Degradors of cyclin-dependent kinase 12 (CDK12) and uses thereof

Abstract

This document provides bifunctional compounds, one part of which (e.g., lenalidomide, thalidomide) is a binder of an E3 ubiquitin ligase (e.g., Cereblon) and the other part of which is a binder of a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))) to induce the degradation of the target protein CDK9 and / or CDK12. Pharmaceutical compositions comprising bifunctional compounds are also provided, as well as methods for treating and / or preventing diseases (e.g., proliferative diseases such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer)). Methods for inducing the degradation of target proteins (e.g., kinases (e.g., CDK (e.g., CDK9 and / or CDK12))) and methods for inducing apoptosis in biological samples or subjects by administering the bifunctional compounds or compositions described herein are also provided.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application USSN 62 / 837,331, filed April 23, 2019, pursuant to 35 U.S. SC § 119(e), which is incorporated herein by reference.

[0003] Government support

[0004] This invention was completed with government support, funded by grant number PO1 CA154303 from the National Institutes of Health. The government holds certain rights to this invention. Background Technology

[0005] Recently, a novel therapeutic strategy for reducing and / or eliminating proteins associated with certain pathological states—PROTAC (proteolysis against chimeras; see, for example, US SN 14 / 792,414, filed July 6, 2015; and US SN 14 / 707,930, filed May 8, 2015, each incorporated herein by reference)—has been developed by creating bifunctional compounds that recruit E3 ubiquitin ligases to target proteins, which subsequently induce ubiquitination and proteasome-mediated degradation of the target protein. E3 ubiquitin ligases are proteins that bind to E2 ubiquitin conjugates, facilitating the linking of ubiquitin to the lysine residue of the target protein via isopeptide bonds (e.g., amide bonds absent on the protein backbone). Ubiquitination of the protein subsequently leads to proteasome degradation of the target protein.

[0006] Cyclin-dependent kinase 12 (CDK12) and cyclin-dependent kinase 13 (CDK13) are regulators of RNA polymerase II-mediated transcriptional elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II. CDK12 and CDK13 play crucial roles in mediating genome stability. However, the detailed mechanisms remain unclear, and the exact site of CDK12 phosphorylation on the CTD is still controversial. Genome-wide screening has also identified CDK12 / cyclin K as playing a key role in mediating genome stability by regulating the expression of DDR genes. Loss of CDK12 / cyclin K severely impairs the expression of several key regulators of genome stability in cells, such as BRCA1, ATR, FANCI, and FANCD2 proteins. Similarly, the exact contribution of CDK12 to this process, particularly its kinase activity, needs to be elucidated. Loss of both CDK12 and CDK13 impairs the expression of several key regulators of genome stability. CDK12 mutations have been found in various cancers, including ovarian, breast, and prostate cancer. These changes on CDK12 sensitize these tumors to DNA damaging agents (such as cisplatin and its derivatives) and DNA repair inhibitors (such as PARP inhibitors). Therefore, CDK12 is a potential therapeutic target for treating cancer and other diseases. The exemplary CDK12 inhibitor THZ531 has been disclosed to bind to atypical cysteine ​​1039 located outside the ATP pocket. A reversible CDK12 inhibitor has also been reported, exhibiting superior selectivity compared to other CDKs (e.g., CDK2, CDK4, CDK9). However, since CDK13 shares the same kinase domain sequence as CDK12, the two currently reported CDK12 inhibitors also show potent inhibitory activity against CDK13. Therefore, developing small molecules that selectively target CDK12 while excluding other targets (e.g., CDK13) is of particular interest.

[0007] Therefore, there is a need to identify compounds that effectively promote the degradation of target proteins (e.g., CDK12, CDK9, which have been found to be associated with certain pathological states, including proliferative diseases such as cancer). In particular, compounds that can target the degradation of certain proteins by utilizing cellular mechanisms involved in protein homeostasis (e.g., ubiquitination and proteasomal degradation) can be used as therapeutic agents. There is a need for compounds that both target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))) and bind to E3 ubiquitin ligases, thereby inducing the proteasomal degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))). Summary of the Invention

[0008] This disclosure stems from the understanding that bifunctional molecules comprising an E3 ubiquitin ligase-binding moiety based on an imide drug (e.g., lenalidomide, thalidomide, VHL ligand) and also comprising a binder and / or inhibitor of a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))) can induce proteasomal degradation of the target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))). Therefore, this disclosure provides novel compounds, compositions, and methods for treating various diseases (e.g., proliferative diseases, such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer)) associated with target proteins (e.g., kinases (e.g., CDK (e.g., CDK9, CDK12))). In contrast to conventional CDK12 inhibitors targeting CDK12 and CDK13, the bifunctional compounds described herein rapidly degrade target proteins (e.g., kinases (e.g., CDK (e.g., CDK9 and / or CDK12))) to low levels, block transcription, and induce apoptosis in a faster and more selective manner. Therefore, the present invention provides novel therapeutic strategies for treating various diseases and conditions, particularly those associated with target proteins (e.g., kinases such as CDKs (e.g., CDK9 and / or CDK12)).

[0009] This document describes bifunctional compounds of formula (I). The compounds described herein comprise a component that binds to a target protein (e.g., a kinase (e.g., CDKs (e.g., CDK9, CDK12))) and a component that binds to an E3 ubiquitin ligase (e.g., lenalidomide, thalidomide), and are therefore used to promote and / or induce the degradation of the target protein (e.g., a kinase (e.g., CDKs (e.g., CDK9, CDK12))). The compounds may be used to treat and / or prevent diseases and conditions, such as proliferative diseases (e.g., cancer) associated with the target protein (e.g., a kinase (e.g., CDKs (e.g., CDK9, CDK12))) in subjects of need. Pharmaceutical compositions and kits comprising the compounds described herein are also provided.

[0010] In one aspect, the present invention provides compounds of formula (I):

[0011]

[0012] And its pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives and prodrugs, of which R 1 R 2 R 3 x, y, L1, L2, D and ring As defined in this article.

[0013] In formula (I), D is the E3 ubiquitin ligase-binding moiety. In some embodiments, D is derived from an immunomodulatory imide drug. In some embodiments, D is derived from lenalidomide. In some embodiments, D is derived from thalidomide. In some embodiments, D is the E3 ubiquitin ligase-binding moiety, wherein D is a compound of formula (IA), (IB), or based on a ligand binding to von Hippel–Lindau (“VHL ligand”). In some embodiments, D is derived from the VHL ligand.

[0014] In some implementations, D is Equation (IA):

[0015]

[0016] Where R 1A R 3A R 4A R 5A R 3’ X A a1, m, and n are as defined in this paper.

[0017] In some implementations, D is Equation (IB):

[0018]

[0019] Where R 1A R 3A R 4A R 3’ X 1 X 2 a1, m, and n are as defined in this paper.

[0020] In some implementations, D is the following formula:

[0021]

[0022] Where R 2 ′、R 4′ R 5’ n1′, n2′ and n3′ are as defined in this paper.

[0023] Exemplary compounds of formula (I) include, but are not limited to:

[0024]

[0025]

[0026]

[0027]

[0028]

[0029] And pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs.

[0030] Other exemplary compounds of formula (I) include, but are not limited to:

[0031]

[0032]

[0033] And pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs.

[0034] On the other hand, this document describes pharmaceutical compositions comprising the compounds described herein, and optionally pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically or preventively effective amount of the compounds described herein. The pharmaceutical compositions may be used to induce the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))) in a subject or cell for the treatment of a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need, or for the prevention of a disease in a subject in need. In some embodiments, the compound administered or used induces the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))) in a subject or cell for the treatment of a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need, or for the prevention of a disease in a subject in need.

[0035] In another aspect, this document describes a kit comprising a container containing a compound or pharmaceutical composition described herein. The kits described herein may comprise single or multiple doses of a compound or pharmaceutical composition. The kits may be used to induce the degradation of target proteins (e.g., kinases such as CDKs (e.g., CDK9, CDK12)). In some embodiments, the kits described herein also include instructions for using the compound or pharmaceutical composition contained in the kit.

[0036] In some embodiments, the applied or used compound induces the degradation of the target protein (e.g., a kinase (e.g., a CDK (e.g., CDK9, CDK12))).

[0037] Another aspect of this disclosure relates to a method of treating a disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition described herein. Another aspect of this disclosure provides a method of preventing a disease in a subject in need, the method comprising administering to the subject a preventatively effective amount of the compound or pharmaceutical composition described herein.

[0038] In another aspect, this disclosure provides the compounds and pharmaceutical compositions described herein for use in the methods of this disclosure (e.g., methods for inducing the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))), methods for inducing apoptosis in subject cells, and methods for treating and / or preventing diseases (e.g., proliferative diseases (e.g., ovarian cancer, breast cancer, or prostate cancer)).

[0039] definition

[0040] The definitions of specific functional groups and chemical terms will be described in more detail below. Chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0041] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be isolated from the mixture 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 may 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, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions sp. 268 (Ellie Liel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This invention also includes the individual isomers, or mixtures of various isomers, that are substantially free of other isomers as described herein.

[0042] When listing a range of values, the aim is to include every value within that range and its subranges. For example, "C 1–6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 .

[0043] A "hydrocarbon chain" refers to a divalent alkyl, alkenyl, or alkynyl group, whether substituted or unsubstituted. A hydrocarbon chain comprises at least one chain between two groups in the hydrocarbon chain, and each node of the chain ("carbon unit") comprises at least one carbon atom. For example, a hydrocarbon chain – C AH(C B H2C C H3) – Contains only one carbon unit C A The term "C" x A hydrocarbon chain is defined as a chain consisting of x carbon units between two groups, where x is a positive integer. If x has more than one possible value, the smallest possible value is used in the definition of a hydrocarbon chain. For example, –CH(C2H5)– is a C1 hydrocarbon chain. It is a C3 hydrocarbon chain. When using numerical ranges, such as C... 1-6 Hydrocarbon chain, as defined herein, can be saturated (e.g., –(CH2)4–). It can also be unsaturated and include one or more C=C and / or C≡C bonds anywhere along its length. For example, –CH=CH–(CH2)2–, –CH2–C≡C–CH2–, and –C≡C–CH=CH– are examples of unsubstituted and unsaturated hydrocarbon chains. In some embodiments, the hydrocarbon chain is unsubstituted (e.g., –(CH2)4–). In some embodiments, the hydrocarbon chain is substituted (e.g., –CH(C2H5)– and –CF2–). Any two substituents on the hydrocarbon chain can be linked to form an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl ring. For example, These are all examples of hydrocarbon chains. Conversely, in some implementations, This is not within the scope of the hydrocarbon chains described in this article.

[0044] "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-10 Alkyl group (e.g., –CH3). In some embodiments, the alkyl group is a substituted C-molecule. 1-10 alkyl.

[0045] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C"). 2-20 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. One or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise stated, each instance of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-10 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-10 Alkenyl group.

[0046] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. 2-20 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be internal (as in 2-butynyl) or terminal (as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkynyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each instance of an alkynyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-10 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-10 Alkyne group.

[0047] "Carbocyclic group" or "carbocyclic" refers to a non-aromatic ring system having 3-10 ring carbon atoms ("C"). 3-10 (carbocyclic group) and ww A non-aromatic ring hydrocarbon group with an ero heteroatom. In some embodiments, the carbocyclic group has 3 to 8 carbon atoms (“C…”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 carbon atoms (“C”). 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 carbon atoms (“C”). 3-6 "Carbocyclic group"). In some embodiments, the carbocyclic group has 5 to 10 carbon atoms ("C"). 5-10 (Carbocyclic group"). An example C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example is C... 3-8 Carbocyclic groups include, but are not limited to, the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include, but are not limited to, the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing embodiments, in some embodiments, the carbocyclic group is either monocyclic (“monocyclic carbocyclic”) or comprises a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, in which case the carbon number continues to represent the number of carbons in the carbocyclic ring system. Unless otherwise stated, each instance of a carbocyclic group is independently optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-10 Carbon cyclic group.

[0048] In some embodiments, "cycloalkyl" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C..."). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 carbon atoms (“C”). 5-6 cycloalkyl group”). In some embodiments, the cycloalkyl group has 5 to 10 carbon atoms (“C10”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0049] A “heterocyclic group” refers to a group having a cyclic carbon atom and 1-4 cyclic heteroatoms in a 3-10 membered nonaromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclic groups”). In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic (“monocyclic heterocyclic groups”) or fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic heterocyclic groups”), and can be saturated or partially unsaturated. A bicyclic heterocyclic system can contain one or more heteroatoms in one or both rings. “Heterocyclic groups” also include cyclic systems in which a heterocycle as defined above is fused with one or more carbocyclic groups, wherein the linking point is on the carbocyclic group or the heterocycle, or cyclic systems in which a heterocycle as defined above is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocycle, in which case the number of ring members continues to indicate the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of the heterocyclic group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted with one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group.

[0050] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has a cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, nitrogen-containing heterocyclic groups, oxygen-containing heterocyclic groups, and thiocyclic heterocyclic groups. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, nitrogen-containing heterocyclic butyl, oxygen-containing heterocyclic butyl, and thiocyclic butyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxapentyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolyl, isoyindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolyl, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0052] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a ring array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms ("C"). 14 "Aryl"; for example, anthracene. "Aryl" also includes cyclic systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or linker is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise stated, each instance of an aryl is optionally substituted independently, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0053] "Aryl" is a subset of alkyl and aryl, referring to an optionally substituted alkyl group that is optionally replaced by an aryl group. In some embodiments, the aryl group is an optionally substituted benzyl group. In some embodiments, the aryl group is a benzyl group. In some embodiments, the aryl group is an optionally substituted phenethyl group. In some embodiments, the aryl group is a phenethyl group.

[0054] "Heteroaryl" refers to a group in a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a ring array), having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, where the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the bonding point is on the heteroaryl ring, and in this case, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linkage is on either the aryl or heteroaryl ring. In this case, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl rings, where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), can have the linkage on either ring, i.e., a ring containing a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0055] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each instance of the heteroaryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0056] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirheptanyl, oxoheptanyl, and thioheptanyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cinnamyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0057] "Heteroaryl" is a subset of alkyl and heteroaryl, referring to an alkyl group that is optionally substituted by a heteroaryl group.

[0058] "Partially unsaturated" refers to a group containing at least one double or triple bond. A "partially unsaturated" ring system also includes rings with multiple unsaturated sites, but excludes aromatic groups (e.g., aryl or heteroaryl) as defined herein. Similarly, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains all single bonds.

[0059] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are divalent bridging groups, further designated by the suffix -ene, for example, alkylene, alkenylene, alkynylene, carbocyclic, heterocyclic, aryl, and heteroaryl.

[0060] The term "optionally substituted" refers to either substituted or unsubstituted.

[0061] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted," whether preceding the term "optionally," means that at least one hydrogen atom is present on the group (e.g., a carbon or nitrogen atom) substituted by a substituent (e.g., a substituent that, upon substitution, produces a stable compound (e.g., a compound that does not spontaneously transform (e.g., through rearrangement, cyclization, elimination, or other reactions)). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with any permissible substituent of the organic compound, any substituent described herein leading to the formation of a stable compound. This invention contemplates any and all such combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein, satisfying the heteroatom's valence and leading to the formation of a stable moiety.

[0062] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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(=NRbb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(ORcc )2、-P(R cc )3 + X - -P(OR) cc )3 + X - -P(R) cc 4. -P(OR) cc 4. -OP(R) cc )2、-OP(R cc )3 + X - -OP(OR) cc 2. -OP(OR) cc )3 + X - -OP(R) cc 4. -OP(OR) cc )4、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0063] Or two paired hydrogen groups on a carbon atom: =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 replace;

[0064] R aa Each instance is independently selected from C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heterochain alkenyl, heterochain alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0065] R bb Each instance is independently selected from hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bbGroups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heterochain alkenyl, heterochain alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X - It is a counter ion;

[0066] R cc Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heterochain alkenyl, heterochain alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0067] R dd Each instance is independently selected from hydrogen, -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 ffOR 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)(OR) ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C2-6 ynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heterochain alkenyl, heterochain ynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two paired R groups dd Substituents can be linked to form =O or =S; where X - It is a counter ion;

[0068] R ee Each instance is independently selected from C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 carbon cyclo group, C 6-10 Aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heterochain alkenyl, heterochain ynyl, carbocyclic, heterocyclic, aryl and heteroaryl are independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0069] R ff Each instance is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff Groups are linked to form 3-10 membered heterocyclic groups or 5-10 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heterochain alkenyl, heterochain alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0070] R gg Each instance is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -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)(OC) 1-6 Alkyl)2、-P(=O)(C 1-6Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero-C 1-6 Alkyl, hetero C 2-6 alkenyl, hetero-C 2-6 alkynyl group, C 3-10 carbon cyclo group, C 6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two paired R gg Substituents can be linked to form =O or =S; where X - It is a counter ion.

[0071] A "counterion" or "anionic counterion" is a negatively charged group that associates with a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., comprising one form of negative charge). Anionic counterions can also be polyvalent (i.e., comprising more than one form of negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F...). – Cl – ,Br – I – NO3 – ClO4 – OH – H2PO4 – HCO3 - HSO4 – Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic-5-sulfonate, ethane-1-sulfonic-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerolate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - PF4 – PF6 – AsF6 – SbF6 – B[3,5-(CF3)2C6H3]4] – B(C6F5)4 - BPh4 – Al(OC(CF3)3)4 – and carborane anions (e.g., CB) 11 H 12 – or (HCB) 11Me5Br6) – Examples of multivalent counterions include CO3. 2- HPO4 2- PO4 3- B4O7 2- SO4 2- S2O3 2- Carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, heptarate, octanoate, azelaate, sebacic acid, salicylates, phthalates, aspartate, glutamate, etc.) and carboranes.

[0072] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0073] The term "acyl" refers to an acyl group having the general formula –C(=O)R X1 –C(=O)OR X1 –C(=O)–O–C(=O)R X1 –C(=O)SR X1 –C(=O)N(R) X1 )2、–C(=S)R X1 –C(=S)N(R) X1 )2 and –C(=S)S(R X1 –C(=NR) X1 )R X1 –C(=NR) X1 OR X1 –C(=NR) X1 )SR X1 and –C(=NR) X1 )N(R X1 )2 groups, wherein R X1Hydrogen; halogen; substituted or unsubstituted hydroxyl group; substituted or unsubstituted thiol; substituted or unsubstituted amino group; substituted or unsubstituted acyl group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl group; substituted or unsubstituted Alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphatic oxy, alkoxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkyl sulfoxy, heteroalkyl sulfoxy, aryl sulfoxy, heteroaryl sulfoxy, mono- or dialiphatic amino, mono- or diheteraliphatic amino, mono- or dialkylamino, mono- or diheteroalkylamino, mono- or diarylamino, or mono- or diheteroarylamino; or two R X1 The groups together form a 5-6 membered heterocyclic ring. Exemplary acyl groups include aldehydes (–CHO), carboxylic acids (–CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azide, nitro, hydroxyl, thiol, halogen, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic sulfoxy, heteroaliphatic sulfoxy, alkyl sulfoxy, heteroalkyl sulfoxy, aryl sulfoxy, heteroaryl sulfoxy, acyloxy, etc., each of which may or may not be further substituted).

[0074] "Alkoxy" or "alkoxy group" refers to the group with the following formula: –O–alkyl.

[0075] Nitrogen atoms may be substituted or unsubstituted, depending on the valence, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, -OH, and -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(Rcc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)(OR) cc )2、-P(=O)(R aa )2、-P(=O)(N(R cc )2)2、C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 2-10 alkenyl, hetero-C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, or two R groups attached to the N atom. cc Groups are linked to form 3-14 membered heterocyclic groups or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heterochain alkenyl, heterochain alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; and wherein R aa R bb R cc and R dd As defined above.

[0076] In some embodiments, the substituents present on the nitrogen atom are nitrogen-protecting groups (also known as amino-protecting groups). Nitrogen-protecting groups include, but are not limited to: -OH, -ORaa, -N(Rcc)2, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As defined herein, nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0077] For example, nitrogen-protecting groups such as amide groups (e.g., –C(=O)R) aa This includes, but is not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridinecarboxamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide), 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobenzamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0078] Nitrogen-protected groups such as urethane groups (e.g., –C(=O)OR) aaThis includes, but is not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothionyl)]carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), and 1,1-dimethyl-2-haloethyl carbamate. 1,1-Dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-Dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-Methyl-1-(4-biphenyl)ethylcarbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylcarbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)carbamate (Pyoc), 2-(N,N-dicyclohexylcarbamate), tert-butylcarbamate (BOC), 1-adamantylcarbamate Acid esters (Adoc), vinyl carbamates (Voc), allyl carbamates (Alloc), 1-isopropylallyl carbamates (Ipaoc), cinnamyl carbamates (Coc), 4-nitrocinnamyl carbamates (Noc), 8-quinolinyl carbamates, N-hydroxypiperidinyl carbamates, alkyl dithiocarbamates, benzyl carbamates (Cbz), p-methoxybenzyl carbamates (Moz), p-nitrobenzyl carbamates, p-bromobenzyl carbamates, p-chlorobenzyl carbamates, 2,4-dichlorobenzyl amino Formate, 4-methylsulfonylbenzylcarbamate (Msz), 9-anthraylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2-(p-toluenesulfonyl)ethylcarbamate, methyl [2-(1,3-dicyano)]carbamate (Dmoc), 4-methylthiophene carbamate (Mtpc), 2,4-dimethylthiophene carbamate (Bmpc), ethyl 2-phosphorylcarbamate (Peoc), 2-triphenylphosphorylisopropylcarbamate (Ppoc), 1,1-Dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromomethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, benzene Methyl (o-nitrophenyl)carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-di) ... 1,1-Dimethylpropynyl carbamate, 2-(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinic acid ester, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate 1-Methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(benzoazo)benzylcarbamate, 2,4,6-tri-tert-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0079] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R) aa This includes, but is not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mrt), 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-pentamethylbenzodihydropyran-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzenesulfonamide.

