Amino pyrimidine degraders and uses thereof

Abstract

Provided herein are CDK2 degrader compounds having a pyridine or pyrimidine targeting moiety and ligase recruitment moiety. Also provided herein are compositions comprising the subject CDK2 degrader compounds. Also provided are methods for using compositions of the disclosure.

Description

AMINO PYRIMIDINE DEGRADERS AND USES THEREOF1. BACKGROUND

[0001] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases.Heterodimerized with regulatory subunits known as cyclins, CDKs become fully activated andregulate key cellular processes including cell cycle progression and cell division. Uncontrolledproliferation is a hallmark of cancer cells. The deregulation of the CDK activity is associated with abnormal regulation of cell-cycle, and is detected in virtually all forms of human cancers.

[0002] CDK2 is a cyclin-dependent kinase that plays a critical role in regulating the transitionfrom the G1 to S phase of the cell cycle. It is involved in several other cellular processes,including DNA replication and repair, transcription, RNA processing, and cytoskeletalorganization, making it an attractive target for cancer therapy. CDK2 is of particular interest because deregulation of CDK2 activity occurs frequently in a variety of human cancers. Although CDK2 is mostly dispensable in the cell cycle of normally functioning cells, it is critical to the abnormal growth processes of cancer cells. The CCNE1 gene produces cyclin E, one of the two major protein binding partners of CDK2. Overexpression of CCNE1 occurs in many tumorcells, causing the cells to become dependent on CDK2 and cyclin E. Abnormal cyclin E activityis also observed in breast, lung, colorectal, gastric, and bone cancers, as well as in leukemia andlymphoma. Likewise, abnormal expression of cyclin A2 is associated with chromosomalinstability and tumor proliferation, while inhibition leads to decreased tumor growth.

[0003] Therefore, CDK2 and its cyclin binding partners represent possible therapeutic targets fornew cancer therapeutics. CDK2 inhibitors are a class of small molecule drugs that block theactivity of CDK2, leading to cell cycle arrest and potentially inducing cell death. However, identifying selective CDK2 inhibitors is difficult due to the extreme similarity between the activesites of CDK2 and other CDKs, for example CDK1. CDK1 is the only essential cyclin dependentkinase in the cell cycle, and its inhibition could lead to unintended side effects.

[0004] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulatoryproteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0005] There are hundreds of known E3 ligases that facilitate the ubiquitination of differentproteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s,monomeric RING E3s, and multi-subunit E3s (see generally Li et al. (PLOS One, 2008, 3,1487), Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307), Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-437), and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347)). Additionally, one of several hundred E3 ubiquitin-ligase enzyme complex components, such as cereblon (CRBN) and von Hippel Lindau (VHL) (Bricelj et al, Front Chem, 2021, 9:707317), facilitate the transfer of ubiquitin to a lysine on the substrate protein. The CRBN and VHL proteins function as critical components in Cullin RING E3 ubiquitin-ligase complexes (Cai and Wang, Cell Div, 2016, 11). Both CRBN and VHL are widely expressed across tissue types and are evolutionarily conserved among vertebrates. CRBN coordinates the ubiquitination and degradation of ion channels, the MEIS2 developmental transcription factor, the AMPK metabolic-regulating kinase, and glutamine synthase. CRBN can also be induced to degrade transcription factors IKZFl and IKZF3 along with casein kinase 1Al by immunomodulatory compounds (Kronke et al. Science, 2014, 343:301-5; Petzold et al., Nature, 2016, 532:127-30).VHL normally ubiquitinates hypoxia-inducible factor lα (HIFl A), the primary transcriptionfactor responsible for promoting angiogenesis (Kaelin, Nat Rev Cancer, 2008, 8:865-73).

[0006] PROTACs are a class of protein-degrading molecules that have the potential to enable themodulation of these difficult to target proteins via TPD. PROTACs are heterobifunctional smallmolecules comprising two ligands (e.g., chemical moieties) joined by a linker. The roles of thetwo ligands are different. One ligand recruits and binds a protein of interest (i.e., target protein) while the other recruits and binds an E3 ubiquitin ligase. This simultaneous binding of theprotein of interest and a ligase by the PROTAC induces ubiquitination of the protein of interestand its subsequent degradation by the ubiquitin–proteasome system (UPS), after which thePROTAC is available to target another copy of the protein of interest. This catalytic-typemechanism of action and event-driven pharmacology differentiate PROTACs from classicalinhibitors, which have a one-to-one relationship with the protein of interest and whosepharmacology is driven by stoichiometry and, usually, by interactions with an active site (seeBekes, et al, Nature Reviews Drug Discovery 2022, 21, 181-200).2. SUMMARY

[0007] Provided herein are CDK degrader compounds having a CDK binding moiety thatincludes a core structure including a 6-membered heteroaryl where the 6-membered ring of thesystem can be a pyridine or pyrimidine. In some embodiments, the compounds have a pyridineor pyrimidine core structure having a 2-amino group that is further substituted. The 2-aminogroup can be linked to a cyclic group having an appended hydrophilic group or substituent orlinked to a ubiquitin E3 ligase-binding ligand. The CDK degrader compounds can be CDK2degraders. Also provided herein are pharmaceutical compositions including the subject CDK(e.g., CDK2) degrader compounds. Also provided are methods for using compounds andcompositions of the disclosure in research and as therapeutics.

