] In some embodiments, R 2 At least one of R is halogen (e.g., F, Cl, Br, I). 2 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 2 is unsubstituted alkyl. 2 If at least one of 1~6 In some embodiments, R 2 At least one instance of R is Me. 2 is Et, Pr, or Bu. 2 If at least one of 1~6 In some embodiments, R 2 is substituted methyl (e.g., -CF, -CFH, -CFH). 2 is a substituted ethyl, a substituted propyl, or a substituted butyl. 2 is substituted or unsubstituted alkenyl. 2 If at least one of 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 2 At least one instance of R is substituted or unsubstituted alkynyl. 2 If at least one of 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 2At least one of R 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, valences permitting). 2 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). 2 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. 2 is substituted or unsubstituted aryl. 2 is substituted or unsubstituted phenyl. 2 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- to 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 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 2 At least one instance of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. 2 -OR if at least one of a (Examples include -OH, -O(substituted or unsubstituted, C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 2 In some embodiments, at least one of R 2 If at least one of a (Examples include -SH, -S (substituted or unsubstituted, C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 2 If there is at least one of -N(R a )2 (e.g., -NH2, -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., -NMe2)). In some embodiments, R 2 In some embodiments, at least one of R 2 In some embodiments, at least one of R 2 If at least one of -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(Ra )2. In some embodiments, R 2 If at least one of the following occurs, it is -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 occurs, -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 occurs, -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 2 If at least one of 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)). In some embodiments, R 2 If at least one of a C(=O)OR a In some embodiments, R 2 If at least one of a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -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 occurs, -OC(=O)R a(Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -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)NH2, -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)).

[0126] 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, 5, or 6.

[0127] In some embodiments, 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, -NO2, -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 n is 1 or 2, valence permitting.

[0128] In some embodiments, L is a single bond. In some embodiments, L is -C(=O)-.

[0129] Formula (I) is R 3 as a substituent on the nitrogen atom. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a substituted or unsubstituted acyl (e.g., -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2). In some embodiments, R 3 is a substituted or unsubstituted alkyl (e.g., substituted or unsubstituted, C 1~6 In some embodiments, R 3 is Me. In some embodiments, R 3 is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. 3 is a nitrogen protecting group (e.g., Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0130] Formula (I) is a ring B [ka] Ring B is a heteroaryl ring. Formula (I) also includes ring C [ka] Ring B and ring C are fused together to form a bicyclic ring. [ka] In one embodiment, [ka] In one embodiment, [ka] In some embodiments, R 4 When is hydrogen, [ka] Also, other tautomeric forms [ka] Also includes.

[0131] Formula (I) is a group containing a substituent R 4 on the nitrogen atom of ring B. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a substituted or unsubstituted acyl (e.g., -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2). In some embodiments, R 4 is a substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 4 is Me. In some embodiments, R 4 is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. 4 is a nitrogen protecting group (e.g., Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0132] Formula (I) is a group containing a substituent R 5a and R 5b on the carbon atom of ring C.

[0133] In some embodiments, R 5a is hydrogen. In some embodiments, R 5ais a halogen (e.g., F, Cl, Br, I). In some embodiments, R 5a is a substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In some embodiments, R 5a is unsubstituted alkyl. In some embodiments, R 5a is the unsubstituted C 1~6 In some embodiments, R 5a is Me. In some embodiments, R 5a is Et, Pr, or Bu. 5a is a substitution C 1~6 In some embodiments, R 5a is a substituted methyl (e.g., -CF, -CFH, -CFH). In some embodiments, R 5a is a substituted ethyl, substituted propyl, or substituted butyl. 5a is substituted or unsubstituted alkenyl. In some embodiments, R 5a is a substituted or unsubstituted C 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 5a is substituted or unsubstituted alkynyl. In some embodiments, R 5a is a substituted or unsubstituted C 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 5a 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, valences permitting). 5a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 5a is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 5ais 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. 5a is substituted or unsubstituted aryl. In some embodiments, R 5a is substituted or unsubstituted phenyl. In some embodiments, R 5a is substituted or unsubstituted naphthyl. In some embodiments, R 5a is substituted or unsubstituted heteroaryl. In some embodiments, R 5a is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, R 5a 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. 5a is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 5a is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. In some embodiments, R 5a -OR a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 5a In some embodiments, R 5a -SR a (Examples include -SH, -S(substituted or unsubstituted C 1~6In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 5a is -N(R a )2 (e.g., -NH2, -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., -NMe2)). In some embodiments, R 5a is -CN or -SCN. In some embodiments, R 5a is -NO2. In some embodiments, R 5a is -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a )2. In some embodiments, R 5a is -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 5a is -C(=O)OR a( Examples include -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 5a is -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 5a is -NR a C(=O)Ra (For example, -NHC(=O) (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)Me) or —NHC(═O)(substituted or unsubstituted phenyl)). In some embodiments, R 5a is -NR a C(=O)OR a In some embodiments, R 5a is -NR a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 5a is -OC(=O)R a (Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -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)NH2, -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)).

[0134] In some embodiments, R 5b is hydrogen. In some embodiments, R 5b is a halogen (e.g., F, Cl, Br, I). In some embodiments, R 5b is a substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In some embodiments, R 5b is unsubstituted alkyl. In some embodiments, R 5b is the unsubstituted C 1~6 In some embodiments, R 5bis Me. In some embodiments, R 5b is Et, Pr, or Bu. 5b is a substitution C 1~6 In some embodiments, R 5b is a substituted methyl (e.g., -CF, -CFH, -CFH). In some embodiments, R 5b is a substituted ethyl, substituted propyl, or substituted butyl. 5b is substituted or unsubstituted alkenyl. In some embodiments, R 5b is a substituted or unsubstituted C 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 5b is substituted or unsubstituted alkynyl. In some embodiments, R 5b is a substituted or unsubstituted C 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 5b 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, valences permitting). 5b is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 5b is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 5b 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. 5b is substituted or unsubstituted aryl. In some embodiments, R5b is substituted or unsubstituted phenyl. In some embodiments, R 5b is substituted or unsubstituted naphthyl. In some embodiments, R 5b is substituted or unsubstituted heteroaryl. In some embodiments, R 5b is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, R 5b 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. 5b is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 5b is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. In some embodiments, R 5b -OR a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 5b In some embodiments, R 5b -SR a (Examples include -SH, -S(substituted or unsubstituted C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 5b is -N(R a )2 (e.g., -NH2, -NH(substituted or unsubstituted C 1~6 alkyl) (e.g., -NHMe), or -N(substituted or unsubstituted C 1~6 alkyl)-(substituted or unsubstituted C1~6 alkyl) (e.g., -NMe2)). In some embodiments, R 5b is -CN or -SCN. In some embodiments, R 5b is -NO2. In some embodiments, R 5b is -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a )2. In some embodiments, R 5b is -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 5b is -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 5b is -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 5b is -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)). In some embodiments, R 5b is -NR a C(=O)OR a In some embodiments, R 5b is -NR a C(=O)N(R a)2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted, C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 5b is -OC(=O)R a (Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -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)NH2, -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)).

[0135] In some embodiments, R 5a and R 5b are the same. In some embodiments, R 5a and R 5b Each of R is hydrogen. 5a and R 5b Each of R is substituted or unsubstituted alkyl. 5a and R 5b Each of R is Me. 5a and R 5b are different from each other. 5a is hydrogen, and R 5b is substituted or unsubstituted alkyl (e.g., Me). In some embodiments, R 5b is hydrogen, and R 5a is substituted or unsubstituted alkyl (eg, Me).

[0136] In some embodiments, R 5a and R 5bare joined to form a substituted or unsubstituted carbocyclyl. 5a and R 5b are joined to form an optionally substituted, monocyclic C3-C6 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). 5a and R 5b are joined to form a substituted or unsubstituted heterocyclyl. 5a and R 5b are joined to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl).