[0080] Other nitrogen-protecting groups include, but are not limited to, phenothiazine-(10)-acyl derivatives, N′-p-toluenesulfonylaminoacyl derivatives, N′-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylated methionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazopentanyl adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one. Ketones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-picolylamino N′–oxide, N–1,1–dimethylthiomethyleneamine, N–benzylamine, N–p-methoxybenzylamine, N–diphenylmethyleneamine, N–[(2–pyridyl)isopropylidene]methyleneamine, N–(N′,N′–dimethylmethylene)amine, N,N′–isopropylidenediamine, N–p-nitrobenzylamine, N–salicylamine, N–5–chlorosalicylaldehydeamine, N–(5–chloro–2–hydroxyphenyl)phenylmethyleneamine, N–cyclohexylamine, N–(5,5–dimethyl–3–oxo–1–cyclohexenyl)amine, N–borane derivatives, N–diphenylboronic acid derivatives N-[phenyl(pentacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitrosamine, N-nitrosamine, amine N-oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylaminophosphate, dibenzylaminophosphate, diphenylaminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys).

[0081] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R.aa -N(R) bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa -SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - -P(OR) cc 2. -P(OR) cc )3 + X - -P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - R aa R bb and R cc As defined herein, oxygen protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd Those described in detail in the edition, John Wiley & Sons, 1999, are incorporated herein by reference.

[0082] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p–AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetramethyl... Hydrogen pyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiopheneyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylbenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl 1-Benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenoyl)ethyl, tert-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-methylpyridinyl, 4-methylpyridinyl, 3-methyl-2-methylpyridinyl N-oxide, diphenylmethyl, p-, p-dinitrophenyl, 5-dibenzodiaryl, triphenylmethyl α-Naphthyl diphenylmethyl, p-methoxyphenyl diphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4′-bromobenzoyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorobenzoimide)methyl, 4,4′,4″-tris(acetylpropionyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthonyl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-Benzodisulfonfuran-2-yl, Benzisothiazolyl, S-dioxin, Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethylsilyl (dimethylthexylsilyl), Tert-butyldimethylsilyl (TBDMS), Tert-butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), Tert-butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylcarbamate, Acetate Chloroacetic acid ester, dichloroacetic acid ester, trichloroacetic acid ester, trifluoroacetic acid ester, methoxyacetic acid ester, triphenylmethoxyacetic acid ester, phenoxyacetic acid ester, p-chlorophenoxyacetic acid ester, 3-phenylpropionate ester, 4-oxovalerate ester (acetylpropionate), 4,4-(ethylenedithio)pentanoate ester (acetylpropionyldithioacetal), neovalerate ester, adamantane ester, crotonate ester, 4-methoxycrotonate ester, benzoate ester, p-benzene benzoate ester, 2,4,6-trimethylbenzoate (methanesulfonate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(benzene) 2-(triphenylphosphino)ethyl carbonate (Psec), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrobenzene carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzene carbonate, alkyl 3,4-dimethoxybenzene carbonate, alkyl o-nitrobenzene carbonate, alkyl p-nitrobenzene carbonate, alkyl thiobenzene carbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid Salts, 2-(meththiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthyl ester, nitrates, N,N,N′,N′-tetramethylphosphodiamethane alkyl ester, N-phenylcarbamate alkyl ester, borate, dimethylphosphono, 2,4-dinitrophenylsulfinic acid alkyl ester, sulfates, methanesulfonates, benzyl sulfonates, and toluenesulfonates (Ts).

[0083] The substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). Sulfur protecting groups include, but are not limited to, -R. aa -N(R) bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa -SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - -P(OR) cc 2. -P(OR) cc )3 + X - -P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where R aa R bb and R cc As defined herein, sulfur protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd Those described in detail in the edition, John Wiley & Sons, 1999, are incorporated herein by reference.

[0084] As used herein, “leaving group” (LG) is a term understood in the art to refer to a molecular fragment that leaves with a pair of electrons during heterogeneous bond cleavage, wherein the molecular fragment is an anionic or neutral molecule. As used herein, the leaving group can be an atom or a group that can be substituted by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halogens (e.g., chlorine, bromine, iodine) and activated substituted hydroxyl groups (e.g., –OC(=O)SR). aa –OC(=O)Raa –OCO2R aa –OC(=O)N(R) bb )2、–OC(=NR bb )R aa –OC(=NR) bb OR aa –OC(=NR) bb )N(R bb )2、–OS(=O)R aa –OSO2R aa –OP(R) cc )2、–OP(R cc 3. –OP(=O)2R aa –OP(=O)(R aa 2. –OP(=O)(OR cc )2、–OP(=O)2N(R bb )2 and –OP(=O)(NR bb )2, where R aa R bb and R cc As defined herein, suitable leaving groups include, but are not limited to, halogens (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkylcarbonyloxy (such as acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxyamino, pixyl, and halocarboxylate. In some cases, the leaving group is a sulfonate, such as toluenesulfonate (toluenesulfonate, –OTs), methanesulfonate (methanesulfonate, –OMs), p-bromobenzenesulfonyloxy (p-bromobenzenesulfonate, –OBs), or trifluoromethanesulfonate (trifluoromethanesulfonate, –OTf). In some cases, the leaving group is p-bromobenzenesulfonate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is nitrobenzenesulfonate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a toluenesulfonate group. The leaving group can also be a phosphonate (e.g., formed during the Mitsunobu reaction) or an internal leaving group, such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, amine, ammonia, alcohol, ether moiety, sulfur-containing moiety, thioether moiety, zinc halide, magnesium moiety, diazonium salt, and copper moiety.

[0085] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., in J. Pharmaceutical Sciences, 1977, 66, 1–19, describe pharmaceutically acceptable salts in detail, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts 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 amino salts formed by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borates, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, polyamate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1–4 Alkyl)4 salts. Representative alkali metal 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 alkyl sulfonates, and aryl sulfonates.

[0086] The term "solvent" refers to the form in which a compound is typically associated with a solvent via a solvation reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. Compounds of formula (I) can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include chemically quantifiable and non-chemically quantifiable solvates. In some cases, solvates can be separated, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvent" includes solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0087] The term "hydrate" refers to a compound that associates with water. Typically, the number of water molecules contained in a hydrate of a compound is in a defined ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0088] The term "tautomer" refers to compounds that are interchangeable forms of a particular compound's structure and vary in the shifts of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they can interconvert by treatment with acids or bases. Another example of tautomerism is the acidification and nitro form of phenylnitromethane, which is also formed by treating it with acids or bases.

[0089] Tautomerism can be associated with obtaining optimal chemical reactivity and biological activity of compounds of interest.

[0090] It should also be understood that compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial atomic arrangements are called "stereoisomers." Compounds that differ in atomic spatial arrangement are called "stereoisomers."

[0091] Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequence rules of Cahn and Prelog, or by the way in which the molecule rotates in a plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. Compounds containing equal proportions of enantiomers are called "racemic compounds."

[0092] The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) that adopts a specific crystalline arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and / or solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to become dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0093] The term "prodrug" refers to a compound, including derivatives of a compound of formula (I), having a cleavable group and becoming a drug-active compound of formula (I) in vivo by solvent decomposition or under physiological conditions. Examples of such compounds include, but are not limited to, ester derivatives. Other derivatives of the compounds of the present invention are active in their acidic and acid-derived forms, but often offer advantages in acid-sensitive forms such as solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides, or anhydrides, or mixed anhydrides, prepared by reacting a parent acid compound with a substituted or unsubstituted amine. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic groups attached to the compounds of the present invention are specific prodrugs. In some cases, it is necessary to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The compounds of formula (I) are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C 12 Substituted aryl and C7-C 12 Arylalkyl esters may be preferred.

[0094] The intended "subjects" include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds, such as chickens, ducks, geese, and / or turkeys). In some embodiments, the animal is a mammal. The animal can be male or female, at any developmental stage. The non-human animal can be a transgenic animal.

[0095] The term "application" means introducing the compound or pharmaceutical composition thereof of the present invention by means of implantation, absorption, ingestion, injection, inhalation or other means.

[0096] The term "treatment" refers to reversing, alleviating, delaying the occurrence of or inhibiting the progression of a "pathological condition" (e.g., a disease, symptom, or illness, or one or more of its signs or symptoms) as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or illness. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example, to delay or prevent recurrence.

[0097] The terms “condition,” “disease,” and “symptom” are used interchangeably.

[0098] The “effective amount” of a compound of formula (I) refers to an amount sufficient to elicit the desired biological response, i.e., to treat the condition. As will be understood by those skilled in the art, the effective amount of a compound of formula (I) can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the route of administration, and the age and health of the subject. Effective amounts include both therapeutic and preventative treatments. For example, in the treatment of cancer, an effective amount of the compound of the present invention can reduce the tumor burden or inhibit tumor growth or spread.

[0099] A "therapeuticly effective amount" of a compound of formula (I) is an amount sufficient to provide therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of the condition. The term "therapeuticly effective amount" can include amounts that improve overall treatment, reduce or prevent symptoms or causes of the condition, or enhance the therapeutic effect of another therapeutic agent.

[0100] The “preventive effective amount” of a compound of formula (I) is an amount sufficient to prevent the condition or one or more symptoms associated with the condition or to prevent its recurrence. The preventive effective amount of a compound means the amount by which a therapeutic agent, alone or in combination with other agents, provides a preventive benefit in the prevention of the condition. The term “preventive effective amount” may also encompass an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0101] "Proliferative disorders" are diseases caused by abnormal growth or extension of cells due to proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant tumors"), benign tumors, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0102] The terms “tumor” and “nebula” are used interchangeably to refer to an abnormal mass of tissue in which the growth of the mass exceeds and is out of sync with the growth of normal tissue. A tumor or neoplasm can be “benign” or “malignant”, depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign tumors” are typically well-differentiated, grow characteristically slower than malignant tumors, and remain confined to the primary site. Furthermore, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign tumors include, but are not limited to, lipomas, chondromas, adenomas, cysts, senile hemangiomas, seborrheic keratosis, nevi, and sebaceous hyperplasia. In some cases, certain “benign” tumors may subsequently develop into malignant tumors, possibly due to additional genetic changes in a subset of the tumor cells; these tumors are called “premalignant tumors.” A typical premalignant tumor is a teratoma. In contrast, “malignant tumors” are typically poorly differentiated (undeveloped) and have characteristic rapid growth, accompanied by progressive invasion, invasion, and destruction of surrounding tissues. Furthermore, malignant tumors often have the ability to metastasize to distant sites.

[0103] The term "metastasis" refers to the spread or migration of cancer cells from a primary or metastatic tumor to another organ or tissue, and is usually identified by the presence of a "secondary tumor" or "secondary cell cluster" of the tissue type of the primary or metastatic tumor, rather than the presence of a "secondary tumor" or "secondary cell cluster" of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to the bone is called metastatic prostate cancer, and includes cancerous prostate cancer cells growing in bone tissue.

[0104] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., bile duct cancer); bladder cancer; breast cancer (e.g., adenocarcinoma, papillary carcinoma, breast cancer, medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma, medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer). Cancer, colon adenocarcinoma; connective tissue cancer; epithelial cancer; 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; ocular cancer (e.g., intraocular melanoma, retinoblastoma); the familiar eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic... Systemic cancers (such as leukemia, including 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)); lymphomas, including Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL) and diffuse large cell lymphoma (DLCL) (e.g., diffuse large cell lymphoma). Large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (such as mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Warren's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;And T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Cezari syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain diseases, gamma chain diseases, μ chain diseases); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastoma; immune cell amyloidosis; renal cell carcinoma (e.g., nephroblastoma); Renal cell carcinoma (also known as Wilms' tumor or kidney cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), undiagnosed myelometaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic myeloid leukemia). Cellular leukemia (CNL), eosinophilic syndrome (HES); neuroblastoma; neurofibroma (such as neurofibromatosis (NF) type 1 or 2, schwannoma); neuroendocrine carcinoma (such as gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (such as bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (such as pancreatic cancer, intraductal papillary mucinous tumor (IPMN), islet cell tumor); penile cancer (such as Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor (PNT); plasmacytoma formation; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer. (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestinal cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small intestinal cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, embryonal testicular 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).

[0105] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a subject's healthy body to heal wounds and restore blood flow to damaged tissues. A healthy body controls angiogenesis through various mechanisms, such as angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal or pathological angiogenesis refers to angiogenesis exceeding that in a normal body, particularly in adults unrelated to normal angiogenesis (such as menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels to nourish diseased tissues and / or damage normal tissues; in the case of cancer, new blood vessels can allow tumor cells to escape into the circulation and remain in other organs (tumor metastasis). In some implementations, angiogenesis is pathological angiogenesis.

[0106] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (e.g., cell smears (such as Pap smears or blood smears) or cell samples obtained by microdissection); whole biological samples (such as yeast or bacterial samples); or cell portions, fragments, or organelles (such as those obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, tissue fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspiration, breast milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules from the first biological sample. Biological samples also include those that are genetically modified, such as transgenic oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells or cell nuclei, or cells or cell lines derived from a biological sample.

[0107] The term "tissue" refers to any biological tissue (including a group of cells, body parts, or organs) or a portion thereof of a subject, including blood and / or lymphatic vessels, which is the object to which the compounds, particles, and / or compositions of the present invention are delivered. The tissue may be abnormal or unhealthy, which may require treatment. The tissue may also be normal or healthy tissue, which has a higher risk of becoming abnormal or unhealthy than normal tissue, which may require preventative measures. In some embodiments, the tissue is the central nervous system. In some embodiments, the tissue is the brain.

[0108] The term “administration” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or composition thereof described herein into or onto a subject.

[0109] The term "treatment" refers to reversing, alleviating, delaying, or inhibiting the progression of the disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, susceptible subjects may be treated before symptoms appear (e.g., based on a history of symptoms). Treatment may also continue after symptoms have resolved, for example, to delay or prevent recurrence.

[0110] The terms “condition,” “disease,” and “symptom” are used interchangeably.

[0111] The term "effective amount" for the compounds described herein refers to an amount sufficient to elicit the desired biological response. The effective amount of the compounds described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the route of administration, and the age and health of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is for prophylactic treatment. In some embodiments, the effective amount is the amount of a single dose of the compounds described herein. In some embodiments, the effective amount is a combination of multiple doses of the compounds described herein.

[0112] The "therapeuticly effective amount" of a compound described herein is an amount sufficient to provide therapeutic benefit in treating a condition or delaying or minimizing one or more symptoms associated with the condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a condition. The term "therapeuticly effective amount" can include amounts that improve overall treatment, reduce or avoid symptoms, signs, or causes of the condition, and / or enhance the therapeutic effect of another therapeutic agent. In some embodiments, the therapeutically effective amount is an amount sufficient to bind a target (e.g., a kinase (e.g., a CDK (e.g., CDK9, CDK12))). In some embodiments, the therapeutically effective amount is an amount sufficient to treat a proliferative disease (e.g., cancer). In some embodiments, the therapeutically effective amount is an amount sufficient to bind a target protein (e.g., a kinase (e.g., a CDK (e.g., CDK9, CDK12))) and / or induce target degradation (e.g., a kinase (e.g., a CDK (e.g., CDK9, CDK12))).

[0113] The preventive effective amount of the compounds described herein is an amount sufficient to prevent the disease or one or more symptoms associated with the disease or to prevent its recurrence. The preventive effective amount of a compound means the amount by which a therapeutic agent, alone or in combination with other agents, provides a preventive benefit in the prevention of the disease. The term "preventive effective amount" may encompass an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. In some embodiments, the preventive effective amount is an amount sufficient to bind to a target (e.g., a kinase (e.g., CDK (e.g., CDK9, CDK12))) and / or induce the degradation of a target (e.g., a kinase (e.g., CDK (e.g., CDK9, CDK12))). In some embodiments, the preventive effective amount is an amount sufficient to treat a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)).

[0114] In some embodiments, the preventive effective amount is an amount sufficient to bind to the target (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))) and / or induce the degradation of the target (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12)))) and to treat and / or prevent diseases (e.g., proliferative diseases (e.g., ovarian cancer, breast cancer, or prostate cancer)).

[0115] "Proliferative disorders" are diseases caused by abnormal growth or extension of cells due to proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant tumors"), benign tumors, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0116] The term "angiogenesis" refers to the physiological process by which new blood vessels form from existing blood vessels. Angiogenesis differs from angiogenesis, which involves the de novo formation of endothelial cells from mesodermal cell precursors. The first blood vessel in a developing embryo forms through angiogenesis, and thereafter angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a crucial process in growth and development, as well as wound healing and granulation tissue formation. However, angiogenesis is also a fundamental step in the transformation of tumors from a benign to a malignant state, leading to the use of angiogenesis inhibitors in cancer treatment. Angiogenesis can be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). "Pathological angiogenesis" refers to abnormal (e.g., excessive or insufficient) angiogenesis that corresponds to and is associated with disease.

[0117] The terms “tumor” and “nebula” are used interchangeably herein and refer to an abnormal mass of tissue in which the growth of the mass exceeds and is not coordinated with the growth of normal tissue. A tumor or neoplasm can be “benign” or “malignant”, depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign tumors” are typically well-differentiated, grow characteristically slower than malignant tumors, and remain confined to the primary site. Furthermore, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites. Exemplary benign tumors include, but are not limited to, lipomas, chondromas, adenomas, cysts, senile hemangiomas, seborrheic keratosis, nevi, and sebaceous hyperplasia. In some cases, certain “benign” tumors may subsequently develop into malignant tumors, possibly due to additional genetic changes in a subset of the tumor cells; these tumors are called “premalignant tumors.” A typical premalignant tumor is a teratoma. In contrast, “malignant tumors” are typically poorly differentiated (undeveloped) and have characteristic rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant tumors often have the ability to metastasize to distant sites. The term "metastasis" refers to the spread or migration of cancer cells from a primary or initial tumor to another organ or tissue, and is usually identified by the presence of a "secondary tumor" or "secondary cell cluster" of the histological type of the primary or initial tumor, rather than by the presence of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has metastasized to the bone is called metastatic prostate cancer, and includes cancerous prostate cancer cells growing in bone tissue.

[0118] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, for example, Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, hematologic malignancies. Other exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); kidney cancer (e.g., nephroblastoma, renal cell carcinoma); acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma); appendix cancer; benign monoclonal immunoglobulinosis; cholangiocarcinoma (e.g., hepatobiliary hepatocellular carcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, papillary breast carcinoma, breast cancer, medullary breast carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g.)). Examples of cancers include: astrocytoma, oligodendroglioma, medulloblastoma; bronchial carcinoma; carcinoid tumors; cervical cancer (e.g., cervical adenocarcinoma); chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); common eosinophilia; gallbladder cancer. Cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., squamous cell carcinoma of the head and neck, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain diseases (e.g., alpha chain diseases, gamma chain diseases, μ chain diseases); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastoma; immune cell amyloidosis; liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); leiomyosarcoma (LMS); mastocytosis (e.g., generalized mastocytosis); muscle cancer; myelodysplastic syndrome ( MDS; mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), heteromyeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannoma); neuroendocrine carcinoma (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor);Osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pineal tumor; primitive neuroectodermal tumor (PNT); plasmacytoma; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA)). Cancers include: melanoma, basal cell carcinoma (BCC); small bowel cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small bowel cancer; sweat gland cancer; synovial tumor; testicular cancer (e.g., seminoma, embryonal testis 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).

[0119] "Protein," "peptide," or "polypeptide" includes polymers of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein is at least three amino acids long. A protein can refer to a single protein or a collection of proteins. The proteins of the present invention preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not exist in nature but can be incorporated into the polypeptide chain) and / or amino acid analogs known in the art may be used alternatively. Furthermore, one or more amino acids in the protein may be modified, for example, by adding chemical entities such as carbohydrate groups, hydroxyl groups, phosphate groups, farnesyl groups, isofarnesyl groups, fatty acid groups, linkers for binding or functionalization, or other modifications. Proteins can also be single-molecule or multi-molecule complexes. Proteins can be fragments of natural proteins or peptides. Proteins can be naturally occurring, recombinant, synthetic, or any combination thereof.

[0120] The term "therapeutic agent" refers to any substance that has therapeutic properties that produce a desired, generally beneficial effect. For example, a therapeutic agent can treat, improve, and / or prevent disease. The therapeutic agents disclosed herein can be biological agents or small molecule therapeutic agents.