[0008] A degrader compound is represented by Formula (X):X) or is a pharmaceuticallyCDK-BM is a cyclin-dependent kinase (CDK) binding moiety; L’ is a divalent moiety (e.g., linker) that connects CDK-BM to UBM; andUBM is an E3 ubiquitin ligase binding moiety.

[0009] In some embodiments, the CDK binding moiety is of Formula (I):or a pharmaceutically acceptable sahereof, wherein:R1is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted(C1-5)alkoxy, haloalkyl, halogen, OH, -CF3, -CF2H, -CFH2, -C2F5, -C2F4H, -C2F3H2, -C2F2H3,-C2FH4, and CN; R3 is selected from a divalent moiety that links to L’ or L”, H, alkyl, carbocycle,heterocycle, aryl, heteroaryl, alkylene-carbocycle, alkylene-heterocycle, alkylene-aryl, alkylene-heteroaryl, substituted versions thereof, and substituted versions thereof that are substituted witha divalent moiety that links to L’ or L”;L10 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-, -S-S-,-S(O)-, -S(O)2-, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, and -NHS(O)2-;Y4is N or CR4; oxy, substituted(C1-5)alkoxy, haloalkyl, halogen, OH, and CN; R5 is or , wherein:clyl, heterocyclyl, aryl, heteroaryl, andsubstituted versions thereof; Z is selected from a bond, sulfonyl, sulfoxide, sulfide, sulfonate ester, sulfonamide, sulfinamide, sulfenamide, sulfoximine, sulfonimidamide, sulfondiimine, sulfondiimidamide, carboxamide, ester, ether, urea, thiourea, and aliphatic group, or Z is adivalent moiety that links to L’ or L”;L1and L2are optional linkers; and * represents the point of attachment of R5to the nitrogen atom; ** represents a point of attachment of Z to L’ or L”; andR6is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN;wherein one of R3 and R5 comprises the divalent moiety that links to L’ or L”.

[0010] It is understood that CDK inhibitor compounds that include a CDK binding moiety of (I)(e.g., as described herein) which is not linked to a UBM, are also encompassed by this disclosure.3. DETAILED DESCRIPTION3.1. Definitions

[0011] When describing the embodiments of the present disclosure, which may includecompounds and pharmaceutically acceptable salts thereof, pharmaceutical compositionscontaining such compounds, and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unless otherwise indicated.

[0012] It will be understood by those within the art that, in general, terms used herein, andespecially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should beinterpreted as “includes but is not limited to,” etc.). It will be further understood by those withinthe art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or“one or more”). The same holds true for the use of definite articles used to introduce claimrecitations. In addition, even if a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers,means at least two recitations, or two or more recitations). Furthermore, in those instances wherea convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together,and / or A, B, and C together, etc.). In those instances where a convention analogous to “at leastone of A, B, or C, etc.” is used, in general such a construction is intended in the sense one havingskill in the art would understand the convention (e.g., “a system having at least one of A, B, orC” would include but not be limited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and / or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood to include the possibilities of“A” or “B” or “A and B.”

[0013] In addition, where features or aspects of the disclosure are described in terms of Markushgroups, those skilled in the art will recognize that the disclosure is also thereby described interms of any individual member or subgroup of members of the Markush group.

[0014] As will be understood by one skilled in the art, for any and all purposes, such as in termsof providing a written description, all ranges disclosed herein also encompass any and allpossible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range being broken down into atleast equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each rangediscussed herein can be readily broken down into a lower third, middle third, and upper third,etc. As will also be understood by one skilled in the art, all language such as “up to,” “at least,”“greater than,” “less than,” and the like include the number recited and refer to ranges which canbe subsequently broken down into sub-ranges as discussed above. Finally, as will be understoodby one skilled in the art, a range includes each individual member. Thus, for example, a grouphaving 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0015] Compounds of this disclosure include those described generally above, and are furtherillustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] The abbreviations used herein have their conventional meaning within the chemical andbiological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0017] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”, “cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments,aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, and that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched,substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, and hybrids thereof, such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0018] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternizedform of any basic nitrogen; or a substituted nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

[0019] The term “unsaturated”, as used herein, means that a moiety has one or more units ofunsaturation.

[0020] The term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is apolymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, for example, from 1 to 6,from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. Representative examples of C1-10 alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, and n-decylene. A substituted alkylene chain is a polymethylene group in which one ormore methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0021] As used herein, the term “cyclopropylene” refers to a divalent cyclopropyl group of thefollowing structure: .

[0022] As used hereterm “bridged bicyclic” refers to any bicyclic ring system, i.e.,carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. Asdefined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bondconnecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and includethose groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include: .

[0023] A dash (“-”) that is not between two letters or symbols is used to indicate a point ofattachment for a substituent. For example, -CN is attached through the carbon atom.