[0137] Formula (I) is a group containing a substituent R 6 and R 7 on the carbon atom of ring C. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is a halogen (e.g., F, Cl, Br, I). In some embodiments, R 6 is a substituted or unsubstituted C 1~3 In some embodiments, R 6 is a substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In some embodiments, R 6 is unsubstituted alkyl. In some embodiments, R 6 is the unsubstituted C 1~6 In some embodiments, R 6 is Me. In some embodiments, R 6 is Et, Pr, or Bu. 6 is a substitution C 1~6 In some embodiments, R 6 is a substituted methyl (e.g., -CF, -CFH, -CFH). In some embodiments, R 6 is a substituted ethyl, substituted propyl, or substituted butyl. 6is hydrogen, halogen, or substituted or unsubstituted alkyl. 6 is substituted or unsubstituted alkenyl. In some embodiments, R 6 is a substituted or unsubstituted C 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 6 is substituted or unsubstituted alkynyl. In some embodiments, R 6 is a substituted or unsubstituted C 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 6 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, valences permitting). 6 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 6 is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 6 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. 6 is substituted or unsubstituted aryl. In some embodiments, R 6 is substituted or unsubstituted phenyl. In some embodiments, R 6 is substituted or unsubstituted naphthyl. In some embodiments, R 6 is substituted or unsubstituted heteroaryl. In some embodiments, R 6is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, R 6 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. 6 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 6 is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. In some embodiments, R 6 -OR a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 6 In some embodiments, R 6 -SR a (Examples include -SH, -S(substituted or unsubstituted C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 6 is -N(R a )2 (e.g., -NH2, -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., -NMe2)). In some embodiments, R 6 is -CN or -SCN. In some embodiments, R 6 is -NO2. In some embodiments, R 6 is -C(=NRa )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a )2. In some embodiments, R 6 is -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 6 is -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 6 is -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 6 is -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)). In some embodiments, R 6 is -NR a C(=O)OR a In some embodiments, R 6 is -NR a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 6 is -OC(=O)R a(Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -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)NH2, -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)).

[0138] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is a halogen (e.g., F, Cl, Br, I). In some embodiments, R 7 is a substituted or unsubstituted C 1~3 In some embodiments, R 7 is a substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., F)). In some embodiments, R 7 is unsubstituted alkyl. In some embodiments, R 7 is the unsubstituted C 1~6 In some embodiments, R 7 is Me. In some embodiments, R 7 is Et, Pr, or Bu. 7 is a substitution C 1~6 In some embodiments, R 7 is a substituted methyl (e.g., -CF, -CFH, -CFH). In some embodiments, R 7 is a substituted ethyl, substituted propyl, or substituted butyl. 7 is hydrogen, halogen, or substituted or unsubstituted alkyl. 7 is substituted or unsubstituted alkenyl. In some embodiments, R7 is a substituted or unsubstituted C 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 7 is substituted or unsubstituted alkynyl. In some embodiments, R 7 is a substituted or unsubstituted C 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 7 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, valences permitting). 7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 7 is a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 7 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. 7 is substituted or unsubstituted aryl. In some embodiments, R 7 is substituted or unsubstituted phenyl. In some embodiments, R 7 is substituted or unsubstituted naphthyl. In some embodiments, R 7 is substituted or unsubstituted heteroaryl. In some embodiments, R 7 is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, R 7is 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. 7 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 7 is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. In some embodiments, R 7 -OR a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 7 In some embodiments, R 7 -SR a (Examples include -SH, -S(substituted or unsubstituted C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 7 is -N(R a )2 (e.g., -NH2, -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., -NMe2)). In some embodiments, R 7 is -CN or -SCN. In some embodiments, R 7 is -NO2. In some embodiments, R 7 is -C(=NR a )R a , -C(=NR a ) OR a, or -C(=NR a )N(R a )2. In some embodiments, R 7 is -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 7 is -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 7 is -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 7 is -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)). In some embodiments, R 7 is -NR a C(=O)OR a In some embodiments, R 7 is -NR a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 7 is -OC(=O)R a (Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)ORa (e.g., -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)NH2, -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, R 6 and R 7 are the same. In some embodiments, R 6 and R 7 Each of R is hydrogen. 6 and R 7 Each of R is substituted or unsubstituted alkyl. 6 and R 7 Each of R is Me. 6 and R 7 are different from each other. 6 is hydrogen, and R 7 is substituted or unsubstituted alkyl (e.g., Me). In some embodiments, R 7 is hydrogen, and R 6 is substituted or unsubstituted alkyl (eg, Me).

[0140] In some embodiments, R 6 and R 7 are joined to form a substituted or unsubstituted carbocyclyl. 6 and R 7 are joined to form an optionally substituted, monocyclic C3-C6 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). 6 and R 7do not combine to form an unsubstituted cyclopropyl. 6 and R 7 do not combine to form a substituted or unsubstituted cyclopropyl. 6 and R 7 do not combine to form a substituted or unsubstituted carbocyclyl. 6 and R 7 are joined to form a substituted or unsubstituted heterocyclyl. 6 and R 7 are joined to form an optionally substituted, monocyclic, 3- to 7-membered heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl).

[0141] Formula (I) is R 8 In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is a substituted or unsubstituted acyl (e.g., -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2). In some embodiments, R 8 is a substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 8 is Me. In some embodiments, R 8 is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. 8 is a nitrogen protecting group (e.g., Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0142] In some embodiments, R 9 is hydrogen. 9 is hydrogen. 9At least one of R is halogen (e.g., F, Cl, Br, I). 9 If at least one of 1~3 In some embodiments, R 9 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 9 If at least one of the following is true, then at least -N(R a )2. In some embodiments, R 9 If at least one of the following occurs, -(CH2) 1~3 -N(substituted or unsubstituted alkyl) (e.g., -CH-N(substituted or unsubstituted alkyl)). In some embodiments, R 9 In some embodiments, at least one of R 9 is unsubstituted alkyl. 9 If at least one of 1~6 In some embodiments, R 9 At least one instance of R is Me. 9 is Et, Pr, or Bu. 9 If at least one of 1~6 In some embodiments, R 9 is substituted methyl (e.g., -CF, -CFH, -CFH). 9 is a substituted ethyl, a substituted propyl, or a substituted butyl. 9 is hydrogen, halogen, or substituted or unsubstituted alkyl. 9 is substituted or unsubstituted alkenyl. 9If at least one of 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 9 At least one instance of R is substituted or unsubstituted alkynyl. 9 If at least one of 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 9 At least one of R 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, valence permitting). 9 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 9 At least one of R is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 9 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. 9 is substituted or unsubstituted aryl. 9 is substituted or unsubstituted phenyl. 9 is substituted or unsubstituted naphthyl. 9 At least one instance of R is substituted or unsubstituted heteroaryl.9 At least one of R is a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl. 9 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. 9 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 9 At least one instance of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. 9 -OR if at least one of a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 9 In some embodiments, at least one of R 9 If at least one of a (Examples include -SH, -S(substituted or unsubstituted C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 9 If there is at least one of -N(R a )2 (e.g., -NH2, -NH(substituted or unsubstituted C 1~6 alkyl) (e.g., -NHMe), or -N(substituted or unsubstituted C 1~6 alkyl)-(substituted or unsubstituted C 1~6alkyl) (e.g., -NMe2)). In some embodiments, R 9 In some embodiments, at least one of R 9 In some embodiments, at least one of R 9 If at least one of -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a )2. In some embodiments, R 9 If at least one of the following occurs, it is -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 9 If at least one of the following occurs, -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 9 If at least one of the following occurs, -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 9 If at least one of 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)). In some embodiments, R 9 If at least one ofa C(=O)OR a In some embodiments, R 9 If at least one of a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 9 If at least one of the following occurs, -OC(=O)R a (Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -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)NH2, -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)).

[0143] In some embodiments, R 10 is hydrogen. 10 is hydrogen. 10 At least one of R is halogen (e.g., F, Cl, Br, I). 10 If at least one of 1~3 In some embodiments, R 10 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 10 If at least one of the following is true, then at least -N(R a )2. In some embodiments, R10 If at least one of the following occurs, -(CH2) 1-3 -N(substituted or unsubstituted alkyl) (e.g., -CH-N(substituted or unsubstituted alkyl)). In some embodiments, R 10 In some embodiments, at least one of R 10 is unsubstituted alkyl. 10 If at least one of 1~6 In some embodiments, R 10 At least one instance of R is Me. 10 is Et, Pr, or Bu. 10 If at least one of 1~6 In some embodiments, R 10 is substituted methyl (e.g., -CF, -CFH, -CFH). 10 is a substituted ethyl, a substituted propyl, or a substituted butyl. 10 is hydrogen, halogen, or substituted or unsubstituted alkyl. 10 is substituted or unsubstituted alkenyl. 10 If at least one of 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 10 At least one instance of R is substituted or unsubstituted alkynyl. 10 If at least one of 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 10At least one of R 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, valence permitting). 10 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 10 At least one of R is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 10 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. 10 is substituted or unsubstituted aryl. 10 is substituted or unsubstituted phenyl. 10 is substituted or unsubstituted naphthyl. 10 At least one instance of R is substituted or unsubstituted heteroaryl. 10 At least one of R is a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl. 10 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.10 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 10 At least one instance of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. 10 -OR if at least one of a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 10 In some embodiments, at least one of R 10 If at least one of a (Examples include -SH, -S(substituted or unsubstituted C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 10 If there is at least one of -N(R a )2 (e.g., -NH2, -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., -NMe2)). In some embodiments, R 10 In some embodiments, at least one of R 10 In some embodiments, at least one of R 10 If at least one of -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(Ra )2. In some embodiments, R 10 If at least one of the following occurs, it is -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 10 If at least one of the following occurs, -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 10 If at least one of the following occurs, -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 10 If at least one of 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)). In some embodiments, R 10 If at least one of a C(=O)OR a In some embodiments, R 10 If at least one of a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted, C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 10 If at least one of the following occurs, -OC(=O)R a(Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -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)NH2, -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)).