[0121] The term “E3 ubiquitin ligase” or “E3 ligase” refers to any protein that can recruit an E2 ubiquitin-binding enzyme that is already loaded with ubiquitin, recognize the protein substrate, and help or directly catalyze the transfer of ubiquitin from the E2 protein to the protein substrate. For E3 ubiquitin ligases, an exemplary sequence from GenBank: ACH72645.1 (Homo sapiens) is: MESGGRPSLCQFILLGTTSV VTAALYSVYR QKARVSQELK GAKKVHLGED LKSILSEAPG KCVPYAVIEG AVRSVKETLNSQFVENCKGV IQRLTLQEHK MVWNRTTHLW NDCSKIIHQR TNTVPFDLVP HEDGVDVAVR VLKPLDSVDLGLETVYEKFH PSIQSFTDVI GHYISGERPK GIQETEEMLK VGATLTGVGE LVLDNNSVRL QPPKQGMQYYLSSQDFDSLL QRQESSVRLW KVLALVFGFA TCATLFFILR KQYLQRQERL RLKQMQEEFQEHEAQLLSRAKPEDRESLKS ACVVCLSSFK SCVFLECGHV CSCTECYRAL PEPKKCPICR QAITRVIPPYNS (SEQ ID NO: 1). For E3 ubiquitin ligases, an exemplary sequence from GenBank: AAP47175.1 (Homo sapiens) is: MEEGNNNEEV IHLNNFHCHR GQEWINLRDG PITISDSSDE ERIPMLVTPA PQQHEEEDLD DDVILTETNKPQRSRPNLIK PAAQWQDLKR LGEERPKKSR AAFESDKSSY FSVCNNPLFD SGAQDDSEDD YGEFLDLGPPGISEFTKPSG QTEREPKPGP SHNQAANDIV NPRSEQKVII LEEGSLLYTE SDPLETQNQS SEDSETELLSNLGESAALAD DQAIEEDCWL DHPYFQSLNQ QPREITNQVV PQERQPEAEL GRLLFQHEFP GPAFPRPEPQQGGISGPSSP QPAHPLGEFE DQQLASDDEE PGPAFPMQES QEPNLENIWG QEAAEVDQEL VELLVKETEARFPDVANGFI EEIIHFKNYY DLNVLCNFLL ENPDYPKRED RIIINPSSSLLASQDETKLP KIDFFDYSKLTPLDQRCFIQ AADLLMADFK VLSSQDIKWA LHELKGHYAI TRKALSDAIK KWQELSPETS GKRKKRKQMNQYSYIDFKFE QGDIKIEKRM FFLENKRRHC RSYDRRALLP AVQQEQEFYE QKIKEMAEHE DFLLALQMNEEQYQKDGQLI ECRCCYGEFP FEELTQCADAHLFCKECLIR YAQEAVFGSG KLELSCMEGS CTCSFPTSELEKVLPQTILY KYYERKAEEE VAAAYADELV RCPSCSFPAL LDSDVKRFSC PNPHCRKETC RKCQGLWKEHNGLTCEELAE KDDIKYRTSI EEKMTAARIR KCHKCGTGLI KSEGCNRMSC RCGAQMCYLC RVSINGYDHFCQHPRSPGAP CQECSRCSLW TDPTEDDEKL IEEIQKEAEE EQKRKNGENT FKRIGPPLEKPVEKVQRVEALPRPVPQNLP QPQMPPYAFAHPPFPLPPVR PVFNNFPLNM GPIPAPYVPP LPNVRVNYDFGPIHMPLEHN LPMHFGPQPR HRF (SEQ ID NO:2). For the E3 ubiquitin ligase, an exemplary sequence from GenBank: AAP47174.1 (Homo sapiens) is: MEEGNNNEEV IHLNNFHCHR GQEWINLRDG PITISDSSDEERIPMLVTPA PQQHEEEDLD DDVILTEDDS EDDYGEFLDL GPPGISEFTK PSGQTEREPK PGPSHNQAANDIVNPRSEQK VIILEEGSLL YTESDPLETQ NQSSEDSETE LLSNLGESAA LADDQAIEED CWLDHPYFQSLNQQPREITN QVVPQERQPE AELGRLLFQH EFPGPAFPRP EPQQGGISGP SSPQPAHPLG EFEDQQLASDDEEPGPAFPM QESQEPNLEN IWGQEAAEVD QELVELLVKE TEARFPDVAN GFIEEIIHFK NYYDLNVLCNFLLENPDYPK REDRIIINPS SSLLASQDETKLPKIDFFDY SKLTPLDQRC FIQAADLLMADFKVLSSQDIKWALHELKGH YAITRKALSD AIKKWQELSP ETSGKRKKRK QMNQYSYIDF KFEQGDIKIE KRMFFLENKRRHCRSYDRRA LLPAVQQEQE FYEQKIKEMA EHEDFLLALQ MNEEQYQKDG QLIECRCCYG EFPFEELTQCADAHLFCKEC LIRYAQEAVF GSGKLELSCM EGSCTCSFPT SELEKVLPQT ILYKYYERKA EEEVAAAYADELVRCPSCSF PALLDSDVKR FSCPNPHCRK ETCRKCQGLW KEHNGLTCEE LAEKDDIKYR TSIEEKMTAARIRKCHKCGT GLIKSEGCNR MSCRCGAQMC YLCRVSINGY DHFCQHPRSP GAPCQECSRC SLWTDPTEDDEKLIEEIQKE AEEEQKRKNG ENTFKRIGPP LEKPVEKVQR VEALPRPVPQ NLPQPQMPPY AFAHPPFPLPPVRPVFNNFP LNMGPIPAPY VPPLPNVRVN YDFGPIHMPL EHNLPMHFGP QPRHRF (SEQ ID NO: 3).

[0122] The term "binding agent" refers to a compound that binds to a protein. The binding agent binds to the K+ of the protein. d Less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

[0123] The term "proteasome" refers to a protease complex that performs protein degradation. Specifically, the proteasome is a multi-subunit enzyme complex that can also play a crucial role in proteins that regulate cell cycle progression and apoptosis. The proteasome hydrolyzes selected proteins.

[0124] The term "CDK" refers to cyclin-dependent kinases. CDKs are a family of protein serine or threonine kinases whose activity is based on association with a non-catalytic regulatory subunit called cyclin. CDKs are involved in the control of the cell cycle. Examples of CDKs include, but are not limited to, CDK9, CDK12, and CDK13. Other examples of CDKs include, but are not limited to, CDK2, CDK4, CDK13, CDK14, CDK15, CDK16, CDK17, and CDK18. The process of eukaryotic cell division can be broadly divided into a series of consecutive phases called G1, S, G2, and m phases. The proper progression of each phase of the cell cycle has been shown to depend heavily on the spatiotemporal regulation of a family of proteins called cyclin-dependent kinases (CDKs) and their various homologous protein chaperones called cyclins. CDKs are CDC2 (also known as CDK1) homologous serine-threonine kinase proteins that can use ATP as a substrate to phosphorylate different polypeptides in a sequence-dependent manner. Cyclins are a family of proteins characterized by homology regions, comprising approximately 100 amino acids, known as "cyclin boxes," which bind to specific CDK chaperone proteins and define their selectivity. Regulation of expression levels, degradation rates, protein levels, and activity levels of various CDKs and cyclins throughout the cell cycle leads to the periodic formation of a series of CDK / cyclin complexes, in which CDKs possess enzymatic activity. The formation of these complexes is controlled through discrete cell cycle checkpoints, allowing the cell division process to continue. Failure to meet prerequisite biochemical criteria at a given cell cycle checkpoint, such as the failure to form the required CDK / cyclin complex, can lead to cell cycle arrest and / or apoptosis. Abnormal cell proliferation is often attributed to the loss of proper cell cycle control. Therefore, inhibiting CDK enzyme activity provides a method by which abnormally dividing cells can be stopped and / or killed. The diversity of CDKs and CDK complexes, and their crucial roles in mediating the cell cycle, provide a broad range of potential therapeutic targets selected based on defined biochemical principles. Attached Figure Description

[0125] Figure 1-3 This demonstrates the rescue of degradation by pretreatment with carfilzomib and the exemplary CDK12 irreversible inhibitor THZ-5-31.

[0126]

[0127] Figure 1The levels of CDK12, CDK13, and CDK9, as well as GAPDH, in T-cell acute lymphoblastic leukemia (T-ALL) cells (i.e., Jurkat (human T lymphocytes) and Molt 4 cells (human acute lymphoblastic leukemia cells)) were shown. Degradation of CDK12, CDK13, and CDK9 was rescued by pretreatment at specified concentrations for 2 hours with the exemplary CDK12 inhibitor THZ-5-31, the exemplary protease inhibitor carfilzomib (CFZ), thalidomide (Thal.), and MLN4924 (an inhibitor of NEDD8-activating enzyme (NAE)), followed by treatment with the exemplary CDK12 inhibitor BSJ-0423 (BSJ-04-023) at 250 nM for 6 hours. The molecular formula of BSJ-04-023 is: The molecular formula of BSJ-04-026 is:

[0128] Figure 2 The levels of CDK12, CDK13, CDK9, and GAPDH in T-ALL Jurkat cells are shown. Cells treated with 250 nM DMSO or the exemplary CDK12 degrader BSJ-0423 (BSJ-04-023) were collected and examined by Western blotting at specified time points.

[0129] Figure 3 This demonstrates dose-dependent inhibitory antiproliferative activity (IC50) at specified concentrations in T-ALL Jurkat cells with and without CRBN knockout (-- / --) and wt% CRBN knockout, following treatment with the exemplary CDK12 inhibitor THZ-5-31 and the CDK12 degrader BSJ-04-023. 50 CRBN knockout conferred approximately 10-fold resistance to BSJ-0423 but not to THZ-5-31, indicating that the activity of BSJ-04-023 in Jurkat cells (wt) is CRBN-dependent.

[0130] Figure 4A The levels of CDK12 and CDK13, as well as GAPDH, in T-cell acute lymphoblastic leukemia (T-ALL) cells, which are Jurkat (human T lymphocytes), are shown. Cells treated with DMSO or CDK12 degrading agents BSJ-04-023, BSJ-04-071, BSJ-04-076, BSJ-04-077, BSJ-04-078, BSJ-04-079, and BSJ-04-100 at specified concentrations were collected and examined by Western blotting at 6 hours.

[0131] Figure 4BThe levels of CDK12 and CDK13, as well as GAPDH, in T-cell acute lymphoblastic leukemia (T-ALL) cells, which are Jurkat (human T lymphocytes), are shown. Cells treated with DMSO or CDK12 degrading agents BSJ-04-023, BSJ-04-086, BSJ-04-089, BSJ-04-098, BSJ-04-099, and BSJ-04-100 at specified concentrations were collected and examined by Western blotting at 6 hours. Detailed Implementation

[0132] The bifunctional compounds described herein interact with targets (e.g., kinases, such as CDKs, such as CDK9, CDK12) and E3 ubiquitin ligases (e.g., Cerebro). As described herein, it is not intended to be construed as being bound by any particular theory; therapeutic effects can result from the degradation, regulation, inhibition, or binding of targets (e.g., kinases, such as CDKs, such as CDK9, CDK12) by the compounds described herein. Therapeutic effects can result from bifunctional compounds comprising conjugates to E3 ubiquitin ligases (e.g., Cerebro) and targets (e.g., kinases, such as CDKs, such as CDK9, CDK12)), thereby inducing the degradation of the target protein. These compounds can be used to induce the degradation of targets (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12))), to treat and / or prevent diseases (e.g., proliferative diseases, such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer)), to treat and / or prevent diseases associated with targets (e.g., kinases (e.g., CDKs (e.g., CDK9, CDK12)))), and / or to induce apoptosis in cells in biological samples or subjects.

[0133] In one aspect, compounds of formula (I) are disclosed:

[0134]

[0135] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug, wherein:

[0136] R 1 Each instance is independently a halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR D1 -N(R) D1a )2 or -SR D1 ;where R D1It is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, oxygen protecting group when attached to an oxygen atom, or sulfur protecting group when attached to a sulfur atom.

[0137] Where R D1a Each occurrence of R is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted ynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, or nitrogen-protecting group; or optionally, R D1a Two instances together with their intermediate atoms form substituted or unsubstituted heterocycles or substituted or unsubstituted heteroaryl rings;

[0138] R 2 Each instance is independently a halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR D1 -N(R) D1a )2 or -SR D1 ;

[0139] R 3 It is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl or nitrogen-protected group;

[0140] R X Each instance is independently a halogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group;

[0141] R Y Each instance is independently a halogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a -SO2R group. Y1 –P(=O)(R Y2 )2、-OR Y1 or –N(R) Y2 )2;

[0142] R Y1 It is a hydrogen, acyl, optionally substituted alkyl group, or an oxygen protecting group when attached to an oxygen atom;

[0143] R Y2 Each instance is independently hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group when attached to a nitrogen atom;

[0144] w is 0, 1, 2, 3, 4, 5, or 6;

[0145] w1 is 0, 1, 2, 3, 4 or 5;

[0146] x is 0, 1, or 2;

[0147] y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0148] L1 is a bond, optionally substituted alkylene, -NR A -, -O-, or -S-; where R A It is hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group;

[0149] L2 is the connector;

[0150] The molecular formula of ring A is: as well as

[0151] D is the E3 ubiquitin ligase binding site.

[0152] Group D

[0153] In some embodiments, D is an E3 ubiquitin ligase-binding moiety. D includes all parts that bind to or are capable of binding to any E3 ubiquitin ligase. For example, in some embodiments, D is capable of binding to E3 ubiquitin ligases such as Cerebrolysin. In some embodiments, D is capable of binding to multiple different E3 ubiquitin ligases. In some embodiments, D binds to Cerebrolysin. In some embodiments, D is based on an immunomodulatory imide drug. In some embodiments, D is derived from lenalidomide. In some embodiments, D is derived from thalidomide.

[0154] Human cereblon (CRBN) is a protein composed of 442 amino acids with an apparent molecular weight of approximately 51 kDa (GenBank: AAH17419). (For the CRBN protein sequence, see: Higgins et al., Neurology. 2004, 63, 1927-31. For more information on the CRBN structure, see Hartmann et al., PLoS One. 2015, 10, e0128342.). Human CRBN contains the N-terminal portion (237 amino acids, from 81 to 317) of an ATP-dependent Lon protease domain, lacks conserved Walker A and Walker B motifs, has 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristylation sites. CRBNs are widely expressed in the testes, spleen, prostate, liver, pancreas, placenta, kidneys, lungs, skeletal muscle, ovaries, small intestine, peripheral blood leukocytes, colon, brain, and retina. CRBNs are located in the cytoplasm, nucleus, and peripheral membrane. (Chang et al., Int. J. Biochem. Mol. Biol. 2011, 2, 287-94.)

[0155] Cereblon is an E3 ubiquitin ligase that forms an E3 ubiquitin ligase complex with regulators of damaged DNA-binding protein 1 (DDB1), Culin-4A (CUL4A), and Culin 1 (ROC1). This complex ubiquitinates many other proteins. Through a mechanism not yet fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates many developmental processes, such as limb and auditory vesicle formation.

[0156] In some embodiments, D is a modulator, binder, inhibitor, or ligand of Cerebrolon. In some embodiments, D is a modulator of Cerebrolon. In some embodiments, D is a binder of Cerebrolon. In some embodiments, D is an inhibitor of Cerebrolon. In some embodiments, D is a ligand of Cerebrolon. In some embodiments, D is any modulator, binder, inhibitor, or ligand of Cerebrolon disclosed in U.S. Patent Application USSN 14 / 792,414, filed July 6, 2015; U.S. Patent Application USSN 14 / 707,930, filed May 8, 2015; and International Patent Application PCT / US2013 / 054663, filed August 13, 2013, each of which is incorporated herein by reference. In some embodiments, D has a binding affinity (K0) of Cerebrolon to Cerebrolon.d The concentration is approximately 1-10 μM. In some embodiments, D is used to target the K+ of Cerebro. d Approximately 3 μM. In some embodiments, the binding affinity of D to Cereblon (K0.05) is... d As disclosed in U.S. Patent Application USSN14 / 792,414, filed July 6, 2015.

[0157] In some embodiments, D is a modulator, binder, inhibitor, or ligand of a Cerebrolon variant. In some embodiments, D is a modulator, binder, inhibitor, or ligand of a Cerebrolon isotype.

[0158] In some embodiments, D comprises an optionally substituted heteroaryl ring. In some embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring. In some embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocycle. In some embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocycle, wherein the heterocycle contains at least one nitrogen. In some embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocycle, wherein each of the fused bicyclic heteroaryl ring and the heterocycle contains at least one nitrogen. In some embodiments, D comprises an optionally substituted fused bicyclic heteroaryl ring and a heterocycle, wherein each of the fused bicyclic heteroaryl ring and the heterocycle contains one nitrogen. In some embodiments, D comprises an optionally substituted phthalimide group, or an analogue or derivative thereof. In some embodiments, D comprises an optionally substituted phthalimide-glutarimide group, or an analogue or derivative thereof.

[0159] In some implementations, D is Equation (EI):

[0160]

[0161] in:

[0162] Ring A is a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted heteroaryl ring;

[0163] Each R 1A It is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy group;

[0164] Each R 3A It is independently H or C1-C3-alkyl;

[0165] Each R 3’ It is independently a C1-C3-alkyl group;

[0166] Each R 4A It is independently H or C1-C3-alkyl; or two R 4ATogether with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings or 4, 5 or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen;

[0167] R 5A It is H, C1-C3 alkyl, F or Cl;

[0168] m is 0, 1, 2, or 3; and

[0169] n is 1 or 2.

[0170] In some embodiments, formula (EI) is derived from an immunomodulatory imide drug (e.g., derived from lenalidomide or thalidomide). In some embodiments, formula (EI) is formula (1A) or formula (1B). In some embodiments, the compound of formula (1A) or formula (1B) may optionally be further substituted.

[0171] In some implementations, D is Equation (IA):

[0172]

[0173] in:

[0174] X A Is it C(O) or C(R)? 3A )2;

[0175] Each R 1A It is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy group;

[0176] R 3A It is an H or C1-C3 alkyl group;

[0177] Each R 3’ It is independently a C1-C3-alkyl group;

[0178] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings or 4, 5 or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen;

[0179] R 5A It is H, C1-C3 alkyl, or halogen;

[0180] m is 0, 1, 2, or 3;

[0181] n is 0, 1, or 2; and

[0182] a1 is 0 or 1.

[0183] In some implementations, D is equation (IA-a):

[0184]

[0185] in:

[0186] X A Is it C(O) or C(R)? 3A )2;

[0187] Each R 1A It is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy group;

[0188] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings or 4, 5 or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen;

[0189] R 5A It is H, C1-C3 alkyl, F or Cl; and

[0190] m can be 0, 1, 2, or 3.

[0191] In some implementations, D is equation (IA-b):

[0192]

[0193] in:

[0194] X A Is it C(O) or C(R)? 3A )2;

[0195] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings, or 4, 5, or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen; and

[0196] R 5A It is H, C1-C3 alkyl, F or Cl.

[0197] In some implementations, D is represented by equation (IA-c):

[0198]

[0199] in:

[0200] Each R 4A It is independently H or C1-C3-alkyl; or two R 4ATogether with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings, or 4, 5, or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen; and

[0201] R 5A It is H, C1-C3 alkyl, F or Cl.

[0202] In some implementations, D is represented by equation (IA-d):

[0203]

[0204] in:

[0205] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings, or 4, 5, or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen; and

[0206] R 5A It is H, C1-C3 alkyl, F or Cl.

[0207] In some implementations, D is Equation (IB):

[0208]

[0209] in:

[0210] -X 1 —X 2 - is C(R) 3A )═N or C(R 3A )2—C(R 3A )2;

[0211] Each R 1A It is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy group;

[0212] R 3A It is an H or C1-C3 alkyl group;

[0213] Each R 3’ It is independently a C1-C3-alkyl group;

[0214] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings or 4, 5 or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen;

[0215] R 5A It is H, C1-C3 alkyl, or halogen;

[0216] m is 0, 1, 2, or 3;

[0217] n is 0, 1, or 2; and

[0218] a1 is 0 or 1.

[0219] In some implementations, D is equation (IB-a):

[0220]

[0221] in:

[0222] -X 1 —X 2 It is C(R) 3A )═N or C(R 3A )2—C(R 3A )2;

[0223] Each R 1A It is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy group;

[0224] Each R 3A It is independently H or C1-C3-alkyl;

[0225] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings or 4, 5 or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen;

[0226] R 5A It is H, C1-C3 alkyl, F or Cl; and

[0227] m can be 0, 1, 2, or 3.

[0228] In some implementations, D is equation (IB-b):

[0229]

[0230] in:

[0231] -X 1 —X 2 It is C(R) 3A )═N or C(R 3A )2—C(R 3A )2;

[0232] Each R 3A It is independently H or C1-C3-alkyl;

[0233] Each R 4AIt is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings, or 4, 5, or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen; and

[0234] R 5A It is H, C1-C3 alkyl, F or Cl.

[0235] In some implementations, D is equation (IB-c):

[0236]

[0237] in:

[0238] Each R 4A It is independently H or C1-C3-alkyl; or two R 4A Together with the carbon atoms they are attached to, they form C(O), C3-C6 carbon rings, or 4, 5, or 6-membered heterocycles containing one or two heteroatoms selected from nitrogen and oxygen; and

[0239] R 5A It is H, C1-C3 alkyl, F or Cl.

[0240] Formulas (IA), (IA-a), and (IA-b) include substituent X. A In some implementations, X A It is C(O). In some implementations, X A It is C(R) 3A )2.

[0241] Formulas (IA), (IA-a), and (IA-b) include the substituent -X. 1 —X 2 In some implementations, -X 1 —X 2 - is C(R) 3A )═N. In some implementations, -X 1 —X 2 - is C(H)═N. In some implementations, -X 1 —X 2 - is C(C1-C3 alkyl)═N. In some embodiments, -X 1 —X 2 - is C(R) 3A )2—C(R 3A 2. In some implementations, -X 1 —X 2 - is C(H)₂—C(H)₂. In some implementations, -X 1 —X 2- is C(H)2—C(C1-C3 alkyl)2. In some embodiments, -X 1 —X 2 - is C(H)2—C(C1-C3 alkyl)2. In some embodiments, -X 1 —X 2 - is C(H)2—C(C1-C3 alkyl)2. In some embodiments, -X 1 —X 2 - is C(C1-C3 alkyl)2—C(C1-C3 alkyl)2.

[0242] In some embodiments, D is a compound based on a von Hippel–Lindau ligand (“VHL ligand”). In some embodiments, D is derived from the VHL ligand. In some embodiments, D has the formula:

[0243] in:

[0244] Each R 2 ′ is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy;

[0245] Each R 4 ′ is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy;

[0246] Each R 5 ′ is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy;

[0247] n1′ is 0, 1, 2, 3, 4, 5 or 6;

[0248] n2′ is 0, 1, 2, 3, or 4; and

[0249] n3′ is 0, 1, or 2.