[0024] When a range of values is listed, it is intended to encompass each value and sub-rangewithin the range. For example, “C1-C6 alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0025] The term “acyl”, as used herein, refers to R-C(O)- groups such as, but not limited to,(alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)- C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality. In some embodiments, it is a C1-10 acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, or heteroaryl portion plus the carbonyl carbon of the acyl group. For example, a C4-acyl has three other ring or chain atoms plus carbonyl.

[0026] The term “alkenyl”, as used herein, refers to an unsaturated straight or branchedhydrocarbon having at least one carbon-carbon double bond, such as a straight or branched groupof 2 to 8 carbon atoms, referred to herein as (C2-C8)alkenyl. Exemplary alkenyl groups include,but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0027] The term “alkyl”, as used herein, refers to a saturated straight or branched hydrocarbon,such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as C1-8 alkyl.Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2- methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2- dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1- butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.

[0028] The term “alkoxy” means a straight or branched chain saturated hydrocarbon containing1 to 12 carbon atoms and a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxy groupsinclude, without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.

[0029] The term “alkynyl”, as used herein, refers to an unsaturated straight or branchedhydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched groupof 2 to 8 carbon atoms, referred to herein as (C2-C8)alkynyl. Exemplary alkynyl groups include,but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- 1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

[0030] The term “aryl”, as used herein, refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. An aryl group may be selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0031] For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5-to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when thecarbocyclic aromatic ring is fused with a cycloalkyl group. Divalent radicals formed fromsubstituted benzene derivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. Divalent radicals derived from univalent polycyclic hydrocarbonradicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom withthe free valence are named by adding “-idene” to the name of the corresponding univalentradical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.

[0032] The term “heteroaryl” refers to a group having 5 to 10 ring atoms, e.g., 5, 6, or 9 ringatoms; having 6, 10, or 14π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term “heteroaryl”, as used herein, also includesgroups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (or in the case of a divalent fused heteroarylene ring system, at least one radical or point of attachment is on a heteroaromatic ring). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbozolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic or bicyclic. Theterm “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0033] The term “cyano”, as used herein, refers to CN.

[0034] The term “cycloalkyl”, as used herein, refers to a saturated or unsaturated cyclic, bicyclic,or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “(C3-C8)cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl,arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonicacid, sulfonamide, and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturatedor partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.

[0035] The terms “halo” or “halogen”, as used herein, refer to -F, -Cl, -Br, and / or -I.

[0036] “Haloalkyl” means an alkyl group substituted with one or more halogens. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0037] A “heterocyclyl” or “heterocyclic” group is a ring structure having from 3 to 12 atoms,for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting ofN, O, and S, wherein the ring N atom may be oxidized to N-O, and the ring S atom may beoxidized to SO or SO2, the remainder of the ring atoms being carbon. The heterocyclyl may be amonocyclic, a bicyclic, a spirocyclic, or a bridged ring system. The heterocyclic group isindependently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, or alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl,tetrahydro-1’H,3’H- spiro[cyclopropane-1,2’-pyrrolizine], hexahydro-1H-pyrrolizinyl,hexahydro-1H-pyrrolo[2,1- c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls,oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl4(1H)-oxide, tetrahydro-2H-thiopyranyl-1-oxide, and tetrahydro-2H-thiopyranyl-1,1-dioxide.Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0038] A “spirocycle”, “spirocyclyl”, or “spirocyclylene” refers to a chemical entity having twoheterocyclyl or two cycloalkyl moieties, as defined herein, or to a combination of one or moreheterocyclyl and one or more cycloalkyl moiety, having one ring atom in common, i.e., the tworings are connected via one common ring atom. Some exemplary spirocyclic ring systems, yet,.

[0039] As used herein, the term partially unsaturated refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass ringshaving multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0040] As used herein, and unless otherwise specified, the suffix “-ene” is used to describe adivalent group. Thus, any of the terms above can be modified with the suffix “-ene” to describe a divalent version of that moiety. For example, a divalent carbocycle is “carbocyclylene”, a divalent aryl ring is “arylene”, a divalent benzene ring is “phenylene”, a divalent heterocycle is “heterocyclylene”, a divalent heteroaryl ring is “heteroarylene”, a divalent alkyl chain is “alkylene”, a divalent alkenyl chain is “alkenylene”, a divalent alkynyl chain is “alkynylene”, and so forth.

[0041] As described herein, compounds of the disclosure may, when specified, contain“optionally substituted” moieties. In general, the term “substituted”, whether preceded by theterm “optionally” or not, means that one or more hydrogens of the designated moiety arereplaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are nd addition,rogen onany individual ring (e.g., refers to at leas ,). Unless otherwise indicated, an “optionally substituted” groupat each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected to conditions to allow for their purification, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0042] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°;-O(CH2)0-4C(O)OR°; -O(CH2)0-4OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, whichmay be substituted with R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted with R°, -CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl which may besubstituted with R°; -NO2; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)N(R°)2; -N(R°)C(S)N(R°)2; -(CH2)0-4N(R°)C(S)N(R°)2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)N(R°)2; -N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSi(R°)3; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4SR°; -SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)N(R°)2;-C(S)N(R°)2; -C(S)SR°; -SC(S)SR°; -(CH2)0-4OC(O)N(R°)2; -C(O)N(OR°)R°; -C(O)C(O)R°;-C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°; -(CH2)0-4S(O)R°; -N(R°)S(O)2N(R°)2; -N(R°)S(O)2R°; -N(OR°)R°;-C(NH)N(R°)2; -P(OR°)2; -P(O)(R°)2; -OP(O)(R°)2; -OP(O)(OR°)2; -SiR°3; -(C1-4 straight orbranched alkylene)O-N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic,-CH2Ph, -O(CH2)0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independentoccurrences of R°, taken together with their intervening atoms(s), form a 3- to 12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.