[0144] In some embodiments, —C(R 9 )(R 10 In some embodiments, -C(R 9 )(R 10 In any instance, R 9 and R 10 In no instance is R unsubstituted phenyl. 9 and R 10 In no case is substituted or unsubstituted phenyl.

[0145] In one embodiment, [ka] If at least one of [ka] wherein bond a is attached to ring D. In some embodiments, [ka] If at least one of [ka] wherein bond a is attached to ring D. In some embodiments, [ka] If at least one of [ka] wherein bond a is attached to ring D. In some embodiments, [ka] If at least one of [ka] where bond a is attached to ring D.

[0146] In one embodiment, [ka] wherein bond a is attached to the ring. [ka] wherein bond a is attached to ring D. In some embodiments, [ka] wherein bond a is attached to ring D. In some embodiments, [ka] wherein bond a is attached to ring D. In some embodiments, [ka] where bond a is attached to ring D.

[0147] R 12 each instance of is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, or a nitrogen protecting group, or R 12 two instances of R are joined to form a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl. 12 is hydrogen. 12 is hydrogen. 12 In any case, R is not hydrogen. 12 In the case of at least one of the following, it is a substituted or unsubstituted acyl (e.g., -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2). In some embodiments, R 12 In the case of at least one of the above, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1~6 In some embodiments, R 12 Each instance of R is substituted or unsubstituted alkyl. 12 At least one instance of R is Me. 12 Each instance of is Me. In some embodiments, R 12 is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. 12 is hydrogen, and R 12 In the case of 1~6 In some embodiments, R12 is hydrogen, and R 12 In some embodiments, R 12 is substituted or unsubstituted phenyl. 12 In some embodiments, at least one of R is a nitrogen protecting group (e.g., Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts). 12 When two of these are joined together, they form a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 12 two instances of R combine to form a substituted or unsubstituted azetidinyl, a substituted or unsubstituted pyrrolidinyl, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted morpholinyl, or a substituted or unsubstituted piperazinyl. 12 When two of the above are joined together, they form a substituted or unsubstituted heteroaryl (e.g., a substituted or unsubstituted 5- to 6-membered, monocyclic heteroaryl containing at least one nitrogen atom in the heteroaryl ring system).

[0148] In some embodiments, R 9 and R 10 are joined to form a substituted or unsubstituted carbocyclyl. 9 and R 10 are joined to form an optionally substituted monocyclic C3-C9 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). 9 and R 10 do not combine to form an unsubstituted cyclopropyl. 9 and R 10 do not combine to form a substituted or unsubstituted cyclopropyl. 9 and R 10 do not combine to form a substituted or unsubstituted carbocyclyl.9 and R 10 do not combine to form a substituted or unsubstituted heterocyclyl. 9 and R 10 are linked to form an optionally substituted monocyclic C3-C9 heterocyclyl (eg, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl).

[0149] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0150] Formula (I) is a ring D [ka] In some embodiments, Ring D is carbocyclyl. In some embodiments, Ring D is a monocyclic, 3- to 7-membered carbocyclyl containing 0, 1, or 2 double bonds in the carbocyclic ring system, valence permitting. In some embodiments, Ring D is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring D is cyclopropyl. In some embodiments, [ka] In one embodiment, [ka] In some embodiments, Ring D is a bicyclic, 5- to 13-membered carbocyclyl containing zero, one, two, or three double bonds in the carbocyclic ring system, as valences permit. In some embodiments, Ring D is a monocyclic, 3- to 7-membered carbocyclyl fused to a phenyl, wherein the monocyclic, 3- to 7-membered carbocyclyl contains zero or one double bond in the non-fused portion of the carbocyclic ring system, as valences permit.

[0151] In some embodiments, ring D is heterocyclyl. In some embodiments, ring D is a monocyclic 3- to 7-membered heterocyclyl. In some embodiments, ring D is a monocyclic 5- or 6-membered heterocyclyl. In some embodiments, each heteroatom in the heterocyclic ring system of ring D is oxygen. In some embodiments, each heteroatom in the heterocyclic ring system of ring D is nitrogen. In some embodiments, ring D is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl. In some embodiments, ring D is tetrahydropyranyl. In some embodiments, [ka] In some embodiments, ring D is tetrahydrofuranyl. [ka] In some embodiments, ring D is piperazinyl. [ka] In some embodiments, ring D is morpholinyl. [ka] In some embodiments, ring D is piperidinyl. [ka] In one embodiment, [ka] In one embodiment, [ka] In some embodiments, Ring D is a bicyclic 5- to 13-membered heterocyclyl. In some embodiments, Ring D is a monocyclic 3- to 7-membered heterocyclyl fused to phenyl. In some embodiments, [ka] In one embodiment, [ka] In one embodiment, [ka] is.

[0152] In one embodiment, [ka] is not pyrrolidinyl. [ka] In one embodiment, [ka] is not piperidinyl. [ka] In some embodiments, when p is 0, Ring D does not contain one or more nitrogen atoms in the ring system. In some embodiments, when p is 2, Ring D is not pyrrolidinyl. In some embodiments, when p is 2, Ring D is not morpholinyl. In some embodiments, when p is 1, Ring D is not cyclohexyl.

[0153] Ring D may contain one or more substituents R 11 R 11 may be attached to any atom of the carbocyclic or heterocyclic ring system (e.g., monocyclic or bicyclic ring system) of Ring D, valence permitting. In certain embodiments, R 11 At least one of R is halogen (e.g., F, Cl, Br, I). 11 If at least one of 1~3 In some embodiments, R 11 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 11 If at least one of the following is true, then at least -N(R a )2. In some embodiments, R 11 If at least one of the following occurs, -(CH2) 1~3 -N(substituted or unsubstituted alkyl) (e.g., -CH-N(substituted or unsubstituted alkyl)). In some embodiments, R 11 In some embodiments, at least one of R 11 is unsubstituted alkyl. 11 If at least one of 1~6 In some embodiments, R 11 At least one instance of R is Me. 11 is Et, Pr, or Bu. 11 If at least one of 1~6 In some embodiments, R 11 is substituted methyl (e.g., -CF, -CFH, -CFH). 11 is a substituted ethyl, a substituted propyl, or a substituted butyl.11 is hydrogen, halogen, or substituted or unsubstituted alkyl. 11 is substituted or unsubstituted alkenyl. 11 If at least one of 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R 11 At least one instance of R is substituted or unsubstituted alkynyl. 11 If at least one of 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R 11 At least one of R 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, valence permitting). 11 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. 11 At least one of R is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). 11 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. 11 is substituted or unsubstituted aryl. 11is substituted or unsubstituted phenyl. 11 is substituted or unsubstituted naphthyl. 11 At least one instance of R is substituted or unsubstituted heteroaryl. 11 At least one of R is a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl. 11 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. 11 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. 11 At least one instance of R is a substituted or unsubstituted 9-11 membered bicyclic heteroaryl. 11 -OR if at least one of a (Examples include -OH, -O(substituted or unsubstituted C 1~6 In some embodiments, R is -O(substituted or unsubstituted phenyl) (e.g., -OMe, -OCF3, -OEt, -OPr, -OBu, or -OBn), or -O(substituted or unsubstituted phenyl) (e.g., -OPh). 11 In some embodiments, at least one of R 11 If at least one of a (Examples include -SH, -S(substituted or unsubstituted C 1~6 In some embodiments, R is -S(substituted or unsubstituted phenyl) (e.g., -SMe, -SCF, -SEt, -SPr, -SBu, or -SBn), or -S(substituted or unsubstituted phenyl) (e.g., -SPh). 11If there is at least one of -N(R a )2 (e.g., -NH2, -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., -NMe2)). In some embodiments, R 11 In some embodiments, at least one of R 11 In some embodiments, at least one of R 11 If at least one of -C(=NR a )R a , -C(=NR a ) OR a , or -C(=NR a )N(R a )2. In some embodiments, R 11 If at least one of the following occurs, it is -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 11 If at least one of the following occurs, -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 11 If at least one of the following occurs, -C(=O)N(R a ) (e.g., —C(═O)NH, —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)). In some embodiments, R 11 If at least one of a C(=O)Ra (For example, -NHC(=O) (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)Me) or —NHC(═O)(substituted or unsubstituted phenyl)). In some embodiments, R 11 If at least one of a C(=O)OR a In some embodiments, R 11 If at least one of a C(=O)N(R a )2 (e.g., -NHC(=O)NH2, -NHC(=O)NH (substituted or unsubstituted C 1~6 alkyl) (e.g., —NHC(═O)NHMe)). In some embodiments, R 11 If at least one of the following occurs, -OC(=O)R a (Examples include -OC(=O)(substituted or unsubstituted alkyl) or -OC(=O)(substituted or unsubstituted phenyl)), -OC(=O)OR a (e.g., -OC(=O)O (substituted or unsubstituted alkyl) or -OC(=O)O (substituted or unsubstituted phenyl)), or -OC(=O)N(R a )2 (e.g., -OC(=O)NH2, -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)). In some embodiments, R 11 In the case of at least one of the groups, it is a nitrogen protecting group (eg, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, Ts).