[0250] In some implementations, D has R 2 Zero instances of ′. In some implementations, D has R 2 One or more instances of '. In some embodiments, n1' is 0. In some embodiments, n1' is 1. In some embodiments, n1' is 2. In some embodiments, n1' is 3. In some embodiments, n1' is 4. In some embodiments, n1' is 5. In some embodiments, n1' is 6. In some embodiments, R 2 Each instance of ' is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R 2At least one instance of ′ is (e.g., F, Cl, Br, or I). In some embodiments, R 2 At least one instance of ′ is –OH. In some implementations, R 2 At least one instance of ′ is an unsubstituted C1-C6 alkyl group (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl). In some embodiments, R 2 At least one example of ′ is a C1-C6 alkoxy group (e.g., -O (unsubstituted C1-C6 alkyl)). In some embodiments, R 2 At least one instance of ′ is –O(Me). In some implementations, R 2 At least one instance of ′ is –O(Et). In some implementations, R 2 At least one instance of ′ is –O (n-propyl). In some embodiments, R 2 At least one instance of ′ is –O (isopropyl). In some embodiments, R 2 At least one instance of ′ is –O (n-butyl).

[0251] In some implementations, D has zero R 4 An example of '. In some implementations, D has R. 4 One or more instances of '. In some embodiments, n2' is 0. In some embodiments, n2' is 1. In some embodiments, n2' is 2. In some embodiments, n2' is 3. In some embodiments, n2' is 4. In some embodiments, R 4 Each instance of ' is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R 4 At least one instance of ′ is (e.g., F, Cl, Br, or I). In some embodiments, R 2 At least one instance of ′ is –OH. In some implementations, R 4 At least one instance of ′ is an unsubstituted C1-C6 alkyl group (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl). In some embodiments, R 4 At least one example of ′ is a C1-C6 alkoxy group (e.g., -O (unsubstituted C1-C6 alkyl)). In some embodiments, R 4 At least one instance of ′ is –O(Me). In some implementations, R 4 At least one instance of ′ is –O(Et). In some implementations, R 4 At least one instance of ′ is –O (n-propyl). In some embodiments, R 4 At least one instance of ′ is –O (isopropyl). In some embodiments, R4 At least one instance of ′ is –O (n-butyl).

[0252] In some implementations, D has zero R 5 An example of '. In some implementations, D has R. 5 One or more instances of '. In some embodiments, n3' is 0. In some embodiments, n3' is 1. In some embodiments, n3' is 2. In some embodiments, n3' is 3. In some embodiments, R 5 Each instance of ' is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R 5 At least one instance of ′ is (e.g., F, Cl, Br, or I). In some embodiments, R 5 At least one instance of ′ is –OH. In some implementations, R 5 At least one instance of ′ is a C1-C6 alkyl group. In some embodiments, R 5 At least one instance of ′ is an unsubstituted C1-C6 alkyl group (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl). In some embodiments, R 5 At least one instance of ′ is an unsubstituted methyl group. In some embodiments, R 5 At least one instance of ′ is an unsubstituted ethyl. In some embodiments, R 5 At least one instance of ′ is an unsubstituted n-propyl group. In some embodiments, R 5 At least one example of ′ is a C1-C6 alkoxy group (e.g., -O (unsubstituted C1-C6 alkyl)). In some embodiments, R 5 At least one instance of ′ is –O(Me). In some implementations, R 5 At least one instance of ′ is –O(Et). In some implementations, R 5 At least one instance of ′ is –O (n-propyl). In some embodiments, R 5 At least one instance of ′ is –O (isopropyl). In some embodiments, R 5 At least one instance of ′ is –O (n-butyl).

[0253] In some implementations, D is the following formula: In some implementations, D is the following formula: Ring A

[0254] Formula (I) includes ring A. In some embodiments, ring A is of formula: In some implementations, ring A is represented by the following formula: In some implementations, ring A is represented by the following formula: In some embodiments, there are zero substituents R on ring A. X Examples. In some implementations, there are one or more substituents R on ring A. X Examples. In some implementations, w is 0. In some implementations, w is 1. In some implementations, w is 2. In some implementations, w is 3. In some implementations, w is 4. In some implementations, w is 5. In some implementations, w is 6. In some implementations, R X At least one instance is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R X At least one instance is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R X At least one instance is an optionally substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl groups (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl). In some embodiments, R X At least one instance of C is the optional substitution. 1-6 Alkyl group. In some embodiments, R X At least one instance is an optionally substituted methyl group. In some embodiments, R X At least one instance is an optionally substituted ethyl. In some embodiments, R X At least one instance is an optionally substituted n-propyl group. In some embodiments, R X At least one instance is an optionally substituted isopropyl group. In some embodiments, R X At least one example is a nitrogen-protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In some embodiments, ring A has the formula: In some implementations, ring A is represented by the following formula: In some implementations, ring A is represented by the following formula:

[0255] In some implementations, ring A is of the form Where R Y Each instance is independently a halogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a -SO2R group. Y1–P(=O)(R Y2 )2、-OR Y1 ; or –N(R) Y2 )2;R Y1 It is a hydrogen, acyl, optionally substituted alkyl group, or an oxygen protecting group when attached to an oxygen atom; R Y2 Each instance is independently hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group when attached to a nitrogen atom; and w1 is 0, 1, 2, 3, 4, or 5. In some embodiments, there are zero substituents R on ring A. Y Examples. In some implementations, there are one or more substituents R on ring A. Y Examples. In some implementations, w1 is 0. In some implementations, w1 is 1. In some implementations, w1 is 2. In some implementations, w1 is 3. In some implementations, w1 is 4. In some implementations, w1 is 5. In some implementations, ring A is of the following formula: In some implementations, ring A is represented by the following formula:

[0256] In some implementations, R Y At least one instance is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R Y At least one instance is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R Y At least one instance is an optionally substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl groups (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl). In some embodiments, R Y At least one instance of C is the optional substitution. 1-6 Alkyl group. In some embodiments, R Y At least one instance is an optionally substituted methyl group. In some embodiments, R Y At least one instance is an optionally substituted ethyl. In some embodiments, R Y At least one instance is an optionally substituted n-propyl group. In some embodiments, R Y At least one instance is an optionally substituted isopropyl group. In some embodiments, R Y At least one example is an optionally substituted acyl group, an optionally substituted alkyl group, or a -SO2R group. Y1 –P(=O)(R Y2 )2、-OR Y1 ; or –N(R) Y2 )2;RY1 It is a hydrogen, acyl, optionally substituted alkyl group, or an oxygen protecting group when attached to an oxygen atom; R Y2 Each instance is independently hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group when attached to a nitrogen atom. In some embodiments, R Y At least one example is an optionally substituted acyl group, -SO2R Y1 –P(=O)(R Y2 )2、-OR Y1 or –N(R) Y2 )2; In some implementations, R Y At least one instance is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R Y At least one instance is –C(=O)N(R) y3 )2, where R y3 Each instance is independently hydrogen or optionally substituted alkyl. In some embodiments, R Y At least one instance is –C(=O)NH(R) y3 ), where R y3 It is an optionally substituted alkyl group. In some embodiments, R Y At least one example is –C(=O)NH (optionally substituted C1-C6 alkyl). In some embodiments, R Y At least one instance is –C(=O)NH(Me). In some implementations, R Y At least one instance is -SO2R Y1 , where R Y1 It is hydrogen, acyl, or optionally substituted alkyl. In some embodiments, R Y At least one instance is -SO2R Y1 , where R Y1 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R Y At least one instance is -SO2R Y1 , where R Y1 It is optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, or optionally substituted n-pentyl. In some embodiments, R Y At least one instance is -SO2R Y1 , where R Y1 It is an optionally substituted isopropyl group. In some embodiments, R Y At least one instance is In some implementations, R Y At least one instance is –P(=O)(R Y2)2, where R Y2 Each instance is independently an optionally substituted alkyl group. In some embodiments, R Y At least one instance is –P(=O)(R Y2 )2, where R Y2 Each instance is an unsubstituted C1-C6 alkyl group. In some embodiments, R Y At least one instance is –P(=O)(R Y2 )2, where R Y2 Each instance is an optionally substituted C1-C6 alkyl group. In some embodiments, R Y At least one instance is –P(=O)(R Y2 )2, where R Y2 Each instance is independently a optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted isobutyl, or optionally substituted n-pentyl. In some embodiments, R Y At least one instance is –P(=O)(R Y2 )2, where R Y2 Each instance of is an optionally substituted methyl group. In some embodiments, R Y At least one instance is

[0257] In some implementations, R Y At least one instance of -OR Y1 or –N(R) Y2 )2; where R Y1 It is a hydrogen, acyl, optionally substituted alkyl group, or an oxygen protecting group when attached to an oxygen atom; R Y2 Each instance is independently hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group when attached to a nitrogen atom. In some embodiments, R Y At least one instance of -OR Y1 (e.g., -OH or –O (optionally substituted C1-C6 alkyl)). In some embodiments, R Y At least one instance is –N(R) Y2 )2 (e.g., -NH2, -NMe2)).

[0258] In some implementations, R Y1 It is a hydrogen, acyl, optionally substituted alkyl group, or an oxygen protecting group when attached to an oxygen atom. In some embodiments, R Y1 It is hydrogen. In some implementations, R Y1 It is an acyl group (e.g., -C(=O)Me). In some embodiments, R Y1It is an substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl groups (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl). In some embodiments, R Y1 It is an oxygen protecting group (e.g., methyl, methoxymethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylxylyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methanesulfonate, benzylsulfonate, or toluenesulfonate (Ts)). In some embodiments, R Y2 Each instance is independently hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group when attached to a nitrogen atom. In some embodiments, R Y2 At least one instance is hydrogen. In some implementations, R Y2 At least one instance is an acyl group (e.g., -C(=O)Me). In some embodiments, R Y2 At least one instance is an optionally substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl groups (e.g., optionally substituted methyl, optionally substituted ethyl, or optionally substituted propyl). In some embodiments, R Y2 At least one example is a nitrogen protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide (Ts)).

[0259] In some implementations, ring A is represented by the following formula: In some implementations, ring A is represented by the following formula: Connectors L1 and L2

[0260] The linker L1 connects the pyrimidine and ring A of form (I). In some embodiments, L1 is a single bond. In some embodiments, L1 is an optionally substituted alkylene group. In some embodiments, L1 is an optionally substituted C-shaped group. 1-6 Alkylene. In some embodiments, L1 is optionally unsubstituted C1. 1-6 Alkylene. In some embodiments, L1 is optionally unsubstituted C1. 2-6 Alkylene. In some embodiments, L1 is optionally unsubstituted C1. 3-6 Alkylene. In some embodiments, L1 is optionally unsubstituted C1. 4-6Alkylene. In some embodiments, L1 is -CH2-. In some embodiments, L1 is -NR. A -, -O-, or -S-; where R A It is a hydrogen, optionally substituted acyl, optionally substituted alkyl, or nitrogen-protecting group. In some embodiments, L1 is -NR. A -, where R A It is hydrogen, an optionally substituted acyl group, an optionally substituted alkyl group, or a nitrogen-protecting group. In some embodiments, L1 is -NH-. In some embodiments, L1 is –N (optionally substituted alkyl)- (e.g., –N (optionally substituted C)-). 1-6 Alkyl group (-). In some embodiments, L1 is -O-. In some embodiments, L1 is -S-. In some embodiments, L1 is -NH-, -O-, or -S-.

[0261] In formula (I), L2 is a divalent moiety that links group D to the piperidine portion of formula (I). In some embodiments, L2 is a substituted or unsubstituted C. 1-50 The hydrocarbon chain, as the shortest path between D and the piperidine portion of formula (I), optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, L2 is a substituted or unsubstituted C. 1-30 Hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-30 Hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, L2 is a substituted or unsubstituted C. 1-24 Hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-24 Hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, L2 is a substituted or unsubstituted C. 1-20 Hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-20 Hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently bounded by –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen-protecting group. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted with -O-. In some embodiments, L2 is any "L0" group or "connector" group referenced in U.S. Patent Application USSN 14 / 707,930, filed May 8, 2015, which is incorporated herein by reference. In some embodiments, L2 is any "L" group referenced in U.S. Patent Application USSN 14 / 792,414, filed July 6, 2015, which is incorporated herein by reference.

[0262] In some embodiments, the chain of linker L2 comprises up to 50 consecutive covalently bonded atoms as the shortest path between D and the piperidine moiety of formula (I), excluding hydrogen atoms and substituents. In some embodiments, the chain of linker L2 comprises up to 50 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 46 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 45 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 40 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 35 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 32 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 30 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 25 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 25 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 23 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 20 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 14 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 15 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 12 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 11 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to 10 consecutively covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to nine consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to eight consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to seven consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to six consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to five consecutive covalently bonded atoms, excluding hydrogen atoms and substituents. In some embodiments, L2 comprises up to three consecutive covalently bonded atoms, excluding hydrogen atoms and substituents.

[0263] In some embodiments, any atom in L2 can be substituted. In some embodiments, no atom in the joint L2 is substituted. In some embodiments, no carbon atom in the joint is substituted.

[0264] In some embodiments, L2 is a linker containing an asymmetric carbon / stereocenter, i.e., an sp with four different groups. 3 A hybrid carbon atom is attached thereto. In some embodiments, the compound containing such an L2 group is enantiomerically enriched or substantially enantiomerically enriched. In some embodiments, the compound containing such an L2 group is enantiomerically pure. In some embodiments, the compound containing such an L2 group is racemic.

[0265] In some embodiments, L2 comprises a substituted or unsubstituted carbocyclic alkylene, a substituted or unsubstituted heterocyclic alkylene, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroalkylene, or a combination thereof. In some embodiments, L2 is a substituted or unsubstituted carbocyclic alkylene, a substituted or unsubstituted heterocyclic alkylene, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroalkylene. In some embodiments, L2 is a connector selected from the group consisting of: substituted and unsubstituted alkylene, substituted and unsubstituted alkenyl, substituted and unsubstituted alynyl, substituted and unsubstituted heteroalkylene, substituted and unsubstituted alynyl, substituted and unsubstituted heterocyclic alkenyl, substituted and unsubstituted carbocyclic alkenyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and combinations thereof.

[0266] The reference to L2 as a combination of at least two instances of the divalent portion described herein refers to a connector consisting of at least one instance of a first divalent portion and at least one instance of a second divalent portion, wherein the first and second divalent portions are identical or different, and are within the scope of the divalent portion described herein, and the instances of the first and second divalent portions are covalently linked to each other consecutively. For example, when L2 is a combination of alkylene and heteroalkylene connectors, -alkylene-heteroalkylene-, -alkylene-(heteroalkylene)2-, and -heteroalkylene-alkylene-heteroalkylene- are all within the range of L, wherein each instance of the alkylene in any connector may be identical or different, and each instance of the heteroalkylene in any connector may be identical or different.

[0267] In some embodiments, L2 comprises at least one instance of a substituted or unsubstituted alkylene group, such as a substituted or unsubstituted C2. 1-6 Alkylene, substituted or unsubstituted C 1-2 Alkylene, substituted or unsubstituted C 2-3 Alkylene, substituted or unsubstituted C3-4 Alkylene, substituted or unsubstituted C 4-5 Alkylene, substituted or unsubstituted C 5-6 Alkylene, substituted or unsubstituted C 3-6 Alkylene, or substituted or unsubstituted C 4-6 Alkylenes. Exemplary alkylenes include unsubstituted alkylenes such as methylene (–CH2–), ethylene (–(CH2)2–), n-propylene (–(CH2)3–), n-butene (–(CH2)4–), n-pentene (–(CH2)5–), and n-hexene (–(CH2)6–).

[0268] In some embodiments, L2 includes at least one instance of a substituted or unsubstituted alkenyl group, such as a substituted or unsubstituted C group. 2-6 alkenyl, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 3-4 alkenyl, substituted or unsubstituted C 4-5 alkenyl, or substituted or unsubstituted C 5-6 Alkenyl group.

[0269] In some embodiments, L2 includes at least one instance of a substituted or unsubstituted alkynyl group, such as a substituted or unsubstituted C group. 2-6 alkyne-based, substituted or unsubstituted C 2-3 alkyne-based, substituted or unsubstituted C 3-4 alkyne-based, substituted or unsubstituted C 4-5 alkyne group, or substituted or unsubstituted C 5-6 Alynyl group.

[0270] In some embodiments, L2 comprises at least one instance of a substituted or unsubstituted heteroalkylene group, such as a substituted or unsubstituted heteroC. 1–6 Alkylene, substituted or unsubstituted heterocarbon 1–2 Alkylene, substituted or unsubstituted heterocarbon 2–3 Alkylene, substituted or unsubstituted heterocarbon 3–4 Alkylene, substituted or unsubstituted heterocarbon 4–5 Alkylene, or substituted or unsubstituted heterocarbon 5–6 Alkylenes. Exemplary heteroalkylenes include unsubstituted heteroalkylenes such as –(CH2)2–O(CH2)2–, –OCH2–, –CH2O–, –O(CH2)2–, –(CH2)2O–, –O(CH2)3–, –(CH2)3O–, –O(CH2)4–, –(CH2)4O–, –O(CH2)5–, –(CH2)5O–, –O(CH2)6– and –O(CH2)6O– as well as amide groups (e.g., -NH-C(=O)- and -C(=O)NH-).

[0271] In some embodiments, L2 includes at least one instance of a substituted or unsubstituted heteroene group, such as a substituted or unsubstituted heteroC group. 2-6 alkenyl, substituted or unsubstituted heterocarbon 2-3 alkenyl, substituted or unsubstituted heterocarbon 3-4 alkenyl, substituted or unsubstituted heterocarbon 4-5 alkenyl, or substituted or unsubstituted heterocyclic C 5-6 Alkenyl group.

[0272] In some embodiments, L2 includes at least one instance of a substituted or unsubstituted heteroynyl group, such as a substituted or unsubstituted heteroC group. 2-6 Hypo-alkynyl, substituted or unsubstituted hetero-C 2-3 Hypo-alkynyl, substituted or unsubstituted hetero-C 3-4 Hypo-alkynyl, substituted or unsubstituted hetero-C 4-5 Hypo-alkynyl, or substituted or unsubstituted hetero-C 5-6 Alynyl group.

[0273] In some embodiments, L2 includes at least one instance of a substituted or unsubstituted carbocyclic group, such as a substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted C 3-4 Carbocyclic group, substituted or unsubstituted C 4-5 Carbocyclic group, or substituted or unsubstituted C 5-6 Subcarbonyl cyclo group.

[0274] In some embodiments, L2 comprises at least one instance of a substituted or unsubstituted heterocyclic group, such as a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted 3-4 membered heterocyclic group, a substituted or unsubstituted 4-5 membered heterocyclic group, or a substituted or unsubstituted 5-6 membered heterocyclic group. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted by a 5-8 membered heterocyclic group having 1-4 cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted by a six membered heterocyclic group having 1-3 cyclic heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted by piperidine or piperazine. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted by piperidine. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted by piperazine. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted with morpholine.

[0275] In some embodiments, L2 comprises at least one instance of a substituted or unsubstituted aryl group, such as a substituted or unsubstituted phenyl group. In some embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently substituted with an optionally substituted phenyl group. In some embodiments, L2 comprises at least one instance of a substituted or unsubstituted heteroaryl group, such as a substituted or unsubstituted 5- or 6-membered heteroaryl group.

[0276] In some embodiments, L2 is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently –NR b – Replace, and R b Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl or nitrogen protecting group, or optionally R b Two instances of R, together with their intermediate atoms, form substituted or unsubstituted heterocycles or substituted or unsubstituted heteroaryl rings. In some embodiments, R b At least one instance is hydrogen. In some implementations, R b At least one instance is substituted or unsubstituted C. 1-6 Alkyl (e.g., substituted or unsubstituted methyl or ethyl). In some embodiments, R b At least one example is a nitrogen protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide (Ts)).

[0277] In some implementations, L2 is an optional replacement for C. 1-45 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), excludes hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently substituents –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-45 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), excludes hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently substituents –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, L2 is an optionally substituted C. 1-24The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), excludes hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently substituents –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-24 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), excludes hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently substituents –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, L2 is an optionally substituted C. 1-20 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), excludes hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently substituents –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-20 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), excludes hydrogen atoms and substituents, optionally wherein one or more chain atoms of the hydrocarbon chain are independently substituents –C(=O)–, –O–, –NR. b -, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting group. In some embodiments, L2 is an optionally substituted C. 1-30 Hydrocarbon chains, wherein one or more chain atoms of the hydrocarbon chain are independently separated by -O- or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 1-30 Hydrocarbon chains, wherein one or more chain atoms of the hydrocarbon chain are independently separated by -O- or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 1-30 A hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently substituted with –O–. In some embodiments, L2 is unsubstituted C. 1-26 A hydrocarbon chain in which one or more chain atoms are independently separated by –C(=O)–, -O-, or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 1-20A hydrocarbon chain in which one or more chain atoms are independently substituted with -O-. In some embodiments, L2 is unsubstituted C. 5-26 A hydrocarbon chain in which one or more chain atoms are independently separated by –C(=O)–, -O-, or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 5-26 A hydrocarbon chain in which one or more chain atoms are independently substituted with -O-. In some embodiments, L2 is unsubstituted C. 5-20 A hydrocarbon chain in which one or more chain atoms are independently separated by –C(=O)–, -O-, or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 5-20 Hydrocarbon chains, wherein one or more chain atoms of the hydrocarbon chain are independently separated by -O- or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 5-15 A hydrocarbon chain in which one or more chain atoms are independently separated by –C(=O)–, -O-, or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 15-20 A hydrocarbon chain in which one or more chain atoms are independently separated by –C(=O)–, -O-, or –NR. b – Substitution. In some implementations, L2 is unsubstituted C. 20-25 A hydrocarbon chain in which one or more chain atoms are independently separated by –C(=O)–, -O-, or –NR. b – Substitution. In some implementations, L2 is substituted or unsubstituted C. 1-45 Hydrocarbon chain. In some embodiments, L2 is a substituted or unsubstituted C2. 5-40 Hydrocarbon chain. In some embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently modified by –C(=O)–, –O–, –S–, –NR. b –, –N=, or =N–. In some embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced by –C(=O)–, –O–, or –NR. b – Replace, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups. In some embodiments, L2 is an unsubstituted C 1-26 A hydrocarbon chain in which at least one chain atom is independently substituted with –O–.