[0043] Suitable monovalent substituents on R° (or the ring formed by taking two independentoccurrences of R° together with their intervening atoms), are independently halogen; -(CH2)0-2R●; -(haloR●), -(CH2)0-2OH; -(CH2)0-2OR●; -(CH2)0-2CH(OR●)2; -O(haloR●); -CN; -N3; -(CH2)0-2C(O)R●; -(CH2)0-2C(O)OH; -(CH2)0-2C(O)OR●; -(CH2)0-2SR●; -(CH2)0-2SH; -(CH2)0-2NH2;-(CH2)0-2NHR●; -(CH2)0-2NR●2; -NO2, -SiR●3; -OSiR●3; -C(O)SR●; -(C1-4 straight or branchedalkylene)C(O)OR●, or -SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic,-CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-memebered saturated, partially unsaturated, or aryl ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0044] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted”group include the following: =O; =S; =NNR#2; =NNHC(O)R#2; =NNHC(O)OR#2;=NNHS(O)2R#2; =NR#; =NOR#; -O(C(R#2))2-3O-; or -S(C(R#2))2-3S-; wherein each independentoccurrence of R#is selected from hydrogen, C1-6 aliphatic which may be substituted as definedbelow, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR#2)2-3O-, wherein each independent occurrence of R#is selected from hydrogen,C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0045] Suitable substituents on the aliphatic group of R# include halogen, -R●, -(haloR●), -OH,-OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, andis independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†,-S(O)2pendentlyhydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or anunsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences or R†, taken together with their interveningatom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0047] Suitable substituents on the aliphatic group of R† are independently halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2,wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one ormore halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0048] Those skilled in the art will appreciate that a bond designated as in a small moleculestructure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. For example the followingstructure: is intended to encompass bot .

[0049] Tho”, as used herein, means an oxto a carbon atomthereby forming a carbonyl.

[0050] The terms “hydroxy” and “hydroxyl”, as used herein, refer to -OH.

[0051] Some of the compounds may exist with different points of attachment of hydrogen,referred to as “tautomers.” For example, compounds including carbonyl -CH2C(O)- groups (ketoforms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both ketoand enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

[0052] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of thedisclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers,racemic mixtures thereof, as well as mixtures of diastereoisomers, are intended to be included inthis disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise,reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0053] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of thedisclosure may contain, in some embodiments, a meso moiety, be a meso compound, or have meso isomerism.

[0054] Diastereomeric mixtures can be separated into their individual diastereoisomers on thebasis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’sacid chloride), separating the diastereoisomers, and converting (e.g., hydrolyzing) the individualdiastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0055] “Stereoisomer” or “optical isomer” means a stable isomer that has at least one chiral atomor restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomersfollowed by separation or recrystallization, chromatographic techniques, use of chiral resolvingagents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0056] It is well-known in the art that the biological and pharmacological activity of a compoundis sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of this disclosure and the knowledge of the prior art.

[0057] Thus, although the racemic form of drug may be used, it is often less effective thanadministering an equal amount of enantiomerically pure drug. Indeed, in some cases, oneenantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case ofibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer;thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity.For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine istoxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos.5,114,946 and 4,818,541.

[0058] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. Inother embodiments, provided herein is a mixture of compounds wherein individual compoundsof the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In other embodiments, thecompound mixture has an (S)-enantiomeric excess from 55% to 99.5%, from 60% to 99.5%,from 65% to 99.5%, from 70% to 99.5%, from 75% to 99.5%, from 80% to 99.5%, from 85% to99.5%, from 90% to 99.5%, from 95% to 99.5%, from 96% to 99.5%, from 97% to 99.5%, from98% to 99.5%, from 99% to 99.5%, or greater than 99.5%. In other embodiments, the compoundmixture has an (R)-enantiomeric purity of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In some other embodiments, the compoundmixture has an (R)-enantiomeric excess of from 55% to 99.5%, from 60% to 99.5%, from 65%to 99.5%, from 70% to 99.5%, from 75% to 99.5%, from 80% to 99.5%, from 85% to 99.5%,from 90% to 99.5%, from 95% to 99.5%, from 96% to 99.5%, from 97% to 99.5%, from 98% to99.5%, from 99% to 99.5%, or greater than 99.5%.

[0059] Individual stereoisomers of compounds of the present disclosure can be preparedsynthetically from commercially available starting materials that contain asymmetric orstereogenic / chiral centers, or by preparation of racemic mixtures followed by resolution methodswell known to those of ordinary skill in the art. These methods of resolution are exemplified by:(1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resultingmixture of diastereomers by recrystallization or chromatography, and liberation of the opticallypure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0060] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferreddisposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially.