[0154] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0155] In some embodiments, Ra is hydrogen. a is hydrogen. a In some embodiments, at least one of R a In any case, R is not hydrogen. a 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 a is unsubstituted alkyl. a If at least one of 1~6 In some embodiments, R a At least one instance of R is Me. a is Et, Pr, or Bu. a If at least one of 1~6 In some embodiments, R a is substituted methyl. a is a substituted ethyl, a substituted propyl, or a substituted butyl. a is substituted or unsubstituted alkenyl. a If at least one of 2~6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In some embodiments, R a At least one instance of R is substituted or unsubstituted alkynyl. a If at least one of 2~6 alkynyl (substituted or unsubstituted ethynyl). In some embodiments, R aAt least one of R 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, valence permitting). a 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 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- to 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 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. a At least one instance of R is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl. a When attached to a nitrogen atom, at least one of R is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). a When attached to an oxygen atom, at least one of R is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl). a When two of these are joined together, they form a substituted or unsubstituted heterocyclyl (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl). a When two of the above are combined, they form a substituted or unsubstituted heteroaryl (for example, a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl).

[0156] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0157] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0158] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0159] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0160] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0161] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0162] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0163] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0164] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0165] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0166] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0167] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0168] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, with the proviso that R 10 is not hydrogen.

[0169] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, with the proviso that R 10 is not hydrogen.

[0170] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally [ka] is.

[0171] In some embodiments, the compound has the formula: [ka] or [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally [ka] is.

[0172] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally [ka] is.

[0173] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally [ka]

[0174] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0175] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0176] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0177] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0178] In some embodiments, the compound has the formula: [ka] or [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally [ka] is.

[0179] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally [ka] is.

[0180] In some embodiments, the compound has the formula: [ka] [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0181] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0182] In some embodiments, the compound has the formula: [ka] or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0183] In certain embodiments, provided compounds (compounds described herein, compounds of the present disclosure) are compounds represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, provided compounds are compounds represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In certain embodiments, provided compounds are compounds represented by Formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, provided compounds are compounds represented by Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, provided compounds are a mixture of tautomers. In certain embodiments, provided compounds are a mixture of enantiomers and / or diastereomers (e.g., a racemic mixture).

[0184] In some embodiments, the molecular weight of a 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 a provided compound, when not in the form of a salt, solvate, hydrate, co-crystal, or prodrug, is less than 1,000 g / mol. In some embodiments, the molecular weight of a provided compound, when not in the form of a salt, solvate, hydrate, co-crystal, or prodrug, is less than 600 g / mol.

[0185] 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., a 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, provided compounds inhibit the activity of the kinase as measured in an assay described herein or known in the art. In some embodiments, provided compounds 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 μM50 , 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.

[0186] Some CDK7 inhibitors have also been reported to inhibit the activity of CDK12 and / or CDK13 (Kwiatowski et al., Nature, 511, 616-620 (2014)). 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, 50 The 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 K of the adduct of the compound or pharmaceutical composition and the first kinase. d the K of the adduct of the compound or pharmaceutical composition and the second kinase dThe selectivity may also be measured by a quotient of the values ​​of the kinase activity. In certain 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 certain embodiments, provided compounds 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). Compounds of the present disclosure may be advantageous over non-selective or less selective kinase inhibitors for treatment and / or prevention in subjects in need thereof. The compounds of the present disclosure may be more selective for inhibiting the activity of a CDK (e.g., CDK7) than other kinases (e.g., kinases other than CDKs, kinases other than CDK7, CDKs other than CDK7) than other compounds (e.g., non-selective kinase inhibitors, less selective kinase inhibitors). In some embodiments, provided compounds are more selective for inhibiting the activity of CDK7 than CDK2 (e.g., by 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., by 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 kinases. In some embodiments, provided compounds bind irreversibly (e.g., covalently) to kinases. 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 these compounds' advantages over other compounds, e.g., selectivity for inhibiting the activity of CDK7 over other kinases (e.g., CDKs other than CDK7). Irreversible binding of certain compounds disclosed herein 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 depicts CDK7-responsive genes, particularly the MYC and MCL-1 genes, as important genes in maintaining cellular malignant or precancerous states. Selective inhibition of CDK7 may be useful for treating or preventing proliferative diseases.

[0187] Compared to other compounds, the compounds of the present disclosure may be more potent, more effective, and / or less toxic when used to treat and / or prevent diseases in subjects in need thereof. Compared to other compounds, the compounds of the present disclosure may also reduce the frequency of side effects, reduce the severity of side effects, increase subject compliance, and / or reduce tolerance when used to treat and / or prevent diseases in subjects in need thereof. Furthermore, the compounds of the present disclosure may be more soluble, more permeable, more stable in microsomes, and / or more bioavailable, and / or exhibit improved pharmacokinetic properties compared to other compounds. The compounds of the present disclosure include a carbocyclyl or heterocyclyl as ring D. Without wishing to be bound by any particular theory, ring D may contribute to one or more of the above advantages of the compounds of the present disclosure over certain other compounds.

[0188] In another aspect, the present disclosure provides methods for preparing the compounds described herein. In some embodiments, the preparation method is a method described herein (e.g., the method described in Example 1).

[0189] Pharmaceutical Compositions, Kits, and Administration In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and, optionally, a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition of the present disclosure includes an effective amount of a compound of the present disclosure.

[0190] 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 protein 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 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).

[0191] 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 protein 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 protein 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).

[0192] In some embodiments, an effective amount is an amount effective to inhibit the activity of a protein 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 protein 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 protein kinase (e.g., a CDK (e.g., CDK7)) by a difference in a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0193] 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 other embodiments, 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.

[0194] In some embodiments, the biological sample, tissue, or cell (e.g., a biological sample, tissue, or cell that has been 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).

[0195] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods of preparation include bringing into association a compound described herein (i.e., the "active ingredient") with the 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 a desired single-dose or multi-dose unit.

[0196] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the 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.

[0197] The relative amounts of the active ingredient, pharmaceutically 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.

[0198] Pharmaceutically acceptable excipients used in the preparation 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 compositions.

[0199] 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.

[0200] 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.

[0201] 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, methylcellulose), and the like. 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.

[0202] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, isapol husk mucilage, 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.

[0203] 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.

[0204] 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.

[0205] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, 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.

[0206] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0207] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0208] 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.

[0209] Other preservatives include tocopherol, tocopheryl 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®.

[0210] 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.

[0211] 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.

[0212] 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 linseed, litsea basil, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, camellia sasanqua, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0213] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, 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 fragrances. 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.

[0214] Injectable preparations, for example, sterile injectable aqueous or oily suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol.Among acceptable vehicles and solvents, water, Ringer's solution (USP), and isotonic sodium chloride solution can be used.In addition, sterile fixed oils are conventionally used as solvents or suspending media.For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, can be used.In addition, fatty acids such as oleic acid are used in injectable preparations.

[0215] Injectable formulations can be 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.

[0216] 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 absorption rate of the drug depends on its dissolution rate at that time, which in turn depends 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.

[0217] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing a conjugate described herein with a suitable non-irritating 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 melt in the rectum or vaginal cavity to release the active ingredient.

[0218] 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, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0219] 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. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmacological arts. They may optionally contain opacifying agents and may be of a composition that releases 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. 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.