[0278] In some implementations, L2 is all-carbon, substituted, or unsubstituted C. 1-45 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), does not include hydrogen atoms or substituents. In some embodiments, L2 is an all-carbon, substituted, or unsubstituted C.1-30 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), does not include hydrogen atoms or substituents. In some embodiments, L2 is an all-carbon, substituted, or unsubstituted C. 1-26 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), does not include hydrogen atoms or substituents. In some embodiments, L2 is an all-carbon, substituted, or unsubstituted C. 1-24 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), does not include hydrogen atoms or substituents. In some embodiments, L2 is an all-carbon, substituted, or unsubstituted C. 1-20 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), does not include hydrogen atoms or substituents. In some embodiments, L2 is an all-carbon, substituted, or unsubstituted C. 1-20 The hydrocarbon chain, as the shortest path between D and the piperidine moiety of formula (I), does not include hydrogen atoms and substituents.

[0279] In some implementations, L2 is the key.

[0280] In some implementations, L2 includes a portion Where g is 1, 2, 3, 4, 5, or 6. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5. In some embodiments, g is 6.

[0281] In some implementations, L2 includes a portion of –NHC(=O)-.

[0282] In some implementations, L2 includes a portion of –NH-.

[0283] In some implementations, L2 is the following formula:

[0284] Among them l R Indicates the connection point with D, and l A Representation and expression Partial connection points; n1 is 1, 2, 3, 4, 5, or 6; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In some implementations, L2 is the following formula: Among them l RIndicates the connection point with D, and l A Representation and expression Partial connection points; n1 is 1, 2, 3, 4, 5, or 6; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In some implementations, L2 is the following formula: Among them l R Indicates the connection point with D, and l A Representation and expression The connection points are: n1 is 1, 2, 3, 4, 5, or 6; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is 1, 2, 3, 4, 5, or 6; and g is 1, 2, 3, 4, 5, or 6. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 9. In some embodiments, n2 is 10. In some embodiments, n3 is 1. In some embodiments, n3 is 2. In some embodiments, n3 is 3. In some embodiments, n3 is 4. In some embodiments, n3 is 5. In some embodiments, n3 is 6. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4. In some embodiments, g is 5. In some embodiments, g is 6.

[0285] In some implementations, L2 is the following formula:

[0286]

[0287] In some implementations, L2 is the following formula:

[0288]

[0289] In some implementations, L2 is the following formula:

[0290]

[0291] In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: In some implementations, L2 is the following formula: Where: n1 is 0 or 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; n3 is 0, 1, or 2; and g is 2 or 3. In some implementations, L2 is the following formula: Wherein: n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n3 is 1. In some embodiments, n3 is 2. In some embodiments, n3 is 3. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, g is 3. In some embodiments, g is 4.

[0292] In some implementations, L2 is the following formula:

[0293] In some implementations, L2 is the following formula:

[0294] Substituent R 1 R 2and R 3

[0295] Formula (I) includes a substituent R on the pyrimidine ring. 1 Zero or more instances. In some embodiments, formula (I) includes a substituent R on the pyrimidine ring. 1 An example. In some implementations, x is 0. In some implementations, x is 1. In some implementations, x is 2. In some implementations, x is 3. In some implementations, x is 4. In some implementations, x is 5. In some implementations, x is 6. In some implementations, R 1 At least one instance is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R 1 At least one instance is Cl. In some implementations, R 1 At least one instance is -Br. In some implementations, R 1 At least one instance of -F. In some implementations, R 1 At least one instance of is -I. In some implementations, R 1 At least one instance is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R 1 At least one instance is an optionally substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl). In some embodiments, R 1 At least one instance of C is the optional substitution. 1-6 alkyl.

[0296] In some implementations, R 1 At least one instance is a substituted or unsubstituted methyl group. In some embodiments, R 1 At least one instance is a substituted methyl group. In some embodiments, R 1 At least one instance is –CF3. In some implementations, R 1 At least one instance is an unsubstituted methyl group. In some embodiments, R 1 At least one instance is a substituted or unsubstituted ethyl. In some embodiments, R 1 At least one instance is substituted or unsubstituted propyl. In some embodiments, R 1 At least one instance is an optionally substituted alkenyl group (e.g., substituted or unsubstituted C). 2-6 Alkenyl). In some embodiments, R 1 At least one instance is an optionally substituted alkynyl group (e.g., substituted or unsubstituted C). 2-6 (Alkyne group). In some embodiments, R 1At least one example is an optionally substituted carbocyclic group (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group containing zero, one, or two double bonds in the carbocyclic system). In some embodiments, R 1 At least one example is an optionally substituted heterocyclic group (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or both atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, R 1 At least one instance is an optionally substituted aryl group (e.g., a substituted or unsubstituted 6- to 10-membered aryl group). In some embodiments, R 1 At least one instance is benzyl. In some embodiments, R 1 At least one instance is a substituted or unsubstituted phenyl. In some embodiments, R 1 At least one example is an optionally substituted heteroaryl group (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R 1 At least one instance is –CN. In some implementations, R 1 At least one instance of –OR D1 (e.g., –OH and –OMe). In some implementations, R Y At least one instance is –N(R) D1a )2 (e.g., -NMe2). In some implementations, R 1 At least one instance is –SR D1 (e.g., -SMe).

[0297] In some implementations, R 1 At least one instance of -OR D1 -N(R) D1a )2 or -SR D1 And R D1 As defined herein. In some implementations, R D1 It is hydrogen. In some implementations, R D1 It is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R D1 It is an substituted alkyl group (e.g., substituted or unsubstituted C14) 1-6 Alkyl). In some embodiments, R D1 It is a substituted or unsubstituted methyl group. In some embodiments, R D1 It is a substituted or unsubstituted ethyl group. In some embodiments, R D1It may be a substituted or unsubstituted propyl group. In some embodiments, R D1 It is an optionally substituted alkenyl group (e.g., substituted or unsubstituted C). 2-6 Alkenyl). In some embodiments, R D1 It is an optionally substituted alkynyl group (e.g., substituted or unsubstituted C). 2-6 (Alkyne group). In some embodiments, R D1 It is an optionally substituted carbocyclic group (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group containing zero, one, or two double bonds in the carbocyclic system). In some embodiments, R D1 It is an optionally substituted heterocyclic group (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or both atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, R D1 It is an optionally substituted aryl group (e.g., a substituted or unsubstituted 6- to 10-membered aryl group). In some embodiments, R D1 It is benzyl. In some embodiments, R D1 It is an optionally substituted phenyl group. In some embodiments, R D1 It is an optionally substituted heteroaryl group (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R D1 It is the oxygen protecting group when attached to an oxygen atom. In some embodiments, R D1 It is a sulfur protecting group when attached to a sulfur atom.

[0298] In some implementations, R D1a At least one instance is hydrogen. In some implementations, R D1a At least one instance is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R D1a At least one instance is an optionally substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl). In some embodiments, R D1a At least one instance is a substituted or unsubstituted methyl group. In some embodiments, R D1a At least one instance is a substituted or unsubstituted ethyl. In some embodiments, R D1a At least one instance is substituted or unsubstituted propyl. In some embodiments, R D1a At least one instance is an optionally substituted alkenyl group (e.g., substituted or unsubstituted C). 2-6 Alkenyl). In some embodiments, R D1aAt least one instance is an optionally substituted alkynyl group (e.g., substituted or unsubstituted C). 2-6 (Alkyne group). In some embodiments, R D1a At least one example is an optionally substituted carbocyclic group (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group containing zero, one, or two double bonds in the carbocyclic system). In some embodiments, R D1a At least one example is an optionally substituted heterocyclic group (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or both atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, R D1a At least one instance is an optionally substituted aryl group (e.g., a substituted or unsubstituted 6- to 10-membered aryl group). In some embodiments, R D1a At least one instance is benzyl. In some embodiments, R D1a At least one instance is an optionally substituted phenyl. In some embodiments, R D1a At least one example is an optionally substituted heteroaryl group (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R D1a At least one example is a nitrogen-protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In some embodiments, R D1a Two instances of this compound, together with their intermediate atoms, form substituted or unsubstituted heterocyclic rings (e.g., substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic rings, wherein one or two atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl rings (e.g., substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl rings, wherein one, two, three, or four atoms of the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl rings, wherein one, two, three, or four atoms of the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, the pyrimidine ring of formula (I) is of formula: In some embodiments, the pyrimidine ring of formula (I) is of formula: In some embodiments, the pyrimidine ring of formula (I) is of formula:

[0299] Formula (I) includes a substituent R on the piperidine ring. 2Zero or more instances. In some embodiments, formula (I) includes a substituent R on the piperidine ring. 2 Zero instances of y. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, n1 is 5. In some embodiments, y is 6. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 7. In some embodiments, y is 8. In some embodiments, y is 9. In some embodiments, R 2 At least one instance is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R 2 At least one instance is Cl. In some implementations, R 2 At least one instance is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R 2 At least one instance is an optionally substituted alkyl group (e.g., substituted or unsubstituted C14). 1-6 Alkyl). In some embodiments, R 2 At least one instance of C is the optional substitution. 1-6 Alkyl group. In some embodiments, R 2 At least one instance is a substituted or unsubstituted methyl group. In some embodiments, R 2 At least one instance is a substituted methyl group. In some embodiments, R 2 At least one instance is –CF3. In some implementations, R 2 At least one instance is an unsubstituted methyl group. In some embodiments, R 2 At least one instance is a substituted or unsubstituted ethyl. In some embodiments, R 2 At least one instance is substituted or unsubstituted propyl. In some embodiments, R 2 At least one instance is an optionally substituted alkenyl group (e.g., substituted or unsubstituted C). 2-6 Alkenyl). In some embodiments, R 2 At least one instance is an optionally substituted alkynyl group (e.g., substituted or unsubstituted C). 2-6 (Alkyne group). In some embodiments, R 2 At least one example is an optionally substituted carbocyclic group (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group containing zero, one, or two double bonds in the carbocyclic system). In some embodiments, R 2At least one example is an optionally substituted heterocyclic group (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or both atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, R 2 At least one instance is an optionally substituted aryl group (e.g., a substituted or unsubstituted 6- to 10-membered aryl group). In some embodiments, R 2 At least one instance is benzyl. In some embodiments, R 2 At least one instance is a substituted or unsubstituted phenyl. In some embodiments, R 2 At least one example is an optionally substituted heteroaryl group (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R 2 At least one instance is –CN. In some implementations, R 2 At least one instance of –OR D1 (e.g., –OH and –OMe). In some implementations, R 2 At least one instance is –N(R) D1a )2 (e.g., -NMe2). In some implementations, R 2 At least one instance is –SR D1 (e.g., -SMe). In some embodiments, the piperidine ring of formula (I) is of formula: In some embodiments, the piperidine ring of formula (I) is of formula:

[0300] Formula (I) includes the substituent R 3 In some implementations, R 3 It is hydrogen. In some implementations, R 2 It is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R 3 It is an optionally substituted acyl group (e.g., -C(=O)Me). In some embodiments, R 3 It is an substituted alkyl group (e.g., substituted or unsubstituted C14) 1-6 Alkyl). In some embodiments, R 3 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 3 It is a substituted or unsubstituted methyl group. In some embodiments, R 3 It is a substituted or unsubstituted ethyl group. In some embodiments, R 3It is an unsubstituted ethyl group. In some embodiments, R 3 It may be a substituted or unsubstituted propyl group. In some embodiments, R 3 It is an unsubstituted n-propyl group. In some embodiments, R 3 It is an unsubstituted methyl or isopropyl group. In some embodiments, R 3 It is an optionally substituted alkenyl group (e.g., substituted or unsubstituted C). 2-6 Alkenyl). In some embodiments, R 3 It is an optionally substituted alkynyl group (e.g., substituted or unsubstituted C). 2-6 (Alkyne group). In some embodiments, R 3 It is an optionally substituted carbocyclic group (e.g., a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclic group containing zero, one, or two double bonds in the carbocyclic system). In some embodiments, R 3 It is an optionally substituted heterocyclic group (e.g., a substituted or unsubstituted 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or both atoms of the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In some embodiments, R 3 It is an optionally substituted aryl group (e.g., a substituted or unsubstituted 6- to 10-membered aryl group). In some embodiments, R 3 It is benzyl. In some embodiments, R 3 It is a substituted or unsubstituted phenyl group. In some embodiments, R 3 It is an unsubstituted phenyl group. In some embodiments, R 3 It is an optionally substituted heteroaryl group (e.g., a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl group, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In some embodiments, R 3 It is a nitrogen-protecting group (e.g., benzyl (Bn), tert-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide (Ts)).

[0301] In some implementations, L1 is the bond, and ring A is the formula: L2 is unsubstituted C 1-24 Hydrocarbon chains, wherein one or more chain atoms of the hydrocarbon chain are independently modified by –C(=O)–, –O–, –NR. b –, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups, R 1 At least one instance is halogen, R3 It is hydrogen or an optional substituted C 1-6 Alkyl group, y is 0, x is 1, and D is the formula: Where X A R 1A R 3A R 3′ R 4A R 5A L1, m, n, and a1 are as defined herein. In some implementations, L1 is the bond, and ring A is the formula: L2 is the formula: R3 is a halogen, R3 is hydrogen, y is 0, x is 1, and D is the formula:

[0302] In some implementations, L1 is the bond, and ring A is the formula: L2 is the formula: R3 is a halogen, R3 is hydrogen, y is 0, x is 1, and D is the formula:

[0303] In some implementations, L1 is the bond, and ring A is the formula: L2 is unsubstituted C 1-24 Hydrocarbon chains, wherein one or more chain atoms of the hydrocarbon chain are independently modified by –C(=O)–, –O–, –NR. b –, -S- or cyclic partial substitution, where R b It is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl or nitrogen protecting groups, R 1 At least one instance is halogen, R 3 It is hydrogen or an optional substituted C 1-6 Alkyl group, y is 0, x is 1, and D is the formula: Where R 2′ R 4′ R 5′ n1, n2, and n3 are as defined herein. In some implementations, L1 is the bond, and ring A is the formula: L2 is the formula: R3 is a halogen, R3 is hydrogen, y is 0, x is 1, and D is the formula:

[0304] In some implementations, L1 is the bond, and ring A is the formula: L2 is the formula: R3 is a halogen, R3 is hydrogen, y is 0, x is 1, and D is the formula:

[0305] In some embodiments, the compound of formula (I) is of formula:

[0306]

[0307] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0308] In some embodiments, the compound of formula (I) is of formula:

[0309]

[0310] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0311] In some embodiments, the compound of formula (I) is of formula:

[0312]

[0313] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0314] Where D is the following formula: and

[0315] L2 is the formula:

[0316] In some embodiments, the compound of formula (I) is of formula:

[0317]

[0318] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0319] Where D is the following formula: and

[0320] L2 is the formula:

[0321] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0322] In some embodiments, the compound of formula (I) is of formula:

[0323]

[0324] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0325] In some embodiments, the compound of formula (I) is of formula:

[0326]

[0327] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0328] In some embodiments, the compound of formula (I) is of formula:

[0329]

[0330] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0331] Where D is the following formula: and

[0332] L2 is the formula:

[0333] n1 is 0 or 1; n2 is 0, 1, 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; g is 2 or 3.

[0334] In some embodiments, the compound of formula (I) is of formula:

[0335]

[0336] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0337] Where D is the following formula: and

[0338] L2 is the formula:

[0339] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0340] In some embodiments, the compound of formula (I) is of formula:

[0341]

[0342] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0343] In some embodiments, the compound of formula (I) is of formula:

[0344]

[0345] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0346] Where D is the following formula: and

[0347] L2 is the formula:

[0348] n1 is 0 or 1; n2 is 0, 1, 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; g is 2 or 3.

[0349] In some embodiments, the compound of formula (I) is of formula:

[0350]

[0351] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0352] Where D is the following formula: and

[0353] L2 is the formula:

[0354] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0355] In some embodiments, the compound of formula (I) is of formula:

[0356]

[0357] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug. In some embodiments, the compound of formula (I) is of formula:

[0358]

[0359] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0360] In some embodiments, the compound of formula (I) is of formula:

[0361]

[0362]

[0363] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0364] In some embodiments, the compound of formula (I) is of formula:

[0365]

[0366] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0367] In some embodiments, the compound of formula (I) is of formula:

[0368]

[0369]

[0370] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0371] In some embodiments, the compound of formula (I) is of formula:

[0372]

[0373] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0374] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0375] L2 is the formula:

[0376] In some embodiments, the compound of formula (I) is of formula:

[0377]

[0378] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0379] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0380] L2 is the formula:

[0381] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0382] In some embodiments, the compound of formula (I) is of formula:

[0383]

[0384] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0385] In some embodiments, the compound of formula (I) is of formula:

[0386]

[0387]

[0388] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0389] In some embodiments, the compound of formula (I) is of formula:

[0390]

[0391] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0392] Where L2 is the following formula:

[0393] In some embodiments, the compound of formula (I) is of formula:

[0394]

[0395] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0396] In some embodiments, the compound of formula (I) is of formula:

[0397]

[0398] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0399] Where L2 is the following formula:

[0400] In some embodiments, the compound of formula (I) is of formula:

[0401]

[0402] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0403] Where L2 is the following formula:

[0404] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0405] In some embodiments, the compound of formula (I) is of formula:

[0406]

[0407] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0408] In some embodiments, the compound of formula (I) is of formula:

[0409]

[0410] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0411] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0412] And L2 is the following formula:

[0413] In some embodiments, the compound of formula (I) is of formula:

[0414]

[0415] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0416] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0417] And L2 is the following formula:

[0418] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0419] In some embodiments, the compound of formula (I) is of formula:

[0420]

[0421] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0422] Where n1 is 0 or 1; n2 is 0, 1, 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; g is 2 or 3.

[0423] In some embodiments, the compound of formula (I) is of formula:

[0424]

[0425] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0426] In some embodiments, the compound of formula (I) is of formula:

[0427]

[0428] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0429] In some embodiments, the compound of formula (I) is of formula:

[0430]

[0431] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0432] In some embodiments, the compound of formula (I) is of formula:

[0433]

[0434]

[0435]

[0436]

[0437] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0438] In some embodiments, the compound of formula (I) is of formula:

[0439]

[0440]

[0441] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0442] In some embodiments, the compound of formula (I) is of formula:

[0443]

[0444]

[0445] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0446] in

[0447] R 1 It is a halogen or optionally substituted C 1-6 Alkyl; and

[0448] L2 is the formula:

[0449] In some embodiments, the compound of formula (I) is of formula:

[0450]

[0451] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0452] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0453] L2 is the formula:

[0454] In some embodiments, the compound of formula (I) is of formula:

[0455]

[0456] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0457] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0458] L2 is the formula:

[0459] n1 is 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; n3 is 1 or 2; g is 2 or 3.

[0460] In some embodiments, the compound of formula (I) is of formula:

[0461]

[0462] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0463] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0464] L2 is the formula:

[0465] n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0466] In some embodiments, the compound of formula (I) is of formula:

[0467]

[0468]

[0469] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0470] In some embodiments, the compound of formula (I) is of formula:

[0471]

[0472] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0473] In some embodiments, the compound of formula (I) is of formula:

[0474]

[0475]

[0476]

[0477] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0478] In some embodiments, the compound of formula (I) is of formula:

[0479]

[0480]

[0481] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0482] In some embodiments, the compound of formula (I) is of formula:

[0483]

[0484]

[0485] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0486] Where L2 is the following formula:

[0487]

[0488] In some embodiments, the compound of formula (I) is of formula:

[0489]

[0490] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug;

[0491] Where L2 is the following formula:

[0492] In some embodiments, the compound of formula (I) is of formula:

[0493]

[0494] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0495] In some embodiments, the compound of formula (I) is of formula:

[0496]

[0497] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0498] In some embodiments, the compound of formula (I) is of formula:

[0499]

[0500]

[0501] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0502] Where L2 is the following formula:

[0503] In some embodiments, the compound of formula (I) is of formula:

[0504]

[0505] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0506] Where L2 is the following formula:

[0507] In some embodiments, the compound of formula (I) is of formula:

[0508]

[0509]

[0510] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0511] Where L2 is the following formula: n1 is 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; n3 is 1 or 2; and g is 2 or 3.

[0512] In some embodiments, the compound of formula (I) is of formula:

[0513]

[0514] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0515] Where L2 is the following formula: n1 is 1; n2 is 3, 4, 5, 6, 7 or 8; n3 is 1 or 2; and g is 2 or 3.

[0516] In some embodiments, the compound of formula (I) is of formula:

[0517]

[0518]

[0519] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0520] In some embodiments, the compound of formula (I) is of formula:

[0521]

[0522] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0523] In some embodiments, the compound of formula (I) is of formula:

[0524]

[0525]

[0526]

[0527] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0528] Where R 1It is a halogen or optionally substituted C 1-6 alkyl;

[0529] And L2 is the following formula:

[0530] In some embodiments, the compound of formula (I) is of formula:

[0531]

[0532] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0533] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0534] And L2 is the following formula:

[0535] In some embodiments, the compound of formula (I) is of formula:

[0536]

[0537]

[0538]

[0539] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0540] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0541] And L2 is the following formula:

[0542] n1 is 1; n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; n3 is 1 or 2; g is 2 or 3.