[0061] The term “pharmaceutically acceptable carrier”, as used herein, refers to any and allsolvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0062] Additionally, as used herein, it refers to pharmaceutical excipients, for example,pharmaceutically and physiologically acceptable organic or inorganic carrier substances suitablefor enteral or parenteral application that do not deleteriously react with the active agent. Suitablepharmaceutically acceptable carriers include water, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure.

[0063] The term “pharmaceutically acceptable composition”, as used herein, refers to acomposition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0064] The term “pharmaceutically acceptable salt(s)” refers to salts of acidic or basic groupsthat may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0065] Chemical names were generated using PerkinElmer ChemDraw® Professional, version19.

[0066] The compounds of the disclosure may contain one or more chiral centers and / or doublebonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers, ordiastereomers. The term “stereoisomers”, when used herein, consists of all geometric isomers,enantiomers, and / or diastereomers. These compounds may be designated by the symbols “R” or“S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0067] As used herein, “cancer” refers to diseases, disorders, and conditions that involveabnormal cell growth with the potential to invade or spread to other parts of the body. Exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.

[0068] As used herein, the term “subject” refers to an animal. Typically, the animal is amammal. A subject also refers to for example, primates (e.g., humans, male or female), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certainembodiments, the subject is a primate. In some embodiments, the subject is a human.

[0069] As used herein, the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction orsuppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0070] A “dosing regimen” (or “therapeutic regimen”), as that term is used herein, is a set of unitdoses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, adosing regimen comprises a plurality of doses each of which is separated from one another by atime period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.

[0071] As will be understood from context, a “reference” compound is one that is sufficientlysimilar to a particular compound of interest to permit a relevant comparison. In some embodiments, information about a reference compound is obtained simultaneously with information about a particular compound. In some embodiments, comparison of a particularcompound of interest with a reference compound establishes identity with, similarity to, or difference of the particular compound of interest relative to the compound.

[0072] As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeuticeffect and / or elicits a desired biological and / or pharmacological effect, when administered to a subject.

[0073] As used herein, the term “therapeutically effective amount” refers to an amount of atherapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, the “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventive effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease or condition, and / or also lessening the severity or frequency of symptoms of the disease or condition. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple doses. For any particular therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example,depending on route of administration, or on combination with other pharmaceutical agents. Also,the specific therapeutically effective amount (and / or unit dose) for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific compositionemployed; the age, body weight, general health, sex, and diet of the subject; the time ofadministration, route of administration, and / or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0074] As used herein, the term “treat,” “treating,” or “treatment” of any disease or disorderrefers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat,” “treating,” or “treatment” refers to alleviating or ameliorating atleast one physical parameter, including those which may not be discernible by the patient. In yetanother embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically,(e.g., through stabilization of a physical parameter), or both. In yet another embodiment, “treat,”“treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0075] As used herein, a subject is “in need of” a treatment if such subject would benefitbiologically, medically, or in quality of life from such treatment.

[0076] Additionally, unless otherwise stated, structures described herein are also meant toinclude compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogenby deuterium (2H) or tritium (3H), or the replacement of a carbon by a 13C- or 14C-carbon atom,are within the scope of this disclosure. Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents. 3.2. Degrader Compounds

[0077] Aspects of the present disclosure include compounds of Formula (X):X)or a pharmaceutically acCDK-BM is a cyclin-dependent kinase (CDK) binding moiety; L’ is a divalent moiety (e.g., linker) that connects CDK-BM to UBM; andUBM is an E3 ubiquitin ligase binding moiety.

[0078] In some embodiments, the CDK-BM of the compound is capable of binding one or moreof CDK2, CDK4, and CDK6. In some embodiments, the CDK-BM of the compound is capableof binding CDK2. In some embodiments, the CDK-BM of the compound is capable of bindingCKD4. In some embodiments, the CDK-BM of the compound is capable of binding CDK6.

[0079] In some embodiments, the UBM of the compound is a cereblon E3 ubiquitin ligasebinding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase bindingmoiety, or an MDM2 E3 ubiquitin ligase binding moiety. In some embodiments, the UBM of thecompound is a cereblon E3 ubiquitin ligase binding moiety. In some embodiments, the UBM of the compound is a VHL E3 ubiquitin ligase binding moiety. In some embodiments, the UBM of the compound is an IAP E3 ubiquitin ligase binding moiety. In some embodiments, the UBM of the compound is an MDM2 E3 ubiquitin ligase binding moiety.