[0220] The active ingredient may be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active ingredient may be admixed with at least one inert diluent, such as sucrose, lactose, or starch. Such solid dosage forms may contain, as is normal practice, additional substances other than inert diluents, such as 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 releases 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.

[0221] 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. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient, and / or any necessary preservatives and / or buffers as needed. In addition, the present disclosure contemplates the use of transdermal patches, which often have the additional 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 suitable 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.

[0222] Devices suitable for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices that limit the effective penetration depth of the needle into the skin. Alternatively or additionally, a conventional syringe can be used in the classic Mantoux method of intradermal administration. Jet injection devices that deliver liquid vaccines to the dermis via a liquid jet source and / or via a needle that generates a jet that penetrates the stratum corneum and reaches the dermis are suitable. Ballistic powder / particle delivery devices that use compressed gas to accelerate a powdered compound through the outer layers of the skin into the dermis are suitable.

[0223] 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) active ingredient, although the concentration of the active ingredient may be 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 described herein.

[0224] The pharmaceutical compositions described herein may be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the oral cavity. Such formulations may comprise dry particles containing 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 containing a dry powder reservoir (into which a continuous stream of propellant can be introduced to disperse the powder) and / or using a self-propelling solvent / powder dispensing container (such as a device containing the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container). 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.

[0225] 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 nonionic and / or solid anionic surfactants, and / or solid diluents (which may have particle sizes similar to those of the particles containing the active ingredient).

[0226] 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 containing the active ingredient, optionally sterilized, and may be conveniently administered using either a nebulizer and / or atomizer device. Such formulations may further contain one or more additional ingredients, including flavoring agents such as saccharin sodium, 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.

[0227] The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having 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.

[0228] Formulations for nasal administration may contain, for example, 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 also be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations may be in the form of, for example, 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 disintegrable composition, and optionally one or more 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 ranging from about 0.1 to about 200 nanometers, and may further comprise one or more additional ingredients described herein.

[0229] 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, including, for example, a 0.1 / 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 include 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 the present disclosure.

[0230] 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. The modification of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modifications using routine experimentation.

[0231] The compound provided herein is typically formulated in dosage unit form for ease of administration and dosage uniformity.However, it will be understood that the total daily use amount of the compositions described herein will be determined by a physician 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 used; the specific composition being used; 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 used; the duration of treatment; the drug that is used in combination with or at the same time as the specific active ingredient being used; and similar factors well known in the medical field.

[0232] 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, vaginal, intraperitoneal, topical (such 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. Specific contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood and / or lymphatic supply, and / or direct administration to the affected area. Generally, the most appropriate route of administration will depend on various factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) 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 subject's eye.

[0233] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, the severity of side effects or disorders, the identity of the particular compound(s), the mode of administration, etc. An effective amount may be contained 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 contain different or substantially the same amounts of a 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 with which the multiple doses are administered to a subject or applied 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 3 days, 1 dose every week, 1 dose every other week, 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 one 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 two 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 three 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 the 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 in a single dose or multiple doses) independently comprise 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 comprise between 1 mg and 3 mg, inclusive, of a compound described herein. In some embodiments, the doses described herein independently comprise between 3 mg and 10 mg, inclusive, of a compound described herein. In some embodiments, the doses described herein independently comprise between 10 mg and 30 mg, inclusive, of a compound described herein. In some embodiments, the doses described herein independently encompass between 30 mg and 100 mg, inclusive, of a compound described herein.

[0234] The dosage ranges 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 doctor 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.

[0235] 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., 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, and / or 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 alters metabolism, inhibits excretion, and / or alters 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 different effects. In certain embodiments, pharmaceutical compositions described herein that include a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is not present in pharmaceutical compositions that include either the compound or the additional pharmaceutical agent, but not both.

[0236] 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 small organic molecules such as 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. In some embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for the treatment and / or prevention of a disease (e.g., a proliferative disease, 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 on a schedule determined for that pharmaceutical. The additional pharmaceutical agents may also be administered together with each other and / or with the compounds or compositions described herein in a single dose, or may be administered separately in different doses. The particular combination employed in a regimen will take into account 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 utilized individually. In some embodiments, the levels utilized in the combination will be lower than the levels utilized individually.

[0237] Additional pharmaceutical agents include cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anticancer agents, cytotoxic agents, antiangiogenic agents, anti-inflammatory 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), Erwinia chrysanthemi-derived asparaginase (asparaginase erwinia chrysanthemi (e.g., Erwinaze), axitinib (e.g., Inlyta), azacitidine (e.g., Mylosar, Vidaza), BEACOPP, belinstat (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, FOLFIRI-nox, 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 mepesuxinate (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), pamidronate disodium (e.g., AREDIA), panitumumab (e.g., Vectibix), panobinostat (e.g., FARYDAK), pazopanib hydrochloride (e.g., VOTRIENT), pegaspargase (e.g., ONCASPAR), peginterferon alfa-2b (e.g., PEG-INTRON), peginterferon alfa-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) tetravalent 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 I-131 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 a combination thereof. In some embodiments, the additional pharmaceutical agent is a cytotoxic chemotherapy (e.g., a cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, 1-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 immunomodulator. 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.

[0238] Also encompassed 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, wherein 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 single 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 single unit dosage form. In some 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.

[0239] In some embodiments, the instructions are for administering a 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 cells 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.

[0240] Method and use The present disclosure also provides methods of using the compounds and pharmaceutical compositions of the present disclosure. In another aspect, the present disclosure provides a method of inhibiting the activity of a kinase in a subject, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present disclosure.

[0241] In another aspect, the disclosure provides a method of inhibiting the 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.

[0242] In another aspect, the disclosure provides a method of inhibiting the 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.

[0243] In another aspect, the present disclosure provides a method for 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 present disclosure.

[0244] In another aspect, the present 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 present disclosure.

[0245] In another aspect, the disclosure provides a method for downregulating 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 disclosure.

[0246] Kinases are implicated in a wide range of diseases. In some embodiments, the kinase is a CDK (e.g., CDK7). The process of eukaryotic cell division can be broadly divided into a series of sequential phases called 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 coordination of a family of proteins known as CDKs and a diverse set of their cognate protein partners (called cyclins). CDKs are serine-threonine kinase proteins homologous to CDC2 (also known as CDK1), which may be able to utilize ATP as a substrate for phosphorylation of various polypeptides in sequence-dependent contexts. Cyclins are a family of proteins characterized by a homology region called a "cyclin box," containing approximately 100 amino acids, which is used to bind to and define selectivity for specific CDK partner proteins.

[0247] Modulation of expression levels, degradation rates, protein levels, and activity levels of various CDKs and cyclins throughout the cell cycle leads to the cyclical formation of a series of CDK / cyclin complexes (where the CDKs are enzymatically active). The formation of these complexes controls passage through 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 enzymatic 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 offer a wide range of potential therapeutic targets, selected based on clear biochemical rationale.

[0248] 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 is also a component of the transcription factor IIH (TFIIH) complex implied a dual role for CDK7: transcription as part of TFIIH and cell cycle regulation as part of the trimeric CAK complex. TFIIH, a multisubunit protein complex, was identified as a factor required for RNA polymerase II (RNAP II)-catalyzed transcription. 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 a nine-subunit TFIIH complex. The dual functions of CDK7 in CAK and CTD phosphorylation support 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.

[0249] The diseases described herein may be associated with abnormal activity of a kinase (e.g., a CDK (e.g., CDK7)). The abnormal activity of the kinase may be elevated and / or aberrant activity. Deregulation of cell cycle progression is a hallmark of proliferative diseases. Some proliferative diseases have abnormalities in kinase activity, some of which are through elevated and / or aberrant kinase activation. Inhibition of the catalytic activity of a CDK is expected to inhibit cell cycle progression by blocking phosphorylation of cell cycle CDKs, and in addition will inhibit the transcription of effectors of cell division. In some embodiments, the kinase is not overexpressed and the activity of the kinase is elevated and / or aberrant. In other certain embodiments, the kinase is overexpressed and the activity of the kinase is elevated and / or aberrant. 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.