[0543] In some embodiments, the compound of formula (I) is of formula:

[0544]

[0545] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0546] Where R 1 It is a halogen or optionally substituted C 1-6 alkyl;

[0547] And L2 is the following formula:

[0548] n1 is 1; n2 is 3, 4, 5, 6, 7, or 8; n3 is 1 or 2; and g is 2 or 3. In some embodiments, the compound of formula (I) is of formula:

[0549]

[0550]

[0551]

[0552]

[0553]

[0554] Or, pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs.

[0555] Each R 1 R 3 n1; N2; n3; and g are as described in this article.

[0556] In some embodiments, the compound of formula (I) is of formula:

[0557]

[0558]

[0559]

[0560]

[0561] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0562] In some embodiments, the compound of formula (I) is of formula:

[0563]

[0564]

[0565]

[0566]

[0567]

[0568] Or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug.

[0569] In some embodiments, the compound of formula (I) is the compound provided in any of the following embodiments. In some embodiments, the compound of formula (I) is the compound provided in Table 1.

[0570] In some embodiments, the compounds described herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

[0571] In some embodiments, the compound of formula (I) selectively binds to CDK12 relative to another protein. In some embodiments, the compound of formula (I) selectively binds to a specific CDK (e.g., CDK9 and / or CDK12) relative to another CDK. In some embodiments, the compound of formula (I) selectively binds to CDK12 relative to another CDK. In some embodiments, the compound of formula (I) selectively binds to CDK12 relative to CDK13. In some embodiments, the compound of formula (I) selectively binds to CDK9 relative to another protein. In some embodiments, the compound of formula (I) selectively binds to CDK9 relative to another CDK. In some embodiments, the compound of formula (I) selectively binds to CDK9 and / or CDK12 relative to other CDKs (e.g., CDK2, CDK4, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18). In some embodiments, the selectivity is between about 2-fold and about 5-fold. In some embodiments, the selectivity is between about 5-fold and about 10-fold. In some embodiments, selectivity is between about 10x and about 20x. In some embodiments, selectivity is between about 20x and about 50x. In some embodiments, selectivity is between about 50x and about 100x. In some embodiments, selectivity is between about 100x and about 200x. In some embodiments, selectivity is between about 200x and about 500x. In some embodiments, selectivity is between about 500x and about 1000x. In some embodiments, selectivity is at least about 1000x.

[0572] In some embodiments, the compound of formula (I) causes selective degradation of CDK12 relative to other proteins in the proteome. In some embodiments, the compound of formula (I) causes selective degradation of CDK12 relative to other kinases. In some embodiments, the compound of formula (I) causes selective degradation of CDK12 relative to other CDKs. In some embodiments, the compound of formula (I) causes selective degradation of CDK12 relative to CDK13. In some embodiments, the compound of formula (I) induces selective degradation of CDK12 relative to other kinases. In some embodiments, the compound of formula (I) induces selective degradation of CDK12 relative to other CDKs. In some embodiments, the compound of formula (I) causes selective degradation of CDK12 relative to CDK13. In some embodiments, the compound of formula (I) induces selective degradation of CDK12 relative to CDK13. In some embodiments, the compound of formula (I) causes selective degradation of CDK9 relative to other proteins in the proteome. In some embodiments, the compound of formula (I) causes selective degradation of CDK9 relative to other kinases. In some embodiments, the compound of formula (I) causes selective degradation of CDK9 relative to other CDKs. In some embodiments, the selectivity is between about 2-fold and about 5-fold. In some embodiments, the selectivity is between about 5-fold and about 10-fold. In some embodiments, the selectivity is between about 10-fold and about 20-fold. In some embodiments, the selectivity is between about 20-fold and about 50-fold. In some embodiments, the selectivity is between about 50-fold and about 100-fold. In some embodiments, the selectivity is between about 100-fold and about 200-fold. In some embodiments, the selectivity is between about 200-fold and about 500-fold. In some embodiments, the selectivity is between about 500-fold and about 1000-fold. In some embodiments, the selectivity is at least about 1000-fold.

[0573] In some embodiments, the compound of formula (I) selectively binds to an E3 ligase relative to another protein. In some embodiments, the selectivity is between about 2-fold and about 5-fold. In some embodiments, the selectivity is between about 5-fold and about 10-fold. In some embodiments, the selectivity is between about 10-fold and about 20-fold. In some embodiments, the selectivity is between about 20-fold and about 50-fold. In some embodiments, the selectivity is between about 50-fold and about 100-fold. In some embodiments, the selectivity is between about 100-fold and about 200-fold. In some embodiments, the selectivity is between about 200-fold and about 500-fold. In some embodiments, the selectivity is between about 500-fold and about 1000-fold. In some embodiments, the selectivity is at least about 1000-fold.

[0574] In some embodiments, the compound of formula (I) is present in the following concentrations: 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 6 Degradation of the target kinase was induced at concentrations of 0 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. Up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100%. In some embodiments, the compound of formula (I) is present in the following concentrations: 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 6 Degradation of target CDK can be induced at concentrations of 0 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less. Up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100%.In some embodiments, the compound of formula (I) is present in the following concentrations: 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less. Degradation of target proteins CDK9 and / or CDK12 can be induced at concentrations of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less.

[0575] In some embodiments, the compound of formula (I) is present in the following concentrations: 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 At concentrations of nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less, the degradation rate of the target kinase can be increased by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100%. In some embodiments, the compound of formula (I) is present in the following concentrations: 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 At concentrations of nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less, the degradation rate of the target CDK can be increased by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100%.In some embodiments, the compound of formula (I) is present in concentrations of 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less. At concentrations of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less, the degradation rate of target proteins CDK9 and / or CDK12 was increased by up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100%.

[0576] Pharmaceutical compositions, kits and administration

[0577] This disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0578] In some embodiments, an effective amount of the compound of formula (I) is provided in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a preventatively effective amount. In some embodiments, the effective amount is an amount that effectively treats a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)). In some embodiments, the effective amount is an amount that effectively prevents a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)). In some embodiments, the effective amount is an amount that effectively treats cancer in a subject in need. In some embodiments, the effective amount is an amount that effectively prevents cancer in a subject in need. In some embodiments, the effective amount is an amount that effectively reduces the risk of developing a disease (e.g., a proliferative disease (e.g., ovarian cancer, breast cancer, or prostate cancer)) in a subject in need.

[0579] In some embodiments, the subject is an animal. The animal can be of any sex and at any developmental stage. 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 companion animal, such as a dog or cat. In some embodiments, the subject is livestock, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., a mouse, rat), a dog, pig, or a non-human primate. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic animal (e.g., a transgenic mouse and a transgenic pig). In some embodiments, the subject is a fish or a reptile.

[0580] In some embodiments, the effective amount is an amount of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the target kinase in the cell for effective induction. In some embodiments, the effective amount is an amount of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the target CDK in the cell for effective induction. In some embodiments, the effective amount is the amount used to effectively induce the degradation of target proteins CDK9 and / or CDK12 in cells by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some embodiments, the effective amount is the amount used to effectively induce the degradation of target proteins CDK9 and / or CDK12 in cells, ranging between the percentages described in this paragraph and another percentage described in this paragraph, including the extreme values.

[0581] This disclosure provides pharmaceutical compositions comprising compounds that interact with an E3 ubiquitin ligase (e.g., cereblon) and a target kinase (e.g., CDK), for the treatment of diseases (e.g., proliferative diseases such as ovarian cancer, breast cancer, or prostate cancer) in subjects of need. This disclosure also provides pharmaceutical compositions comprising compounds that interact with an E3 ubiquitin ligase (e.g., cereblon) and target proteins CDK9 and / or CDK12, for the treatment of diseases (e.g., proliferative diseases such as ovarian cancer, breast cancer, or prostate cancer) in subjects of need. In some embodiments, the composition is used to treat cancer. In some embodiments, the composition is used to treat ovarian cancer. In some embodiments, the composition is used to treat breast cancer. In some embodiments, the composition is used to treat prostate cancer.

[0582] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk as a single unit dose and / or multiple single unit doses. A “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient to be given to a subject and / or a convenient portion of that dose, such as half or one-third of the dose.

[0583] In the pharmaceutical compositions described herein, the relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any other components will vary depending on the sex, age, and / or condition of the subject being treated, and further on the route of administration of the composition. The composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0584] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavorings and flavorings may also be present in the composition.

[0585] 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.

[0586] Exemplary granulating agents and / or dispersants include potato starch, corn starch, cassava starch, sodium starch glycolate, clay, alginate, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (cross-linked polyvinylpyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium dodecyl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0587] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth gum, cartilage, cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, 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., carboxylated polymethylene, polyacrylic acid, acrylic polymers, and carboxylated vinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), and dehydrated sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate). Polyoxyethylene sorbitan Polyoxyethylene sorbitan monooleate Sorbitan monopalmitate Sorbitan monostearate Sorbitan tristearate Glyceryl monooleate, sorbitan monooleate Polyoxyethylene esters (e.g., polyoxyethylene monostearate) Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., ), polyoxyethylene ether (e.g., polyoxyethylene lauryl ether) Poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, ethyl lauryl sulfate, sodium lauryl sulfate F-68, poloxamer P-188, cetrimonium bromide, hexadecylpyridine chloride, benzalkonium chloride, sodium docusate and / or mixtures thereof.

[0588] Exemplary adhesives include starch (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., gum arabic, sodium alginate, Irish moss extract, Panwar gum, Ghatti gum, Isapol shell mucilage, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate). (and larch arabinogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silica, polymethyl methacrylate, wax, water, alcohol and / or mixtures thereof.

[0589] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0590] Exemplary antioxidants include alpha-tocopherol, ascorbic acid, ascorbate palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0591] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium EDTA, disodium EDTA, trisodium EDTA, calcium disodium EDTA, dipotassium EDTA, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid 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, benzyl chloride, benzyl alcohol, bromonitrol, cetyltrimethylammonium bromide, cetylpyridine chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, hexanediol, imine, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0592] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0593] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol.

[0594] 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.

[0595] Other preservatives include tocopherol, tocopheryl acetate, dexamethasone methanesulfonate, hexadecyltrimethylammonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium bisulfite, and sodium metabisulfite. Plus Methylparaben, 115. II. and

[0596] Exemplary buffers include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium acetopropionate, valeric acid, calcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydrogen phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginate, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and mixtures thereof.

[0597] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl benzoate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0598] Exemplary natural oils include almond, apricot kernel oil, avocado, babassu, bergamot, blackcurrant seed, borage, juniper, chamomile, rapeseed, coriander, carnation, castor bean, cinnamon, cocoa butter, coconut, cod liver oil, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba oil, kukui nuts, bright lavender, and lavender. Grass, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowsweet seed, mink, nutmeg, olive, orange, orange trout, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone resin, soybean, sunflower, tea tree, thistle, ailanthus, vetiver, walnut, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic / capric triglyceride, caprylic / capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecyl alcohol, oleyl alcohol, silicone oil, and mixtures thereof.

[0599] 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 ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g., cottonseed, peanut, corn, germ, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers. In some embodiments for parenteral administration, the conjugates described herein are combined with solubilizers such as… Alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0600] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable carriers and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0601] Injectable formulations can be sterilized, for example by filtration through a bacterial trapping filter or by incorporating a sterile solid composition in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0602] To prolong the effect of a drug, it is often desirable to slow its absorption from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of a drug depends on its dissolution rate, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil carrier.

[0603] Compositions for rectal or vaginal application are typically suppositories, which can be prepared by mixing the conjugate described herein with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or suppository wax), which is solid at ambient temperature but liquid at body temperature, and thus melts and releases the active ingredient in the rectal or vaginal cavity.

[0604] Oral solid dosage forms 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) filler or extender (such as starch, lactose, sucrose, glucose, mannitol, and silica), (b) binder (such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), (c) humectant (such as glycerin), (d) disintegrant (such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate), (e) solution blocker (such as paraffin), (f) absorption enhancer (such as quaternary ammonium compounds), (g) wetting agent (such as cetyl alcohol and glyceryl monostearate), (h) absorbent (such as kaolin and bentonite), and (i) lubricant (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate), and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include buffers.

[0605] Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (such as enteric coatings and other coatings well known in the field of pharmacology). They may optionally contain light-blocking agents and can be compositions that release the active ingredient only or preferably in a specific part of the intestine, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Similar solid compositions can be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0606] The active ingredient can be in the form of microcapsules containing one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation). In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Such dosage forms can, in accordance with conventional practices, contain 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 pellets, the dosage form can contain buffers. They may optionally contain light-blocking agents and can be compositions that release the active ingredient only or preferably in a specific part of the intestine, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymers and waxes.

[0607] Topical and / or transdermal dosage forms of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, and / or patches. Typically, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any desired preservative and / or buffering agent as needed. Furthermore, this disclosure contemplates the use of transdermal patches, which generally offer the additional advantage of 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. Optionally or additionally, the rate can be controlled by providing a rate-controlled membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0608] Suitable devices for delivering intradermal drug compositions as described herein include short-needle devices. Intradermal compositions can be administered via devices that limit the effective penetration length of the needle into the skin. Optionally or additionally, conventional syringes can be used for the classic Mantoux method of intradermal administration. Jet injection devices that deliver liquid formulations to the dermis via liquid jet syringes and / or via needles that pierce the stratum corneum and generate a jet reaching the dermis are suitable. Ballistic powder / particle delivery devices that use compressed gas to accelerate compounds in powder form through the outer layer of skin to the dermis are suitable.

[0609] Formulations suitable for topical application include, but are not limited to, liquid and / or semi-liquid formulations, 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. Topical formulations may, for example, contain from about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be up to the solubility limit of the active ingredient in the solvent. Formulations for topical application may further contain one or more of the additional ingredients described herein.

[0610] The pharmaceutical compositions described herein can be prepared, packaged, and / or marketed as formulations suitable for oral or pulmonary administration. Such formulations may comprise dry particles containing the active ingredient and having a diameter in the range of about 0.5 to about 7 nm, or in the range of about 1 to about 6 nm. These compositions are conveniently administered in dry powder form using a device including a dry powder reservoir and / or using a self-propelled solvent / powder dispensing container (e.g., a device containing the active ingredient dissolved and / or suspended in a low-boiling-point propellant in a sealed container), the propellant stream being directed to the dry powder reservoir to disperse the powder. Such powder comprises particles wherein at least 98% by weight of the particle diameter is greater than 0.5 nm and at least 95% by weight of the particle diameter is less than 7 nm. Alternatively, at least 95% by weight of the particle diameter is greater than 1 nm and at least 90% by weight of the particle diameter is less than 6 nm. The dry powder composition may include a solid fine powder diluent, such as sugar, and is conveniently provided in unit doses.

[0611] Low-boiling-point propellants typically include liquid propellants with a boiling point below 65°F at atmospheric pressure. Typically, the propellant comprises 50 to 99.9% (w / w) of the composition, and the active ingredient comprises 0.1 to 20% (w / w) of the composition. The propellant may further contain additional components, such as liquid nonionic and / or solid anionic surfactants and / or solid diluents (which may have a particle size on the same order of magnitude as the particles containing the active ingredient).

[0612] The pharmaceutical compositions described herein for pulmonary administration can deliver the active ingredient in the form of droplets of solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or diluted alcoholic solutions and / or suspensions, optionally sterile, containing the active ingredient, and conveniently administered using any nebulizer and / or nebulizing device. Such formulations may further contain one or more additional ingredients, including but not limited to flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives such as methylparaben. The average diameter of the droplets delivered via this route of administration can range from about 0.1 to about 200 nm.

[0613] The formulations described herein for pulmonary administration can also be used for intranasal administration of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient, with an average particle size of about 0.2 to 500 micrometers. This formulation is administered by rapid inhalation through the nasal cavity from a powder container near the nostrils.

[0614] Formulations for nasal administration may, for example, contain from about 0.1% (w / w) to 100% (w / w) of the active ingredient, and may contain one or more of the additional ingredients described herein. The pharmaceutical compositions described herein may be prepared, packaged, and / or sold as formulations for oral administration. Such formulations may be in the form of tablets and / or lozenges, for example, prepared using conventional methods, and may contain, for example, 0.1% to 20% (w / w) of the active ingredient, the balance comprising orally soluble and / or biodegradable compositions, and optionally one or more of the additional ingredients described herein. Alternatively, formulations for oral administration may contain powders and / or atomized and / or atomized solutions and / or suspensions containing the active ingredient. Such powdered, atomized, and / or atomized formulations, when dispersed, may have an average particle and / or droplet size in the range of about 0.1 to about 200 nM, and may further contain one or more of the additional ingredients described herein.

[0615] Although the description of pharmaceutical compositions provided herein is primarily directed toward pharmaceutical compositions suitable for human administration, those skilled in the art will understand that such compositions are generally suitable for administration to a wide variety of animals. Modifications to pharmaceutical compositions suitable for human administration are well known to make them suitable for administration to a wide variety of animals, and such modifications can be made by ordinary veterinary pharmacologists through common experimental design and / or practice.

[0616] For ease of administration and uniform dosage, the compounds described herein are typically formulated in dosage units. However, it should be understood that the total daily dosage of the compositions described herein will be determined by a physician within reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the disease being treated and its severity; the activity of the specific active ingredient used; the specific ingredient used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well-known in the medical field.

[0617] The compounds and compositions described herein can be administered via any route, including enterally (e.g., orally), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intraventricularly, transdermally, intradermally, rectally, intravaginally, intraperitoneally, topically (by powder, ointment, cream, and / or drops), mucosally, nasally, buccally, sublingually; by endotracheal instillation, bronchial instillation, and / or inhalation; and / or as oral sprays, nasal sprays, and / or aerosols. Particularly considered routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topically administered via blood and / or lymphatic supply, and / or direct administration to the affected site. Generally, the most suitable route of administration depends on a number of factors, including the nature of the drug (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 topically administering to the subject's eyes.

[0618] The exact amount of compound required to achieve an effective dose varies from subject to subject, depending on factors such as subject type, age and general condition, severity of side effects or illness, characteristics of the specific compound, method of administration, etc. An effective dose 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 to a biological sample, tissue, or cell, any two doses of the multiple doses comprise different or substantially the same amounts of the compound described herein. In some embodiments, when multiple doses are administered to a subject or to a biological sample, tissue, or cell, the frequency of administration of multiple doses to the subject or to the biological sample, tissue, or cell may be three doses daily, two doses daily, one dose daily, one dose every two days, one dose every three days, one dose weekly, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In some embodiments, the frequency of administration of multiple doses to a subject or to a biological sample, tissue, or cell is one dose daily. In some embodiments, the frequency of administration of multiple doses to a subject or to a biological sample, tissue, or cell is two doses daily. In some implementations, multiple doses are administered to the subject or to the biological sample, tissue, or cells at a frequency of three doses per day. In some implementations, when multiple doses are administered to the subject or to the biological sample, tissue, or cells, the duration between the first and last dose of the multiple dose is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, biological sample, tissue, or cells. In some implementations, the duration between the first and last dose of the multiple dose is three months, six months, or one year. In some implementations, the duration between the first and last dose of the multiple dose is the lifetime of the subject, biological sample, tissue, or cells. In some embodiments, a dose (e.g., any dose, whether single or multiple) independently comprises 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1000 mg, or 1 g to 10 g (including endpoint values) of the compound described herein. In some embodiments, a dose described herein independently comprises 1 mg to 3 mg (including 1 mg and 3 mg) of the compound described herein. In some embodiments, a dose described herein independently comprises 3 mg to 10 mg (including 3 mg and 10 mg) of the compound described herein. In some embodiments, a dose described herein independently comprises 10 mg to 30 mg (including 10 mg and 30 mg) of the compound described herein.In some embodiments, the dosage described herein independently includes 30 mg to 100 mg (inclusive) of the compound described herein.

[0619] The dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. The dosage given to, for example, children or adolescents, can be determined by a physician or person skilled in the art and may be less than or equal to the dosage given to adults.

[0620] The compounds or compositions described herein may be administered in combination with one or more other pharmaceutical agents (e.g., therapeutic and / or preventative active agents). The compounds or compositions may be administered in combination with other pharmaceutical agents that enhance their activity (e.g., for treating a disease in a subject with this need, for preventing a disease in a subject with this need, for inducing the degradation of a target protein, and / or for reducing the risk of disease in a subject with this need (e.g., potency and / or efficacy)), improve bioavailability, enhance their ability to cross the blood-brain barrier, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in subjects, biological samples, tissues, or cells. It should also be understood that the treatment employed may achieve the desired effect on the same condition, and / or may achieve different effects. In some embodiments, pharmaceutical compositions comprising the compounds described herein and other pharmaceutical agents exhibit a synergistic effect that is not present in pharmaceutical compositions comprising the compounds and one but not both of the other pharmaceutical agents.

[0621] Compounds or compositions may be administered simultaneously, before, or after one or more additional agents, and may be used as, for example, combination therapy. Agents include therapeutically active agents. Agents also include prophylactic active agents. Agents include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use under Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, 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 agents are agents for treating and / or preventing diseases (e.g., proliferative diseases (e.g., ovarian cancer, breast cancer, or prostate cancer)). Each additional agent may be administered according to a dosage and / or schedule determined for that agent. Additional agents may also be administered together with each other and / or with the compounds or compositions described herein in a single dose or separately in different doses. The specific combinations used in the formulation will take into account the compatibility of the compounds described herein with other agents and / or the desired therapeutic and / or preventative effects. Generally, it is expected that the levels of other agents used in combination will not exceed the levels at which they are used alone. In some embodiments, the levels used in combination will be lower than the levels at which they are used alone.