[0080] In some embodiments, the UBM is a cereblon E3 ubiquitin ligase binding moietyrepresented by Formula (Xa): a)or is a pharmaceuticallX1 is a divalent moiety selected from a covalent bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-,;X3 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-, -S-S-;L” is a divalent moiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-150 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independentlyselected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-,-P(O)OR-, -PQ is ava ent mo ety se ecte rom a on or an optona y su st tute saturated or partially unsaturated, straight or branched aliphatic C1-10 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independentlyselected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-,-P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-;each CyA is independently an optionally substituted ring system selected from a 3- to 12-membered saturated or partially unsaturated carbocyclene; a phenylene; a 3- to 12-memberedsaturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 5- to 6- or 8- to 12-membered heteroarylene having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a combination of anyof these ring systems including variants thereof;R1 is H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -C(O)R, -OC(O)R,-OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-, -N(R)C(S)S-, -N(R)C(O)S-,-N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2, -P(O)(OR)2, -P(O)(NR2)OR,-OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2, -OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2,-Si(R)3, or an optionally substituted C1-6 aliphatic; and each R is independently hydrogen, deuterium, or an optionally substituted straight,branched, or cyclic group selected from C1-6 aliphatic, phenyl, a 4- to 7-membered saturated orpartially unsaturated heterocyclyl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and a 5- to 6-membered heteroaryl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

[0081] In some embodiments, X1 is a divalent moiety selected from a covalent bond, -C(R)2-,-Si(R)2-, -N(R)-, -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-,-C(S)-, and . In some embodiments, X1is a covalent bond. In some embodiments, X1is-C(R)2-. Inmbodiments, X1 is -Si(R)2-. In some embodiments, X1 is -N(R)-. In someembodiments, X1 is -O-. In some embodiments, X1 is -S-. In some embodiments, X1 is -S-S-. Insome embodiments, X1 is -S(O)-. In some embodiments, X1 is -S(O)2-. In some embodiments, X1is -P(O)R-. In some embodiments, X1 is -P(O)OR-. In some embodiments, X1 is -P(O)N(R)2-. Insome embodiments, X1 is -C(O)-. In some embodiments, X1 is -C(S)-. In some embodiments, X1.

[0082] In some embodiments, X2 is C or Si. In some embodiments, X2 is C. In someembodiments, X2is Si.

[0083] In some embodiments, X3 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-,-N(R)-, -O-, -S-, and -S-S-. In some embodiments, X3 is a bond. In some embodiments, X3 is-C(R)2-. In some embodiments, X3 is -Si(R)2-. In some embodiments, X3 is -N(R)-. In someembodiments, X3 is -O-. In some embodiments, X3 is -S-. In some embodiments, X3 is -S-S-.

[0084] In some embodiments, L” is a divalent moiety selected from a bond or an optionallysubstituted saturated or partially unsaturated, straight or branched aliphatic C1-150 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-,-P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-. In some embodiments, L” is adivalent moiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-125 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-,-C(O)-, -C(S)-, and -CyA-. In some embodiments, L” is a divalent moiety selected from a bond oran optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-100 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-,-S(O)(NR)-, -S(NR)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-. In someembodiments, L” is a divalent moiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-75 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-,-P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-. In some embodiments, L” is a divalentmoiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-50 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-, -NR-, -S-,-S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-,r anoptionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-25 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-,-S(O)(NR)-, -S(NR)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-.

[0085] In some embodiments, one or more carbon atoms of the chain are replaced by -O-. Insome embodiments, one or more carbon atoms of the chain are replaced by -NR-. In someembodiments, one or more carbon atoms of the chain are replaced by -S-. In some embodiments,one or more carbon atoms of the chain are replaced by -S(O)-. In some embodiments, one ormore carbon atoms of the chain are replaced by -S(NR)-. In some embodiments, one or morecarbon atoms of the chain are replaced by -S(O)2-. In some embodiments, one or more carbonatoms of the chain are replaced by -S(O)(NR)-. In some embodiments, one or more carbon atomsof the chain are replaced by -S(NR)2-. In some embodiments, one or more carbon atoms of thechain are replaced by -P(O)R-. In some embodiments, one or more carbon atoms of the chain arereplaced by -P(O)OR-. In some embodiments, one or more carbon atoms of the chain arereplaced by -P(O)N(R)2-. In some embodiments, one or more carbon atoms of the chain arereplaced by -C(O)-. In some embodiments, one or more carbon atoms of the chain are replacedby -C(S)-. In some embodiments, one or more carbon atoms of the chain are replaced by -CyA-.

[0086] In some embodiments, Q is a divalent moiety selected from a bond or an optionallysubstituted saturated or partially unsaturated, straight or branched aliphatic C1-12 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent groupindependently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-,-P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-. In some embodiments, Q is adivalent moiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-10hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independently selected from -O-,-NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-,-C(O)-, -C(S)-, and -CyA-. In some embodiments, Q is a divalent moiety selected from a bond oran optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-8 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by adivalent group independently selected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-,-S(O)(NR)-, -S(NR)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-. In someembodiments, Q is a divalent moiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-5 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independentlyselected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-,-P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-. In some embodiments, Q is -O-. In someembodiments, Q is -NR-. In some embodiments, Q is -S-. In some embodiments, Q is -S(O)-. Insome embodiments, Q is -S(NR)-. In some embodiments, Q is -S(O)2-. In some embodiments, Qis -S(O)(NR)-. In some embodiments, Q is -S(NR)2-. In some embodiments, Q is -P(O)R-. Insome embodiments, Q is -P(O)OR-. In some embodiments, Q is -P(O)N(R)2-. In someembodiments, Q is -C(O)-. In some embodiments, Q is -C(S)-. In some embodiments, Q is-CyA-.