[0250] The diseases described herein may also be associated with the inhibition of apoptosis of cells in a subject. Apoptosis is the process of programmed cell death. Inhibition of apoptosis can lead to uncontrolled cell proliferation and thus to proliferative diseases. Cell cycle CDKs (e.g., CDK1, 2, 4, and 6) are activated by phosphorylation by CDK7 / cyclin H (also known as CAK). Therefore, inhibition of CDK7 may result in failure to activate cell cycle CDKs and result in cell cycle arrest at multiple points in the cell cycle. CDK7 activates transcription by phosphorylating the CTD of RNAP II. Inhibition of CTD phosphorylation has been shown to inhibit the transcription and reduce the expression of short-lived proteins, including those involved in apoptosis regulation. It is understood in the art that stalling of RNA polymerase can activate 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 may therefore be useful for treating and / or preventing diseases (e.g., proliferative diseases, cystic fibrosis).

[0251] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the 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 to treat the disease. In some embodiments, the effective amount is effective to treat the disease and to inhibit the activity of a kinase. In some embodiments, the effective amount is effective to treat the disease and to downregulate the transcription of MYC or MCL-1.

[0252] In another aspect, the present disclosure provides a method for 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.

[0253] 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.

[0254] In another aspect, the present 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 present disclosure.

[0255] 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.

[0256] 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.

[0257] 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 precancerous cell.

[0258] 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 (e.g., increased activity, unwanted activity) of a kinase. 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 (e.g., overexpression) of a kinase. 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 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 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.

[0259] 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, an endocrine therapy, a cytotoxic chemotherapy, an epigenetic modifier, a glucocorticoid, an immunotherapy, or a radiation therapy. In some embodiments, the additional treatment is a cytotoxic chemotherapy. In some embodiments, the additional treatment is an immunotherapy. In some embodiments, the additional treatment is a radiation therapy. The compounds or pharmaceutical compositions of the present disclosure and the additional treatment may also act synergistically in the methods and uses of the present disclosure.

[0260] 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; or a method of downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell).

[0261] In another aspect, provided herein is the use of a compound or pharmaceutical composition of the present disclosure 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; or a method of downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell).

[0262] In another aspect, provided herein is a compound or pharmaceutical composition of the present disclosure 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; or a method of downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell).

[0263] 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 offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0264] Example 1. Compound synthesis The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Reactions were carried out on 0.25 mm E. Merck precoated silica gel plates (60 F 254 Thin layer chromatography (TLC) with a SunFire™ C 18 A Waters LCMS system (Waters 2489 UV / Visible Detector, Waters 3100 Mass, Waters 515 HPLC Pump, Waters 2545 Binary Gradient Module, Waters Reagent Manager, Waters 2767 Sample Manager) was used with a column (4.6 x 50 mm, 5 μm particle size): solvent gradient = 95% A at 0 min, 0% A at 5 min; solvent A = 0.5% TFA in water; solvent B = methanol; flow rate = 1.5 mL / min. Purification of reaction products was performed by flash chromatography using a CombiFlash® Rf with a Teledyne Isco RediSep® Rf High Performance Gold or Silicycle SiliaSep™ High Performance column (4 g, 12 g, 24 g, 40 g, 80 g, or 120 g) or by C 18 The run was performed on a Waters preparative HPLC system with a column: solvent gradient = 100% A at 0 min, 0% A at 15 min; solvent A = 0.5% TFA in water; solvent B = methanol; flow rate = 20 mL / min. All compounds were >95% pure and analyzed on a Waters LCMS system. 1 H NMR and 13 C NMR spectra were obtained using a Varian Inova-600 or 400 MHz spectrometer. Chemical shifts are 1 H NMR indicates chloroform (δ=7.24) or 1 H NMR indicates dimethyl sulfoxide (δ=2.50), and 13C NMR is reported relative to dimethyl sulfoxide (δ=39.51). Data are reported as (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

[0265] Example 1.1. (S)—N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 200) The synthesis of compound 200 follows Scheme 1. The synthesis of compound 201 and compound 208 follows a similar methodology. Scheme 1. [ka]

[0266] tert-Butyl (S)-(2-(dimethylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate [ka] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (3 g, 11.6 mmol) in DCM (50 mL) was added CDI (1.9 g, 11.6 mmol), and the mixture was stirred at room temperature for 1 h. Dimethylamine (2 M in THF, 11.6 mL, 23.2 mmol) was then added. The mixture was stirred overnight at room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH / DCM = 0-5%) to give tert-butyl (S)-(2-(dimethylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate as a white solid. LCMS: 287 [M+H] + .

[0267] (S)-2-Amino-N,N-dimethyl-2-(tetrahydro-2H-pyran-4-yl)acetamide [ka] Tert-butyl (S)-(2-(dimethylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate was dissolved in DCM (30 mL) and stirred at 0° C. for 5 min, then TFA (10 mL) was added. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give (S)-2-amino-N,N-dimethyl-2-(tetrahydro-2H-pyran-4-yl)acetamide, which was used in the next step without any purification. LCMS: 187 [M+H] + .

[0268] (S)-N 1 ,N 1 -Dimethyl-2-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diamine [ka] A solution of (S)-2-amino-N,N-dimethyl-2-(tetrahydro-2H-pyran-4-yl)acetamide (11.6 mmol) in dry THF (50 mL) was stirred at 0 °C for 10 min, and then LiAlH (2.5 M in THF, 9.28 mL, 23.2 mmol) was carefully added under a N atmosphere. After the addition, the mixture was stirred at 60 °C for 3 h and cooled to room temperature. Cold water (882 μL) was added dropwise to the mixture at 0 °C, followed by careful addition of NaOH solution (15% aq., 882 μL), followed by 3 × 882 μL water again. The mixture was warmed to room temperature, and ethyl ether was added. The mixture was stirred for 10 min and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1.75 N NH in MeOH / DCM = 0-20%) to give (S)-N 1 ,N 1-dimethyl-2-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diamine (1.6 g, 80% over 3 steps) was obtained as a yellow liquid. LCMS: 173 [M+H] + .

[0269] tert-Butyl 6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate [ka] t To a solution of 4-chloro-2-methylthieno[2,3-d]pyrimidine (221 mg, 1.2 mmol) and 5-(tert-butyl)1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (390 mg, 1.2 mmol) in BuOH (6 mL) was added Pd(dba) (55 mg, 0.06 mmol), XPhos (57 mg, 0.12 mmol), and KCO (497 mg, 3.6 mmol). The mixture was stirred under N protection at 100 °C for 4 h, cooled to room temperature, and then filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (EA / hexane=0-80%) to give tert-butyl 6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (445 mg, 92%). LCMS: 401 [M+H] + .

[0270] Ethyl 6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate [ka] To a solution of tert-butyl 6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (445 mg, 1.1 mmol) and DIEA (363 μL, 2.2 mmol) in THF (10 mL) was added ethyl chloroformate (127 μL, 1.3 mmol) at 0° C. The mixture was stirred at 50° C. for 1 h, then concentrated under reduced pressure, extracted with EA, and washed twice with water. The organic layer was then concentrated under reduced pressure. The residue was dissolved in TFA / DCM (v / v=1 / 3, 10 mL). The resulting mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, and then purified by silica gel column chromatography (1.75 N NH in MeOH / DCM = 0-10%) to give ethyl 6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (202 mg, 45%) as a TFA salt. LCMS: 373 [M+H] + .

[0271] (S)—N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 200) [ka] (S)-N in dry toluene (2 mL) 1 ,N 1To a solution of 5,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diamine (45 mg, 0.26 mmol) was added phosgene (15% wt toluene, 0.2 mL). The mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The residue was dissolved in dioxane (3 mL), and then ethyl 6,6-dimethyl-3-((2-methylthieno[2,3-d]pyrimidin-4-yl)amino)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (80 mg, 0.16 mmol) and DIEA (129 μL, 0.78 mmol) were added. The mixture was stirred at 80 °C for another 2 h. The mixture was concentrated under reduced pressure and then purified by silica gel column chromatography (1.75 N NH in MeOH / DCM = 0-15%) to give the intermediate (28 mg, 22%).

[0272] The intermediate was then dissolved in a mixture of isopropanol (IPA, 1 mL) and LiOH (1 M aq., 1 mL). The mixture was stirred at room temperature for 10 min, concentrated under reduced pressure, and purified by preparative HPLC (MeOH / water, 0.035% TFA) to give the TFA salt of compound 200 (27.6 mg, 90%). LCMS: 499 [M+H] + .

[0273] 1 H NMR(500MHz,DMSO-d6)δ10.57(s,1H),9.11(s,1H),7.86(d,J=6.0Hz,1H),7.61(d,J=5.9Hz,1H) ,5.88(d,J=9.3Hz,1H),4.58(q,J=11.6Hz,2H),4.01-3.95(m,1H),3.90-3.81(m,2H),3.24(ddd ,J=15.3,8.5,4.0Hz,4H),2.83(d,J=4.8Hz,3H),2.79(d,J=4.8Hz,3H),2.61(s,3H),1.70(d,J= 1.9Hz,6H), 1.65(dt,J=11.0,3.7Hz,1H),1.56(d,J=13.0Hz,2H),1.27(qt,J=12.2,4.7Hz,2H).