[0622] Other agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modulators, 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, contraceptives, analgesics, and combinations thereof. In some embodiments, the additional agent is an antiproliferative agent (e.g., an anticancer agent). In some embodiments, the additional agent is abiraterone acetate (e.g., ZYTIGA), ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine (e.g., KADCYLA), bismaleitol afatinib (e.g., GILOTRIF), interleukin-1 (e.g., PROLEUKIN), alemtuzumab (e.g., CAMPATH), anastrozole (e.g., ARIMIDEX), arsenic trioxide (e.g., TRISENOX), and erwiniachrysanthemi asparaginase (e.g., ERWINAZE). Axitinib (e.g., INLYTA), azacitidine (e.g., MYLOSAR, VIDAZA), BEACOPP, belistat (e.g., BELEODAQ), bendamustine hydrochloride (e.g., TREANDA), BEP, bevacizumab (e.g., AVASTIN), bicalutamide (e.g., CASODEX), bleomycin (e.g., BLENOXANE), bortezomib (e.g., BLINCYTO), bortezomib (e.g., VELCADE), ixazomib (e.g., NINLARO), bosutinib (e.g., BOSULIF), brentuximab Vedotin (e.g., ADCETRIS), busulfan (e.g., BUSULFEX, MYLERAN), cabazitaxel (e.g., JEVTANA), cabozantinib malate (e.g., COMETRIQ), CAF, capecitabine (e.g., XELODA), CAPOX, carboplatin (e.g., PARAPLAT, PARAPLATIN), carboplatin-paclitaxel, carfilzomib (e.g., KYPROLIS), carmustine (e.g., BECENUM, BICNU) Carmustine implants (e.g., Gliadelwafer, 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), Dacaltamycin (e.g., COSMEGEN), Dasatinib (e.g., SPRYCEL), Daunorubicin Hydrochloride (e.g., CERUBIDINE), Decitabine (e.g., DACOGEN), Degarelix, Diftitox (e.g., ONTAK), Denosumab (e.g., PROLIA, XGEVA), Denutoximab (e.g., UNITUXIN), Docetaxel (e.g., TAXOTERE), Doxorubicin Hydrochloride (e.g., ADRIAMYCIN PFS, ADRIAMYCIN) RDF), doxorubicin hydrochloride liposomes (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, FUFLEX), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-Cetuximab, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant (e.g., FASLODEX), gefitinib (e.g., IRESSA), gemcitabine hydrochloride (e.g., GEMZAR), gemcitabine-cisplatin, gemcitabine-oxazone Lipoplatin, goserelin acetate (e.g., ZOLADEX), Hyper-CVAD, tiimomab (e.g., ZEVALIN), ibrutinib (e.g., IMBRUVICA), ICE, ederalix (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), ixaprilone (e.g., IXEMPRA), lanreotide acetate (e.g., ...SOMATULINE DEPOT, lapatinib disulfonate (e.g., TYROPE), lenalidomide (e.g., REVLIMID), lenvatinib (e.g., LENVIMA), letrozole (e.g., FEMARA), leucovorin (e.g., WELLCOVORIN), leuprolide acetate (e.g., LUPRON DEPOT, LUPRON DEPOT-3MONTH, LUPRON DEPOT-4MONTH, LUPRON DEPOT-PED, LUPRON, VIADUR), cytarabine liposomes (e.g., DEPOCYT), lomustine (e.g., CEENU), meloratadine hydrochloride (e.g., MUSTARGEN), medroxyprogesterone acetate (e.g., MEGACE), mercaptopurines (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, nerabine (e.g., ARRANON), nilotinib (e.g., TASIGNA), nivolumab (e.g., OPDIVO), oxetuzumab (e.g., GAZYVA), OEPA, oframumab (e.g., ARZERRA), OFF, olaparib (e.g., LYNPARZA), homoharringtonine (e.g., SYNRIBO), OPPA, oxaliplatin (e.g., ELOXATIN), paclitaxel (e.g., TAXOL), paclitaxel albumin-stabilized nanoparticle formulations (e.g., ABRAXANE), PAD, palbociclib (e.g., IBRANCE), pamidronate disodium (e.g., AREDIA), panitumumab (e.g., VECTIBI) X), Pabistat (e.g., FARYDAK), Pazopanib hydrochloride (e.g., VOTRIENT), Pegaspargase (e.g., ONCASPAR), Pegylated interferon alpha-2b (e.g., PEG-INTRON), Pegylated interferon alpha-2b (e.g., SYLATRON), Pembrolizumab (e.g., KEYTRUDA), Pemetrexed disodium (e.g., ALIMTA), Pertuzumab (e.g., PERJETA), Prednisolone (e.g., MOZOBIL), Pomalidomide (e.g., POMALYST), Bonatinib hydrochloride (e.g., ICLUSIG), Pralatrexate (e.g., FOLOTYN), Prednisone, Procaine hydrochloride (e.g., MATULANE), Radium-223 dichloride (e.g., XOFIGO), Raloxifen hydrochloride (e.g., EVISTA, KEOXIFENE), Ramucirumab (e.g.,Recombinant HPV bivalent vaccine (e.g., CERVARIX), recombinant human papillomavirus (e.g., HPV) nonavalent vaccine (e.g., GARDASIL 9), recombinant human papillomavirus (e.g., human papillomavirus) quadrivalent vaccine (e.g., GARDASIL), recombinant interferon alpha-2b (e.g., INTRONA), regorafenib (e.g., STIVARGA), rituximab (e.g., RITUXAN), romidesin (e.g., ISTODAX), ruxolitinib phosphate (e.g., JAKAFI), stutuximab (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), tesiromoximide (e.g., TORISEL), thalidomide (e.g., SYNOVIR, THALOMID), thiotepa, topotecan hydrochloride (e.g., HYCAMTIN), toremifene (e.g., FARESTON), tosimomumab and iodine I131 tosimomumab (e.g., BEXXAR), TPF, trametesinib (e.g., MEKINIST), trastuzumab (e.g., HERCEPTIN), VAMP, vandetanib (e.g., CAPRELSA), VEIP, vemurafenib (e.g., ZELBORAF), vincristine sulfate (e.g., VELBAN, VELSAR), vincristine sulfate (e.g., VINCASAR) PFS), vincristine sulfate liposomes (e.g., MARQIBO), vinorelbine tartrate (e.g., NAVELBINE), vemodega (e.g., ERIVEDGE), vorinostat (e.g., ZOLINZA), XELLI, XELOX, aflibercept (e.g., ZALTRAP), or zoledronic acid (e.g., ZOMETA). In some embodiments, additional agents are ENMD-2076, PCI-32765, AC220, dovitinib lactate (e.g., TKI258, CHIR-258), BIBW 2992 (e.g., TOVOKTMTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (e.g., (e.g., AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tevozanib (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, tesiromoxim (e.g., CCI-779), everolimus (e.g., RAD-001), ridaforolimus, AP235) 73 (e.g., Ariad), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126 and OSI-027), Olimerson, Gemcitabine, Erythromycin, Leucovorin, Pemetrexed, Cyclophosphamide, Dacarbazine, Procaine, Prednisolone, Dexamethasone, Camptothecin, Phloromycin, Asparaginase, Aminopterin, Methoxypterin, Bofirmycin, Melphalan, Leucidine, Leucidine, Chloramic acid mustard, Trabettetidine, Procarbazine, Diclofenac, Erythromycin, Aminopterin and Hexamethylmelamine or combinations thereof. In some embodiments, the additional agent is a cytotoxic chemotherapeutic agent (e.g., gemcitabine, cytarabine, daunorubicin, doxorubicin, vincristine, L-asparaginase, cyclophosphamide, or etoposide). In some embodiments, the additional agent is an epigenetic modifier, such as azacytidine or cytidine bromide. In some embodiments, the additional agent is ruxotinib, BBT594, CHZ868, CYT387, or BMS911543. In some embodiments, the additional agent is a tyrosine kinase inhibitor. In some embodiments, the additional 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, additional agents are etoposide, obaclavin, navicola, JQ1, 4-(((5'-chloro-2'-(((1R,4R)-4-(((R)-1-methoxypropyl-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridine]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carboxynitrile, JIB04, or cisplatin. In some embodiments, additional agents are kinase binders or inhibitors (e.g., CDKs). In some embodiments, additional agents are antibodies or fragments thereof (e.g., monoclonal antibodies). In some embodiments, additional agents are tyrosine kinase inhibitors.In some embodiments, the additional agent is selected from epigenetic or transcriptional regulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (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), protein stability modulators (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other differentiation-promoting drugs. In some embodiments, the additional agent is a glucocorticoid (e.g., cortisol, cortisone, prednisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydrocortisone acetate, or deoxycorticosterone acetate). In some embodiments, the adjunctive treatment is immunotherapy (e.g., immunotherapeutic monoclonal antibodies). In some embodiments, the additional agent is an immunomodulator. In some embodiments, the additional agent is an immune checkpoint inhibitor. In some embodiments, the additional agent is a programmed cell death 1 protein (PD-1) inhibitor. In some embodiments, the additional agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In some embodiments, the additional agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In some implementations, additional agents are T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitors, lymphocyte activation gene-3 (LAG3) inhibitors, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitors, differentiation cluster 276 (CD276 or B7-H3) inhibitors, B and T lymphocyte attenuator (BTLA) inhibitors, galactoglobulin-9 (GAL9) inhibitors, checkpoint kinase 1 (Chk1) inhibitors, adenosine A2A receptor (A2AR) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, cytotoxic cell immunoglobulin-like receptor (KIR) inhibitors, or T-cell activation V-domain Ig inhibitors (VISTA) inhibitors. In some embodiments, the PD-1 inhibitor is nivolumab, pidilimumab, pebrololimumab, MEDI-0680, REGN2810, or AMP-224. In some embodiments, the PD-L1 inhibitor is atezolizumab, duvalimumab, BMS-936559, avermab, or CA-170. In some embodiments, the CTLA-4 inhibitor is ipilimumab or trimemumab. In some embodiments, an additional agent is an aromatase inhibitor. In some embodiments, the compounds or pharmaceutical compositions described herein may be administered in combination with anticancer therapies, including but not limited to surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.In some embodiments, the compounds or pharmaceutical compositions described herein may be administered in combination with chemotherapy. In some embodiments, the compounds or pharmaceutical compositions described herein may be administered in combination with immunotherapy. In some embodiments, the compounds or pharmaceutical compositions described herein may be administered in combination with chemotherapy or immunotherapy.

[0623] This disclosure also includes kits (e.g., pharmaceutical kits). The provided kits may contain the pharmaceutical compositions or compounds described herein and containers (e.g., vials, ampoules, bottles, syringes and / or dispenser packages, or other suitable containers). In some embodiments, the provided kits may optionally further include a second container containing pharmaceutical excipients for diluting or suspending the pharmaceutical compositions or compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein provided in the first and second containers are combined to form a unit dosage form.

[0624] Therefore, in one aspect, a kit is provided comprising a first container containing the compounds or pharmaceutical compositions described herein. In some embodiments, the kit can be used to treat diseases (e.g., proliferative diseases (e.g., ovarian cancer, breast cancer, or prostate cancer)). In some embodiments, the kit can be used to prevent diseases (e.g., proliferative diseases (e.g., ovarian cancer, breast cancer, or prostate cancer)).

[0625] In some embodiments, the kits described herein also include instructions for using the compounds or pharmaceutical compositions contained in the kit. The kits described herein may also include information required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions provide for treating a disease (e.g., a proliferative disease, such as ovarian cancer, breast cancer, or prostate cancer) in a subject of need. In some embodiments, the kit and instructions provide for preventing a disease (e.g., a proliferative disease, such as ovarian cancer, breast cancer, or prostate cancer) in a subject of need. In some embodiments, the kit and instructions provide a method for inducing the degradation of a target (e.g., a kinase, such as a CDK, such as CDK9, CDK12)) in a subject, biological sample, tissue, or cell. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

[0626] Treatment methods and uses

[0627] The compounds described herein are capable of binding (e.g., reversibly or irreversibly) to E3 ubiquitin ligases (e.g., Cereblon) and target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12))) and inducing the degradation of the target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12))). Therefore, this disclosure also provides methods for inducing the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12)) in subjects, biological samples, tissues, or cells. The compounds described herein are capable of binding (e.g., reversibly or irreversibly) to E3 ubiquitin ligases (e.g., Cereblon) and target proteins (e.g., CDK9 and / or CDK12) and inducing the degradation of the target proteins CDK9 and / or CDK12. Therefore, this disclosure also provides methods for inducing the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12)) in subjects, biological samples, tissues, or cells. Therefore, this disclosure also provides methods for inducing the degradation of target proteins (e.g., CDK9 and / or CDK12) in subjects, biological samples, tissues, or cells. This disclosure further provides methods for inducing apoptosis in cells, tissues, biological samples, or cells of a subject. This disclosure further provides methods for treating diseases such as proliferative disorders in subjects in need.

[0628] In some embodiments, this application provides a method for binding a ubiquitin receptor E3 ubiquitin ligase (e.g., Cereblon) and promoting the degradation of a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))). In some embodiments, this application provides a method for binding a ubiquitin receptor E3 ubiquitin ligase (e.g., Cereblon) and promoting the degradation of a target protein CDK9 and / or CDK12. On the other hand, this disclosure provides a method for inducing the degradation of a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))) in a subject of need, the method comprising administering an effective amount of the compound or pharmaceutical composition described herein to the subject. On the other hand, this disclosure provides a method for inducing the degradation of a target protein CDK9 and / or CDK12 in a subject of need, the method comprising administering an effective amount of the compound or pharmaceutical composition described herein to the subject. On the other hand, this disclosure provides a method for inducing the degradation of a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))) in a biological sample, tissue, or cell, the method comprising contacting the biological sample, tissue, or cell with an effective amount of the compound or pharmaceutical composition described herein. On the other hand, this disclosure provides a method for inducing the degradation of target proteins CDK9 and / or CDK12 in biological samples, tissues, or cells, the method comprising contacting the biological sample, tissue, or cells with an effective amount of the compound or pharmaceutical composition described herein.

[0629] On the other hand, this disclosure provides a method for inducing apoptosis in a biological sample, tissue, or cell, the method comprising contacting the biological sample, tissue, or cell with an effective amount of the compound or pharmaceutical composition described herein.

[0630] In some embodiments, this application provides a method for binding an E3 ubiquitin ligase (e.g., Cereblon) and a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))) and selectively inducing the degradation of the target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))).

[0631] The use of bifunctional compounds that combine E3 ubiquitin ligases (e.g., Cereblon) and target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12))) provides a strategy for treating diseases associated with (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12))) (e.g., proliferative diseases), as a research tool for studying the role of CDK9 and / or CDK12 in cells, or as a research tool for studying diseases associated with (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12))) (e.g., proliferative diseases).

[0632] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts, cocrystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives or prodrugs or combinations thereof for use in treating diseases, such as proliferative disorders, in subjects in need.

[0633] This disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, prodrug, or composition thereof in the preparation of a medicament for treating a disease (e.g., a proliferative disease) in a subject in need.

[0634] In some embodiments, the method of this disclosure includes administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0635] In some embodiments, the treated subject is an animal. This animal can be of any sex and at any developmental stage. In some embodiments, the subject is a mammal. In some embodiments, the treated subject is a human. 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 companion animal, such as a dog or cat. In some embodiments, the subject is livestock, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., a mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic animal.

[0636] Some of the methods described herein may include the combined administration of one or more additional agents with the compound described herein. The additional agents may be administered simultaneously with the compound of formula (I) or at different times. For example, the compound of formula (I) and any additional agent may be administered in the same or different dosing regimens. All or part of a dose of the compound of formula (I) may be administered before, after, within a dosing regimen of the additional agent, or in combination thereof. The timing of administration of the compound of formula (I) and the additional agent may differ for different additional agents.

[0637] In some embodiments, the additional agent includes an agent for treating a disease (such as a proliferative disease) in a subject in need. In some embodiments, the additional agent may be used to treat a proliferative disease. In some embodiments, the additional agent may be used to treat an inflammatory disease. In some embodiments, the additional agent may be used to treat a proliferative disease.

[0638] On the other hand, the present invention provides a method for inducing the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12)))), the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug or a combination thereof.

[0639] On the other hand, this disclosure provides a method for binding an E3 ubiquitin ligase and promoting the degradation and / or ubiquitination of a target protein (e.g., a kinase (e.g., a CDK (e.g., CDK9 and / or CDK12)))) and / or ubiquitination), the method comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt, cocrystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative or prodrug or a combination thereof.

[0640] All types of biological samples described herein or known in the art are considered to be within the scope of this invention. In some embodiments, the disease treated or prevented using the compounds described herein (e.g., proliferative diseases (e.g., ovarian cancer, breast cancer, or prostate cancer)) is cancer. All types of cancer disclosed herein or known in the art are considered to be within the scope of this invention. In some embodiments, proliferative diseases are cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is recurrent breast cancer. In some embodiments, the cancer is mutant breast cancer. In some embodiments, the cancer is HER2+ breast cancer. In some embodiments, the cancer is HER2- breast cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colon cancer.

[0641] In another aspect, this disclosure provides pharmaceutical compositions described herein for binding E3 ubiquitin ligases and CDK9 and / or CDK12 and promoting the degradation of target proteins (e.g., kinases (e.g., CDKs (e.g., CDK9 and / or CDK12))); inducing apoptosis in subjects, biological samples, tissues or cells; and treating and / or preventing proliferative diseases.

[0642] Example

[0643] To provide a more complete understanding of this disclosure, the following embodiments are illustrated. The synthetic and biological embodiments described in this application are for illustrative purposes of the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way.

[0644] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art. It should be understood that, unless otherwise stated, other process conditions may be used, provided that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by those skilled in the art through conventional optimization procedures.

[0645] Example 1: Synthesis and preparation of compounds of exemplary formula (I)

[0646] The compounds of formula (I) can be prepared using the synthetic schemes and steps described in detail below.

[0647] Synthesis of N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (BSJ-04-023)

[0648]

[0649] (R)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (8)

[0650] To a solution of 3-(2,5-dichloropyrimidin-4-yl)-1-(benzenesulfonyl)-1H-indole (7) (404 mg, 1.0 mmol) in 5 mL of NMP, tert-butyl(R)-3-aminopiperidine-1-carboxylic acid ester (300 mg, 1.5 mmol) and DIPEA (0.52 mL, 3.0 mmol) were added. The reaction mixture was heated to 125 °C and stirred overnight. The mixture was then heated to room temperature and extracted with 100 mL of ethyl acetate (EA) and 50 mL of water. The organic layer was washed with 50 mL of saturated Na₂CO₃ and 50 mL of brine, dried over anhydrous Na₂SO₄, and evaporated to give a yellow residue, which was dissolved directly in 2.5 mL of DCM, followed by the slow addition of 2.5 mL of TFA in an ice bath. The mixture was heated to room temperature and stirred for 0.5 h. The solvent was then evaporated, and the residue was purified by reversed-phase HPLC (5-95% MeOH in H2O) to give 8(TFA salt) as a yellow solid (407 mg, 87% in two steps). LC-MS: m / z 468 [M+1]. 1 H NMR(500MHz,DMSO-d6)δ8.61(s,1H),8.53-8.47(m,1H),8.45-8.19(m,1H),8.09(d ,J=7.8Hz,2H),8.05-7.96(m,1H),7.88-7.69(m,2H),7.66-7.58(m,2H),7.51-7.3 2(m,2H),4.19(br,1H),3.38-3.27(m,1H),3.16(d,J=1.5Hz,1H),3.15-3.07(m,1H ),2.82(q,J=11.0Hz,2H),2.00(br,1H),1.87(br,1H),1.73(br,1H),1.54(br,1H). 13C NMR (126MHz, DMSO) δ159.49,159.39,158.13,136.42,135.18,133.69,130.11,129.61,129.58,128.82,128 .73,128.44,127.06,125.63,124.41,117.07,115.17,115.12,112.92,46.17,44.96,42.85,28.18,20.33.

[0651] (R)-N-(1-(7-aminoheptyl)piperidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (9)

[0652] To a solution of 8 (103 mg, 0.22 mmol) in 2 mL of DMSO, tert-butyl(7-bromoheptyl)carbamate (4) (129 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol) were added. The mixture was heated to 80 °C and stirred for 24 h. The mixture was then cooled to room temperature, extracted, dried, filtered, and concentrated to give a Boc-protected intermediate, which was then dissolved in 2 mL of dioxane, followed by the addition of 1 mL of 1N NaOH solution, and stirred at room temperature for 4 h. The reaction mixture was extracted with DCM, dried over anhydrous Na₂SO₄, and evaporated to give a brown residue (LC-MS: m / z 541 [M+1]). The residue was dissolved in 2 mL of DCM, and then 2 mL of TFA was added in an ice bath. The resulting mixture was then heated to room temperature and stirred for 0.5 h. The solvent was then evaporated, and the residue was purified by reversed-phase HPLC (5-95% MeOH in H2O) to give 9 (TFA salt) as a pale yellow solid (56.3 mg, 58% in three steps). LC-MS: m / z 441 [M+1].