[0087] In some embodiments, each CyA is independently an optionally substituted ring systemselected from a 3- to 12-membered saturated or partially unsaturated carbocyclene; a phenylene;a 3- to 12-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 5- to 6- or 8- to 12-memberedheteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;and a combination of any of these ring systems including variants thereof. In some embodiments,CyA is an optionally substituted 3- to 12-membered saturated or partially unsaturatedcarbocyclene. In some embodiments, CyA is an optionally substituted phenylene. In someembodiments, CyA is an optionally substituted 3- to 12-membered saturated or partiallyunsaturated heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen,and sulfur. In some embodiments, CyA is an optionally substituted 5- to 6- or 8- to 12-memberedheteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, CyA is an optionally substituted 5- to 6-membered heteroarylene having1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In someembodiments, CyA is an optionally substituted 5- to 6-membered heteroarylene having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments,CyA is an optionally substituted 8- to 12-membered heteroarylene having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyA is anoptionally substituted 8- to 12-membered heteroarylene having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

[0088] In some embodiments, R1 is H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2,-C(O)R, -OC(O)R, -OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-, -N(R)C(S)S-,-N(R)C(O)S-, -N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2, -P(O)(OR)2,-P(O)(NR2)OR, -OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2, -OP(O)(NR2)2, -Si(OH)2R,-Si(OH)(R)2, -Si(R)3, or an optionally substituted C1-6 aliphatic. In some embodiments, R1 is H.In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments,R1 is -OR. In some embodiments, R1 is, -SR. In some embodiments, R1 is -S(O)R. In someembodiments, R1 is -S(O)2R. In some embodiments, R1 is -N(R)2. In some embodiments, R1 is-C(O)R. In some embodiments, R1 is -OC(O)R. In some embodiments, R1 is -OC(O)O-. In someembodiments, R1 is -N(R)C(O)N(R)-. In some embodiments, R1 is -N(R)C(S)N(R)-. In someembodiments, R1 is -N(R)C(O)O-. In some embodiments, R1 is -N(R)C(S)S-. In someembodiments, R1 is -N(R)C(O)S-. In some embodiments, R1 is -N(R)C(S)O-. In someembodiments, R1 is -N(R)C(O)R. In some embodiments, R1 is -C(O)N(R)2. In someembodiments, R1 is -OP(O)(OR)2. In some embodiments, R1 is -P(O)(OR)2. In someembodiments, R1 is -P(O)(NR2)OR. In some embodiments, R1 is -OP(O)(NR2)OR. In someembodiments, R1 is -N(R)P(O)(NR2)OR. In some embodiments, R1 is -P(O)(NR2)2. In someembodiments, R1 is -OP(O)(NR2)2. In some embodiments, R1 is -Si(OH)2R. In someembodiments, R1 is -Si(OH)(R)2. In some embodiments, R1 is -Si(R)3. In some embodiments, R1is an optionally substituted C1-6 aliphatic. In some embodiments, R1 is an optionally substitutedC1-5 aliphatic. In some embodiments, R1 is an optionally substituted C1-4 aliphatic. In someembodiments, R1 is an optionally substituted C1-3 aliphatic. In some embodiments, R1 is anoptionally substituted C1-2 aliphatic. In some embodiments, R1 is an optionally substituted C1aliphatic. In some embodiments, R1 is an optionally substituted C2 aliphatic. In someembodiments, R1 is an optionally substituted C3 aliphatic. In some embodiments, R1 is anoptionally substituted C4 aliphatic. In some embodiments, R1 is an optionally substituted C5aliphatic. In some embodiments, R1 is an optionally substituted C6 aliphatic.

[0089] In some embodiments, each R is independently hydrogen, deuterium, or an optionallysubstituted straight, branched, or cyclic group selected from C1-6 aliphatic, phenyl, a 4- to 7-membered saturated or partially unsaturated heterocyclyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ris hydrogen. In some embodiments, R is deuterium. In some embodiments, R is an optionallysubstituted straight, branched, or cyclic group selected from C1-6 aliphatic. In some embodiments,R is phenyl. In some embodiments, R is a 4- to 7-membered saturated or partially unsaturatedheterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, R is a 5- to 6-membered heteroaryl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments of Formula (Xa), Q is represented by the structure:wherein:Q1is N or CRA; Q2is N or C; Q3is N or C; Q4is N or CRA; Q5is N or CRA; Q6is N or CRA; Z1 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2;)2;)2;, , , , , , , , , or C(RA)2; andeach RA is independently selected from H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R,-N(R)2, -C(O)R, -OC(O)R, -OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-,-N(R)C(S)S-, -N(R)C(O)S-, -N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2,-P(O)(OR)2, -P(O)(NR2)OR, -OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2,-OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and an optionally substituted C1-6 aliphatic.

[0091] In some embodiments, Q1 is N or CRA. In some embodiments, Q1 is N. In someembodiments, Q1 is CRA.

[0092] In some embodiments, Q2 is N or C. In some embodiments, Q2 is N. In someembodiments, Q2is C.

[0093] In some embodiments, Q3 is N or C. In some embodiments, Q3 is N. In someembodiments, Q3is C.

[0094] In some embodiments, Q4 is N or CRA. In some embodiments, Q4 is N. In someembodiments, Q4is CRA.