[0274] Example 1.2. (S)—N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-3-((2-methylthieno[3,2-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 201) [ka] Compound 201 (42 mg, 22%) was obtained according to the synthetic route of compound 200, except that 4-chloro-2-methylthieno[2,3-d]pyrimidine was replaced with 4-chloro-2-methylthieno[3,2-d]pyrimidine. LCMS: 499 [M+H] + .

[0275] 1 H NMR(500MHz,DMSO-d6)δ11.65(s,1H),9.18(s,1H),8.45(d,J=5.5Hz,1H),7.52(d,J=5.4Hz,1 H),5.97(d,J=9.3Hz,1H),4.53(d,J=7.3Hz,2H),3.97(s,1H),3.87(dq,J=12.2,4.5Hz,2H),3. 29-3.19(m,4H),2.82(d,J=4.8Hz,3H),2.80(d,J=4.8Hz,3H),2.72(s,3H),1.71(d,J=3.1Hz, 6H),1.66(dt,J=7.6,3.9Hz,1H),1.55(d,J=13.1Hz,2H),1.26(dtd,J=17.8,12.2,6.1Hz,2H).

[0276] Example 1.3. (S)—N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-3-((2-(trifluoromethyl)pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 208) [ka] Compound 208 (43 mg, 20%) was obtained according to the synthetic route of compound 200, except that 4-chloro-2-methylthieno[2,3-d]pyrimidine was replaced with 4-chloro-2-(trifluoromethyl)pyrimidine. LCMS: 497 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.53(s,1H),10.57(s,1H),8.42(s,1H),7.01(s,1H),4.49(s,2H),3.94-3.73(m,4H),3.24(t dd,J=11.7,4.8,2.1Hz,3H),2.36(s,6H),1.66(d,J=3.7Hz,7H),1.54-1.44(m,2H),1.28(qdd,J=12.1,7.1,4.5Hz,2H).

[0277] Example 1.4. (S)-3-((6-acrylamidoisoquinolin-1-yl)amino)-N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 202) The synthesis of compound 202 follows Scheme 2. The synthesis of compounds 203, 204, 206, and 209 follows a similar methodology. Scheme 2. [ka]

[0278] Tert-butyl 6,6-dimethyl-3-((6-nitroisoquinolin-1-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (compound 4-173) [ka] tTo a solution of 1-chloro-6-nitroisoquinoline (250 mg, 1.2 mmol) and 5-(tert-butyl)1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (390 mg, 1.2 mmol) in BuOH (6 mL) was added pd2(dba)3 (55 mg, 0.06 mmol), XPhos (57 mg, 0.12 mmol), and K2CO3 (497 mg, 3.6 mmol). The mixture was stirred at 100 °C under N2 atmosphere for 4 h, cooled to room temperature, and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (EA / hexane = 0-5%) to give compound 4-173 (309 mg, 61%) as a red solid. LCMS: 425 [M+H] + .

[0279] 5-(tert-butyl) 1-ethyl 6,6-dimethyl-3-((6-nitroisoquinolin-1-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (compound 4-174) [ka] To a solution of compound 4-173 (309 mg, 0.73 mmol) and DIEA (241 uL, 1.46 mmol) in THF (5 mL) was added ethyl chloroformate (70 uL, 1.3 mmol) at 0 °C. The mixture was stirred at 50 °C for 1 h, concentrated, and extracted with EA. The organic layer was washed twice with water and concentrated under reduced pressure to give compound 4-174, which was used in the next step without any purification. LCMS: 497 [M+H] + .

[0280] Ethyl 6,6-dimethyl-3-((6-nitroisoquinolin-1-yl)amino)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate TFA salt (compound 4-175) [ka] Compound 4-174 (0.73 mmol) obtained from the last step was dissolved in TFA / DCM (v / v=1 / 3, 8 mL). The mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, and purified by preparative HPLC (MeOH / water, 0.035% TFA) to give compound 4-175 (162 mg, 44% over two steps) as a TFA salt. LCMS: 397 [M+H] + .

[0281] Ethyl (S)-5-((2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamoyl)-6,6-dimethyl-3-((6-nitroisoquinolin-1-yl)amino)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (Compound 4-179) [ka] (S)-N in dry toluene (2 mL) 1 ,N 1 To a solution of 4-dimethyl-2-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diamine (45 mg, 0.26 mmol), phosgene (15% wt in toluene, 0.2 mL) was added. The mixture was stirred at 80 °C for 2 h and concentrated under reduced pressure. The residue was dissolved in dioxane (3 mL), and then compound 4-175 (85 mg, 0.17 mmol) and DIEA (129 uL, 0.78 mmol) were added. The mixture was stirred at 80 °C for another 2 h, concentrated under reduced pressure, and then purified by silica gel column chromatography (MeOH / DCM = 0-15%) to give compound 4-179 (44 mg, 45%) as an orange solid. LCMS: 595 [M+H] + .

[0282] Ethyl (S)-3-((6-aminoisoquinolin-1-yl)amino)-5-((2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamoyl)-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (Compound 4-182) [ka] To a solution of compound 4-179 (44 mg, 0.074 mmol) in MeOH (10 mL) was added Pd / C. The mixture was stirred under H2 atmosphere at room temperature for 3 h and filtered. The filtrate was concentrated under reduced pressure to give compound 4-182 (42 mg, 100%) as a white solid. LCMS: 565 [M+H] + .

[0283] (S)-3-(3-(4-acrylamidobenzamido)benzamido)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 202) [ka] To a solution of compound 4-182 (42 mg, 0.074 mmol) in acetonitrile (2 mL) was added acryloyl chloride (diluted in acetonitrile) dropwise at 0 °C until the reaction was complete. The mixture was then extracted with excess EA and washed twice with water. The organic layer was then concentrated under reduced pressure and dissolved in a mixture of isopropanol (IPA, 1 mL) and LiOH (1 M aq., 1 mL). The resulting mixture was stirred at room temperature for 10 min, concentrated under reduced pressure, and purified by preparative HPLC (MeOH / water, 0.035% TFA) to give the TFA salt of compound 202 (10.1 mg, 21%). LCMS: 547 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.94(s,1H),9.21(s,1H),8.76(d,J=9.1Hz,1H),8.45(d,J=2.1Hz,1H),7.99(d d,J=9.1,2.2Hz,1H),7.93(d,J=6.9Hz,1H),7.46(d,J=6.9Hz,1H),6.55(dd,J=16.9,10.2Hz,1H),6.39(dd,J=17.0,1. 8Hz,1H),5.99-5.77(m,2H),4.52(dd,J=57.5,11.6Hz,2H),3.98(d,J=9.3Hz,1H),3.86(d,J=10.3Hz,2H),3.25(dd,J= 12.1,5.6Hz,4H),2.82(t,J=5.1Hz,6H),1.73(s,6H),1.67(d,J=7.0Hz,1H),1.55(d,J=13.0Hz,2H),1.32-1.24(m,2H).

[0284] Example 1.5. (S)-3-((5-acrylamidoisoquinolin-1-yl)amino)-N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 203) [ka] Compound 203 (4.5 mg, 14%) was obtained according to the synthetic route of compound 202, except that 1-chloro-6-nitroisoquinoline was replaced with 1-chloro-5-nitroisoquinoline. LCMS: 547 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ10.69(s,1H),10.26(s,1H),8.97(s,1H),8.48(d,J=8.4Hz,1H),8.11(d,J=7.7Hz,1H),8.05(d,J=6. 4Hz,1H),7.73(t,J=8.0Hz,1H),7.40(s,1H),6.69(dd,J=17.0,10.2Hz,1H),6.34(dd,J=17.0,1.9Hz,1H),5.93-5.81(m,2H) ,4.59-4.42(m,2H),3.98(td,J=11.9,11.3,7.2Hz,1H),3.87(dd,J=10.8,4.1Hz,2H),3.24(td,J=11.4,10.6,4.0Hz,4H),2. 81(t,J=5.0Hz,6H),1.71(d,J=6.5Hz,3H),1.66(dd,J=7.7,3.8Hz,1H),1.55(d,J=13.0Hz,2H),1.26(dt,J=12.3,5.6Hz,2H).