[0653] Synthesis of N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (BSJ-04-023)

[0654] To a solution of 9 (18.6 mg, 0.0422 mmol) in 2 mL of DMF, 6 (14 mg, 0.0422 mmol), HATU (33 mg, 0.0844 mmol), and DIPEA (37 μL, 0.211 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then the solvent was evaporated and purified by reversed-phase HPLC (5-95% MeOH in H2O) to give BSJ-04-023 (TFA salt) (30.7 mg, 83%) as a pale yellow solid. LC-MS: m / z 756 [M+1]. 1 H NMR(500MHz,DMSO-d6)δ11.90(d,J=3.3Hz,1H),11.12(s,1H),9.42(s,1H),8.54-8.41(m,1H),8.38- 8.26(m,1H),7.93(q,J=5.8Hz,1H),7.85-7.73(m,1H),7.50(d,J=7.3Hz,3H),7.43-7.32(m,1H),7.2 7-7.09(m,2H),5.11(dd,J=12.8,5.4Hz,1H),4.76(d,J=3.3Hz,2H),3.19-2.97(m,5H),2.97-2.67(m ,3H),2.65-2.51(m,2H),2.15-1.95(m,4H),1.70-1.51(m,2H),1.49-1.36(m,3H),1.34-1.10(m,8H). 13 C NMR (126MHz, DMSO) δ172.80,169.89,166.73,166.66,165.54,159.39,158.27,157.99,155.04,136.94,136.07,133.04,131.11,131.05,126 .21,122.45,120.75,120.42,116.83,116.10,113.84,111.95,67.68, 56.19,48.81,38.24,30.95,28.90,28.09,26.00,25.93,23.21,22.00.

[0655] Synthesis of N-(6-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-2,BSJ-04-078)

[0656] I-2 was synthesized from 3 (21.1 mg, 0.045 mmol), tert-butyl(4-bromohexyl)carbamate (12.6 mg, 0.045 mmol), and 6 (10 mg, 0.03 mmol) following a similar procedure to that of I-1. I-2 was obtained as a grayish-white solid (14.7 mg, 44% in 4 steps). LC-MS: m / z 741 [M+1]. 1 H NMR(500MHz,DMSO-d6)δ11.90(t,J=3.3Hz,1H),11.12(s,1H),9.43(s,1H),8.48(t,J=2.9Hz,1H), 8.39-8.28(m,1H),8.03-7.90(m,1H),7.85-7.75(m,1H),7.55-7.48(m,3H),7.42-7.37(m,1H),7.2 3(t,J=7.5Hz,1H),7.17(t,J=7.5Hz,1H),5.15-5.07(m,1H),4.76(d,J=3.6Hz,2H),3.20-2.98(m,5 H),2.96-2.70(m,3H),2.64-2.53(m,2H),2.15-1.71(m,4H),1.71-1.37(m,5H),1.35-1.03(m,6H).

[0657] Synthesis of N-(5-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)pentyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-3,BSJ-04-079)

[0658] I-3 was synthesized from 3 (21.1 mg, 0.045 mmol), tert-butyl(5-bromopentyl)carbamate (11.9 mg, 0.045 mmol), and 6 (10 mg, 0.03 mmol) following a similar procedure to that of I-1. I-3 (14.4 mg, 44% in 4 steps) was obtained as a grayish-white solid. LC-MS: m / z 727 [M+1]. 1H NMR (500MHz, DMSO-d6) δ11.89(d,J=3.2Hz,1H),11.12(s,1H),9.44(s,1H),8.48(t,J=3.1Hz,1H),8.31( s,1H),8.02-7.91(m,1H),7.85-7.75(m,1H),7.50(d,J=7.5Hz,3H),7.42-7.36(m,1H),7.26-7.21(m,1H ),7.20-7.12(m,1H),5.11(dd,J=12.8,5.4Hz,1H),4.76(d,J=4.7Hz,2H),3.22-2.99(m,6H),2.95-2.71 (m,4H),2.65-2.53(m,2H),2.15-1.94(m,3H),1.72-1.57(m,2H),1.55-1.37(m,3H),1.34-1.13(m,4H).

[0659] Synthesis of N-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-4,BSJ-04-080)

[0660] I-4 was synthesized from 3 (21.1 mg, 0.045 mmol), tert-butyl(4-bromobutyl)carbamate (11.4 mg, 0.045 mmol), and 6 (10 mg, 0.03 mmol) following a similar procedure to that of I-1. I-4 (15.1 mg, 47% in 4 steps) was obtained as a grayish-white solid. LC-MS: m / z 713 [M+1]. 1H NMR (500MHz, DMSO-d6) δ11.90(d,J=3.2Hz,1H),11.12(s,1H),9.50(s,1H),8.48(t,J=2.7Hz,1H),8.32( d,J=12.8Hz,1H),8.03(t,J=5.8Hz,1H),7.85-7.74(m,1H),7.50(q,J=6.7Hz,3H),7.43-7.35(m,1H),7.2 6-7.21(m,1H),7.20-7.13(m,1H),5.15-5.05(m,1H),4.77(d,J=7.8Hz,2H),3.67-3.27(m,2H),3.23-3.0 7(m,5H),2.96-2.69(m,3H),2.64-2.52(m,2H),2.09-1.93(m,3H),1.92-1.59(m,4H),1.56-1.39(m,3H).

[0661] Synthesis of N-(2-(2-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-5, BSJ-04-026)

[0662] I-5 was synthesized from 3 (21.1 mg, 0.045 mmol), tert-butyl(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethyl)carbamate (16.0 mg, 0.045 mmol), and 6 (10 mg, 0.03 mmol) following a similar procedure to that of I-1. I-5 (16.5 mg, 45% in 4 steps) was obtained as a grayish-white solid. LC-MS: m / z 817 [M+1]. 1H NMR(500MHz,DMSO-d6)δ11.90(d,J=4.2Hz,1H),11.13(s,1H),9.63(s,1H),8.48(d,J=2.9Hz ,1H),8.32(s,1H),7.97(t,J=5.7Hz,1H),7.90-7.76(m,1H),7.68-7.45(m,3H),7.38(dd,J= 8.6,2.2Hz,1H),7.30-7.14(m,2H),5.15-5.07(m,1H),4.77(s,2H),4.46-4.12(br,2H),3.8 4-3.65(m,4H),3.43-3.18(m,10H),3.00-2.71(m,4H),2.66-2.52(m,2H),2.19-1.73(m,6H).

[0663] Synthesis of N-(2-(2-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-6, BSJ-04-098)

[0664] I-6 was synthesized from 3 (21.1 mg, 0.045 mmol), tert-butyl(2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (14.0 mg, 0.045 mmol), and 6 (10 mg, 0.03 mmol) following a similar procedure to that of I-1. I-6 (16.7 mg, 48% in 4 steps) was obtained as a grayish-white solid. LC-MS: m / z 772 [M+1]. 1H NMR (500MHz, DMSO-d6) δ11.89(d,J=3.3Hz,1H),11.12(s,1H),9.63(s,1H),8.48(dd,J=5.2,3.0Hz,1H),8.32(d, J=15.6Hz,1H),8.03-7.90(m,1H),7.85-7.75(m,1H),7.49(dd,J=7.4,2.2Hz,3H),7.38(dd,J=9.4,3.9Hz,1H),7. 27-7.10(m,2H),5.11(dd,J=12.9,5.4Hz,1H),4.76(d,J=4.3Hz,2H),3.81-3.64(m,3H),3.63-3.50(m,4H),3.44 (d,J=5.8Hz,2H),3.41-3.22(m,6H),2.99-2.73(m,3H),2.65-2.53(m,1H),2.13-1.92(m,3H),1.92-1.73(m,2H).

[0665] Synthesis of N-(2-(2-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-7, BSJ-04-099)

[0666] The synthesis method of I-7 is similar to that of I-1. LC-MS: m / z 801 [M+1].

[0667] Synthesis of N-(6-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-6-oxohexyl)-2-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide (I-8,BSJ-04-071)

[0668] The synthesis method of I-8 is similar to that of I-1. LC-MS: m / z 756 [M+1]. 1H NMR(500MHz,DMSO-d6)δ11.85(s,1H),11.11(d,J=2.6Hz,1H),8.49-8.41(m,1H),8.27(d,J=3.7Hz,1H),7.9 8-7.91(m,1H),7.84-7.71(m,1H),7.52-7.43(m,2H),7.41-7.34(m,2H),7.33-7.03(m,3H),5.15-5.06(m,1H ),4.75(d,J=3.6Hz,2H),4.53-3.88(m,4H),3.21-3.10(m,1H),3.08-2.96(m,2H),2.95-2.83(m,2H),2.83- 2.69(m,1H),2.65-2.53(m,2H),2.43-2.21(m,1H),2.14-1.90(m,3H),1.86-1.72(m,1H),1.69-0.90(m,9H).

[0669] N-(5-(4-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carbonyl)phenyl)piperazin-1-yl)pentyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide(I-9,BSJ-04-077)

[0670] The synthesis method of I-9 is similar to that of I-1. LC-MS: m / z 915 [M+1].

[0671] N-(3-(4-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carbonyl)phenyl)piperazin-1-yl)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide(I-10, BSJ-04-076)

[0672] The synthesis method of I-10 is similar to that of I-1. LC-MS: m / z 887 [M+1].

[0673] N-(7-(4-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carbonyl)phenyl)piperazin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide(I-11,BSJ-04-100)

[0674] The synthesis method of I-11 is similar to that of I-1. LC-MS: m / z 943 [M+1].

[0675] N-(7-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carbonyl)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide(I-12,BSJ-04-086)

[0676] The synthesis method of I-12 is similar to that of I-10. LC-MS: m / z 866 [M+1].

[0677] N-(7-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-carbonyl)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)oxy)acetamide(I-13, BSJ-04-089)

[0678] The synthesis method of I-13 is similar to that of I-10. LC-MS: m / z 852 [M+1].

[0679] Synthesis of N-(7-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide (I-14; BSJ-04-116)

[0680]

[0681] (R)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(piperidin-3-yl)pyrimidine-2,4-diamine (3)

[0682] To a solution of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine 1 (345 mg, 1.0 mmol) in 5 mL of NMP, tert-butyl(R)-3-aminopiperidine-1-carboxylic acid ester (300 mg, 1.5 mmol) and DIPEA (0.52 mL, 3.0 mmol) were added. The reaction mixture was heated to 125 °C and stirred overnight. The mixture was then heated to room temperature and extracted with 100 mL of ethyl acetate (EA) and 50 mL of water. The organic layer was washed with 50 mL of saturated Na₂CO₃ and 50 mL of brine, dried over anhydrous Na₂SO₄, and evaporated to give a yellow residue, which was dissolved directly in 2.5 mL of DCM. Then, 2.5 mL of TFA was slowly added under ice bath conditions. The mixture was heated to room temperature and stirred for 0.5 h. The solvent was then evaporated, and the residue was purified by reversed-phase HPLC (5-95% MeOH in H2O) to give 3(TFA salt) as a yellow solid (368 mg, 90% in two steps). LC-MS: m / z 410 (M+1). 1 H NMR(500MHz,DMSO-d6)δ9.54(s,1H),8.81(br,2H),8.29-8.10(m,1H),7.92-7.82 (m,1H),7.78(s,1H),7.37(s,1H),4.03(br,1H),3.50-3.40(m,1H),3.39-3.28(br ,1H),3.23-3.13(m,1H),2.90-2.74(m,3H),1.97(s,1H),1.93-1.82(m,1H),1.72- 1.61(m,1H),1.55(d,J=36.1Hz,1H),1.18(d,J=2.1Hz,3H),1.16(d,J=2.1Hz,3H). 13 C NMR (126MHz, DMSO) δ158.77,158.49,158.20,154.97,154.70,153.93,138.10,135.07,1 31.01,123.37,116.95,114.62,54.92,46.26,45.08,43.03,28.07,20.55,14.87,14.83.

[0683] (R)-N2-(1-(7-aminoheptyl)piperidin-3-yl)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine(5)

[0684] To a solution of 3 (90 mg, 0.22 mmol) in 2 mL of DMSO, add tert-butyl(7-bromoheptyl)carbamate (4) (129 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol). Heat the mixture to 80 °C and stir for 24 hours. Then cool the mixture to room temperature, extract, dry, filter, and concentrate to obtain a light brown residue, which is then dissolved in 1 mL of DCM, followed by the slow addition of 1 mL of TFA in an ice bath. The mixture is then heated to room temperature and evaporated after 0.5 hours. The residue is purified by reversed-phase HPLC (5-95% MeOH in H₂O) to give a light gray solid of 5 (TFA salt) (115 mg, 65% in two steps). LC-MS: m / z 523 [M+1].

[0685] Synthesis of N-(7-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide (I-14; BSJ-04-116)

[0686] To a solution of 5 (22 mg, 0.0422 mmol) in 2 mL of DMF, 6 (14 mg, 0.0422 mmol), HATU (33 mg, 0.0844 mmol), and DIPEA (37 μL, 0.211 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then the solvent was evaporated and purified by reversed-phase HPLC (5-95% MeOH in H2O) to give I-14;BSJ-04-116 (TFA salt) as a grayish-white solid (30.7 mg, 87%). LC-MS: m / z 838 [M+1]. 1H NMR (500MHz, DMSO-d6) δ11.12(s,1H),9.52(s,1H),9.41(s,1H),8.63(br,1H),8.19(d,J=11.9Hz,1H),7.93(t ,J=6.2Hz,1H),7.87-7.71(m,3H),7.50(d,J=7.3Hz,1H),7.43-7.26(m,3H),5.11(dd,J=12.9,5.4Hz,1H),4.7 6(s,2H),3.49-3.31(m,3H),3.20-3.11(m,2H),3.10-2.97(m,2H),2.95-2.77(m,2H),2.75-2.53(m,2H),2.10 -2.00(m,2H),2.00-1.88(m,2H),1.86-1.53(m,3H),1.52-1.36(m,4H),1.33-1.20(m,6H),1.20-1.11(m,6H). 13 C NMR (126MHz, DMSO) δ172.81,169.89,166.73,166.66,165.55,158.31,158.03,155.04,154.95,136.96,135.06,133.04,131.05,120. 43,116.84,116.12,67.69,56.16,54.98,48.82,38.24,30.95,28.89,28.08,26.01,25.91,25.87,23.19,22.00,14.92,14.85,14.81.

[0687] Synthesis of (2S,4R)-1-((S)-14-(tert-butyl)-1-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-15; BSJ-05-063)

[0688]

[0689] ((R)-11-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)undecanoic acid(11)

[0690] To a solution of DMSO (2 mL) containing 90 mg (0.22 mmol), tert-butyl 11-bromoundecanoate (11) (150 mg, 0.44 mmol) and DIPEA (0.115 mL, 0.66 mmol) were added. The mixture was heated to 80 °C and stirred for 24 hours. The mixture was then cooled to room temperature, extracted, dried, filtered, and concentrated to give a light brown residue, which was then dissolved in 1 mL of DCM, followed by the slow addition of 1 mL of TFA under ice bath conditions. The mixture was then heated to room temperature and evaporated after 0.5 hours. The residue was purified by reversed-phase HPLC (5-95% MeOH in H2O) to give a light yellow oily 11 (TFA salt) (94 mg, 70% in two steps). LC-MS: m / z 594 [M+1].

[0691] Synthesis of (2S,4R)-1-((S)-2-(11-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)undecanoamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-15, BSJ-05-063))

[0692] To a solution of 11 (26 mg, 0.0422 mmol) in 2 mL of DMF, 12 (19 mg, 0.0422 mmol), HATU (33 mg, 0.0844 mmol), and DIPEA (37 μL, 0.211 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then the solvent was evaporated and purified by reversed-phase HPLC (5-95% MeOH in H2O) to give BSJ-06-63 (TFA salt) as a grayish-white solid (33 mg, 75%). LC-MS: m / z 1020 [M+1].

[0693] Synthesis of (2S,4R)-1-((S)-14-(tert-butyl)-1-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-oyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-16; BSJ-05-064)

[0694]

[0695] The synthesis of compound I-16 (BSJ-05-064) was similar to that of compound I-16 (BSJ-05-064), synthesized from 3 (47.4 mg, 0.0844 mmol), tert-butyl 3-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)propionate (30 mg, 0.0844 mmol), and 12 (23.3 mg, 0.0844 mmol). Compound I-16 (BSJ-05-064) was obtained as a yellow solid (20.6 mg, 24% in 4 steps). LC-MS: m / z 1041 [M+1].

[0696] Synthesis of (2R,4S)-1-((S)-2-(11-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)undecanoamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (I-17; ZXH-7-091))

[0697] Compound I-17 is a negative control for compound I-15. It was synthesized using a method similar to that used for compound I-15. LC-MS: m / z 1020 [M+1].

[0698] Example 2: CDK12 Bioanalysis

[0699] Cyclin-dependent kinases 12 and 13 (CDK12 / 13) are regulators of transcriptional elongation mediated by RNA polymerase II, functioning as kinases via phosphorylation on the C-terminal repeat domain (CTD) of RNA polymerase II. CDK12 plays a crucial role in mediating genome stability, and its loss impairs the expression of several key regulators of genome stability. CDK12 mutations have been found in a variety of tumors, including those of the ovary, breast, and prostate. Previous CDK12 inhibitors, including, for example, covalently THZ531 (chemical structure shown above) and other inhibitors, have been non-selective and have also been observed to effectively inhibit CDK13.

[0700] The novel bifunctional compounds disclosed here conjugate CDK12 inhibitors to E3 ligase ligands to induce CDK12 protein degradation (see the accompanying drawings and the chemical structures of exemplary CDK inhibitors in Table 1 below). The CDK12 degradation activities of the exemplary compounds are shown in Table 1.

[0701] Degradation tests of CDK12 were conducted using compounds of exemplary formula (I). The test results for CDK12 degradation by the exemplary CDK12 degrading compounds described in Table 1 are shown in... Figure 1-3Table 1 also shows the CDK12 degradation activities of exemplary CDK12 inhibitor compounds 1-13 described in Table 1 below, where at 100 nM, "+++" indicates greater than 90% CDK12 degradation, "++" indicates 80% CDK12 degradation, and "+" indicates 60% CDK12 degradation. "N / A" indicates no activity detected by Western blotting at concentrations up to 500 nM.

[0702] Table 1. Exemplary CDK12 Degrading Compounds

[0703]

[0704]

[0705]

[0706]

[0707] Example 3: Pharmacokinetic Study of Exemplary Compounds

[0708] Standard pharmacokinetic parameters were determined by administering the exemplary compound BSJ-05-063 to male C57BI / 6 mice and performing standard pharmacokinetic studies. A single intravenous (IV) injection of a 2 mg / kg solution of compound BSJ-05-063 in 5 / 5 / 90 DMSO / Cremophor EL / water was administered, and pharmacokinetic parameters were evaluated. Plasma concentrations of BSJ-05-063 reported at each of eight time points (5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, and 8 h post-administration) are averages from three test animals (male C57BI / 6 mice). The pharmacokinetic results of the exemplary compound BSJ-05-063 are shown in Table 2 below.

[0709] Table 2. Mean pharmacokinetic parameters of the exemplary compound BSJ-05-063 (IV administration).

[0710]

[0711] Equivalents and scope

[0712] In the claims, articles such as “a,” “an,” and “the” may indicate one or more members unless indicated to the contrary or clearly apparent from the context. A claim or description including “or” among one or more members of the group is considered satisfied if one, more than one, or all of the group members are present in, used in, or otherwise associated with the given product or process, are present in, used in, or otherwise associated with the given product or process. This disclosure includes embodiments in which exactly one member of the group is present in, used in, or associated with the given product or process. This disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with the given product or process.

[0713] Furthermore, this disclosure includes all variations, combinations, and substitutions, wherein one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, any claim relying on another claim may be modified to include one or more limitations found in any other claim relying on the same basic claim. Elements are presented as lists, for example, in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from a group. It should be understood that, in general, when this disclosure or an aspect described herein is referred to as including specific elements and / or features, certain embodiments or aspects described herein consist of or are substantially composed of these elements and / or features. For simplicity, these embodiments are not specifically set forth herein. It should also be noted that the terms “comprising” and “including” are open-ended and allow for the inclusion of additional elements or steps. Where a range is given, the endpoints are included. Furthermore, unless otherwise stated or apparent from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges may present any specific value or subrange within the range of the different embodiments described herein, up to one-tenth of a unit of the lower limit of the range, unless the context expressly specifies otherwise.

[0714] This application relates to various published patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any cited references ...

Claims

1. The following compounds Or its pharmaceutically acceptable salt or stereoisomer, wherein: R 1 It is halogen; R 2 It does not exist; R 3 It is hydrogen; R X It does not exist; R Y yes w is 0; w1 is 1; x is 1; y is 0; L2 is Among them l A Indicates the connection point with D, and l R Representation and expression Partial connection points; Where D is the following formula:

2. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salts or stereoisomers.

3. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salts or stereoisomers.

4. The compound according to claim 3, wherein R Y yes 5. The compound according to claim 3, wherein R Y yes 6. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein D is of the formula:

7. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein D is of the formula:

8. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salts or stereoisomers.

9. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salts or stereoisomers.

10. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 Yes –Br.

11. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 It is –Cl.

12. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L2 is of the formula: Among them l A Indicates the connection point with D, and l R Representation and expression The connection points of the parts.

13. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L2 is of the formula: Among them l A Indicates the connection point with D, and l R Representation and expression The connection points of the parts.

14. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salts or stereoisomers.

15. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salts or stereoisomers.

16. A pharmaceutical composition comprising the compound of any one of claims 1-15 or a pharmaceutically acceptable salt or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound for treating a disease in a subject in need.

18. The pharmaceutical composition according to claim 17, wherein the disease is a proliferative disease.

19. Use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 16-18 in the preparation of a medicament for treating a proliferative disease in a subject of need.

20. The use according to claim 19, wherein the proliferative disease is cancer.

21. The use according to claim 20, wherein the cancer is ovarian cancer.

22. The use according to claim 20, wherein the cancer is breast cancer.

23. The use according to claim 20, wherein the cancer is prostate cancer.

24. The use according to claim 19, further comprising administering a therapeutically effective amount of another agent to the subject.

25. The use according to claim 24, wherein the additional agent is an antiproliferative agent.

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