[0285] Example 1.6. (S)-3-((5-acrylamidopyridin-2-yl)amino)-N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 204) [ka] Compound 204 (1.6 mg, 7%) was obtained according to the synthetic route of compound 202, except that 1-chloro-6-nitroisoquinoline was replaced with 2-chloro-5-nitropyridine. LCMS: 497 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ10.29(s,1H),10.00(s,1H),9.01(s,1H),8.61(d,J=2.6Hz,1H),7.92(dd,J=9.1,2.6Hz,1 H),7.00(d,J=9.1Hz,1H),6.43(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.0,2.0Hz,1H),5.89(d,J=9.2Hz,1H),5.78 (dd,J=10.1,2.0Hz,1H),4.51(d,J=11.5Hz,1H),4.38(d,J=11.4Hz,1H),3.97(s,1H),3.88(td,J=11.9,4.0Hz,2H) ,3.22(d,J=13.7Hz,4H),2.81(dd,J=4.9,2.1Hz,6H),1.67(d,J=7.6Hz,6H),1.59-1.50(m,2H),1.28-1.20(m,2H).

[0286] Example 1.7. (S)-3-((5-acrylamidopyrimidin-2-yl)amino)-N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 206) [ka] Compound 206 (2.2 mg, 5%) was obtained according to the synthetic route of compound 202, except that 1-chloro-6-nitroisoquinoline was replaced with 2-chloro-5-nitropyrimidine. LCMS: 498 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.07(s,1H),10.23(s,1H),9.70(s,1H),8.71(s,2H),6.42(dd,J=17. 0,10.1Hz,1H),6.27(dd,J=17.0,1.9Hz,1H),5.79(dd,J=10.1,2.0Hz,1H),5.38(s,1H),4.39( d,J=18.7Hz,2H),3.85(ddd,J=16.8,11.6,4.3Hz,2H),3.75(p,J=7.1Hz,1H),3.26-3.15(m,2H ),2.31(d,J=7.5Hz,2H),2.16(s,6H),1.62(s,6H),1.51(t,J=14.8Hz,2H),1.35-1.26(m,2H).

[0287] Example 1.8. (S)-3-((4-acrylamidophenyl)amino)-N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 209) [ka] Compound 209 was obtained according to the synthetic route of compound 202, except that 1-chloro-6-nitroisoquinoline was replaced with 1-chloro-4-nitrobenzene (2.4 mg, 7%). LCMS: 496 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.95(s,1H),9.91(s,1H),8.19(s,1H),7.50(d,J=8.5Hz,1H),6 .40(dd,J=17.0,10.1Hz,2H),6.20(dd,J=17.0,2.1Hz,1H),5.69(dd,J=10.1,2.1Hz,1H), 5.37(s,1H),4.20(s,2H),3.83(d,J=13.0Hz,2H),3.77-3.69(m,1H),3.20(d,J=9.6Hz,2 H),2.28(d,J=7.3Hz,1H),2.14(s,6H),1.62(s,6H),1.49(t,J=16.8Hz,2H),1.24(s,2H).

[0288] Example 1.9. (S)-3-(4-Acrylamidobenzamido)-N-(2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound 205) The synthesis of compound 205 follows Scheme 3. The synthesis of compound 207, compound 210, compound 065, and compound 079 follows a similar methodology. Scheme 3. [ka]

[0289] 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 (1135 mg, 3.5 mmol) and 4-nitrobenzoyl chloride (775 mg, 4.2 mmol) in DCM (25 mL) was added DIEA (1.7 mL, 10.5 mmol), and the mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure and purified by silica gel column chromatography (EA / hexane = 0 to 35%) to give 5-(tert-butyl) 1-ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (520 mg, 31%) as a yellow solid. LCMS: 474 [M+H] + .

[0290] Ethyl 6,6-dimethyl-3-(4-nitrobenzamido)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate [ka] The product from the last step was dissolved in TFA / DCM (v / v=1 / 3, 4 mL) and stirred at room temperature for 1 h, then concentrated under reduced pressure and used in the next step without any purification. LCMS: 374 [M+H] + .

[0291] Ethyl (S)-5-((2-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)ethy...

Claims

1. formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: Ring A is aryl or heteroaryl; R 1 is the expression: 【Chemistry 2】 Represented by; m is 0 or 1; R 2 each occurrence independently represents 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 is; n is 0 or 1, and when ring A is aryl, m=1 and n=0, and when ring A is heteroaryl, one of n and m is 1 and the other is 0; R 3 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, or a nitrogen protecting group; R 4 is hydrogen, or substituted or unsubstituted alkyl; R 5a and R 5b Each of is independently hydrogen, halogen, or unsubstituted C 1～6 is alkyl; R 6 and R 7 each instance of is independently hydrogen, 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, or substituted or unsubstituted heteroaryl, or R 6 and R 7 combine to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; R 8 is hydrogen or unsubstituted C 1～6 Alkyl; 【Chemistry 3】 Bond a is attached to ring D; R 12 Each occurrence of is independently a halogen, or an unsubstituted C 1～6 Alkyl or R 12 when two of the following are joined together to form an unsubstituted 3- to 7-membered, monocyclic heterocyclyl; R 11 each occurrence is independently halogen, or substituted or unsubstituted alkyl; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, as valences permit; and R a is 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 or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein the two in the formula (I) are linked to form a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl.

2. 4. The compound of formula: 【Chemistry 4】 2. The compound of claim 1, wherein the compound is: 【Request 3】 【Chemistry 5】 2. The compound of claim 1, wherein the compound is: 【Request 4】 【Chemical 6】 2. The compound of claim 1, wherein the compound is:

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

6. 6. The compound of claim 5, wherein Ring A is pyridinyl, pyrimidinyl, isoquinolinyl, thieno[2,3-d]pyrimidinyl, or thieno[3,2-d]pyrimidinyl, or a pharma- ceutically acceptable salt, solvate, or tautomer, stereoisomer, or isotopically labeled derivative thereof.

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

8. 8. The compound of claim 7, or a pharma- ceutically acceptable salt, solvate, or tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein Ring A is phenyl.

9. 9. The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein m is 0.

10. R 2 each occurrence is independently selected from halogen, unsubstituted methyl, -CF 3 , -CF 2 H, -CFH 2 10. The compound of any one of claims 1 to 9, wherein:

11. 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein n is 0.

12. R 3 The compound of any one of claims 1, 2, and 5-11, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein is hydrogen.

13. R 4 The compound of any one of claims 1, 2, and 5-12, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein is hydrogen.

14. R 5a and R 5b or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each of is hydrogen.

15. R 6 is hydrogen, halogen, or substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

16. R 7 is hydrogen, halogen, or substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

17. R 8 The compound of any one of claims 1, 2, and 5-16, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein is hydrogen.

18. R 12 or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of is unsubstituted methyl.

19. 19. The compound of any one of claims 1 to 3, and 5 to 18, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein q is 0.

20. 4. The compound of formula: 【Chemistry 7】 2. The compound of claim 1, wherein the compound is:

21. formula: 【Chemistry 8】 or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

22. 22. The compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein the solvate is a hydrate.

23. 22. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof.

24. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof; and Optionally, a pharma- ceutically acceptable excipient 13. A pharmaceutical composition comprising:

25. 25. The pharmaceutical composition of claim 24 for use in treating a disease in a subject in need thereof.

26. 26. The pharmaceutical composition of claim 25, wherein the disease is cancer.

27. 26. The pharmaceutical composition of claim 25, wherein the disease is adrenocortical carcinoma, bone cancer, breast cancer, brain cancer, colon cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, liver cancer, lung cancer, melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, or testicular cancer.

28. 26. The pharmaceutical composition of claim 25, wherein the disease is leukemia or lymphoma.

29. 26. The pharmaceutical composition of claim 25, wherein the disease is a benign neoplasm, an inflammatory disease, an autoimmune disease, or pathological angiogenesis.

30. 26. The pharmaceutical composition of claim 25, wherein the disease is rheumatoid arthritis.

31. 26. The pharmaceutical composition of claim 25, wherein the disease is cystic fibrosis.

32. 25. The pharmaceutical composition of claim 24 for use in inhibiting the activity of a kinase in a subject, biological sample, tissue, or cell, downregulating the transcription of MYC or MCL-1 in a subject, biological sample, tissue, or cell, inhibiting cell growth, or inducing cell apoptosis.

33. The pharmaceutical composition according to any one of claims 25 to 32, wherein the subject is a human.

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

25. The method, comprising contacting a biological sample, tissue, or cell with an effective amount of the pharmaceutical composition of claim 24.

35. A compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition according to claim 24; and Instructions for using the compound, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition Including the kit.

Images