[0095] In some embodiments, Q5 is N or CRA. In some embodiments, Q5 is N. In someembodiments, Q5is CRA.

[0096] In some embodiments, Q6 is N or CRA. In some embodiments, Q6 is N. In someembodiments, Q6is CRA.

[0097] In some embodiments, Z1 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2. In someembodiments, Z1 is N. In some embodiments, Z1 is NRA. In some embodiments, Z1 is C. In someembodiments, Z1is O. In some embodiments, Z1is S. In some embodiments, Z1is CRA. In someembodiments, Z1 is C(=O). In some embodiments, Z1 is C(=NRA). In some embodiments, Z1 isC(RA)2.

[0098] In some embodiments, Z2 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2. In someembodiments, Z2is N. In some embodiments, Z2is NRA. In some embodiments, Z2is C. In some embodiments, Z2is O. In some embodiments, Z2is S. In some embodiments, Z2is CRA. In someembodiments, Z2 is C(=O). In some embodiments, Z2 is C(=NRA). In some embodiments, Z2 isC(RA)2.

[0099] In some embodiments, Z3 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2. In someembodiments, Z3 is N. In some embodiments, Z3 is NRA. In some embodiments, Z3 is C. In someembodiments, Z3is O. In some embodiments, Z3is S. In some embodiments, Z3is CRA. In someembodiments, Z3 is C(=O). In some embodiments, Z3 is C(=NRA). In some embodiments, Z3 isC(RA)2.

[0100] In some embodiments, Z4 is a bond, N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2.In some embodiments, Z4 is a bond. In someome embodiments, Z4 isNRA. In some embodiments, Z4is C. In some embodiments, Z4is O. In some embodiments, Z4isS. In some embodiments, Z4 is CRA. In some embodiments, Z4 is C(=O). In some embodiments,Z4 is C(=NRA). In some embodiments, Z4 is C(RA)2.

[0101] In some embodiments of any one of the above, each RA is independently selected from H,halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -C(O)R, -OC(O)R, -OC(O)O-,-N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-, -N(R)C(S)S-, -N(R)C(O)S-, -N(R)C(S)O-,-N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2, -P(O)(OR)2, -P(O)(NR2)OR, -OP(O)(NR2)OR,-N(R)P(O)(NR2)OR, -P(O)(NR2)2, -OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and anoptionally substituted C1-6 aliphatic. In some embodiments, RA is H. In some embodiments, RA ishalogen. In some embodiments, RA is -CN. In some embodiments, RA is -OR. In someembodiments, RA is -SR. In some embodiments, RA is -S(O)R. In some embodiments, RA is-S(O)2R. In some embodiments, RA is -N(R)2. In some embodiments, RA is -C(O)R. In someembodiments, RA is -OC(O)R. In some embodiments, RA is -OC(O)O-. In some embodiments,RA is -N(R)C(O)N(R)-. In some embodiments, RA is -N(R)C(S)N(R)-. In some embodiments, RAis -N(R)C(O)O-. In some embodiments, RA is -N(R)C(S)S-. In some embodiments, RA is-N(R)C(O)S-. In some embodiments, RA is -N(R)C(S)O-. In some embodiments, RA is-N(R)C(O)R. In some embodiments, RA is -C(O)N(R)2. In some embodiments, RA is-OP(O)(OR)2. In some embodiments, RA is -P(O)(OR)2. In some embodiments, RA is-P(O)(NR2)OR. In some embodiments, RA is -OP(O)(NR2)OR. In some embodiments, RA is-N(R)P(O)(NR2)OR. In some embodiments, RA is -P(O)(NR2)2. In some embodiments, RA is-OP(O)(NR2)2. In some embodiments, RA is -Si(OH)2R. In some embodiments, RA is-Si(OH)(R)2. In some embodiments, RA is -Si(R)3. In some embodiments, RA is optionallysubstituted C1-6 aliphatic. In some embodiments, RA is an optionally substituted C1 aliphatic. Insome embodiments, RA is an optionally substituted C2 aliphatic. In some embodiments, RA is anoptionally substituted C3 aliphatic. In some embodiments, RA is an optionally substituted C4aliphatic. In some embodiments, RA is an optionally substituted C5 aliphatic. In someembodiments, RA is an optionally substituted C6 aliphatic. In some embodiments, RA is anoptionally substituted C1 aliphatic. In some embodiments, RA is an optionally substituted C2aliphatic. In some embodiments, RA is an optionally substituted C3 aliphatic. In someembodiments, RA is an optionally substituted C4 aliphatic. In some embodiments, RA is anoptionally substituted C5 aliphatic. In some embodiments, RA is an optionally substituted C6aliphatic.

[0102] In some embodiments, Q is selected from:,,

[0103] In some embodiments . In some embodiments, Q isisisiss.In some embodiments, Q isisIn some embodiments, Q is.In some embodiments, n some embodiment .In some embodiments, n some embodiment Insome embodiments, n some embodiment In someembodiments, n some embodiment meembodiments, . In someembodiments, meembodiments, n some embodiment In someembodiments, n some embodiment In someembodiments, n some embodiment In someembodiments, . In some embodiment . In someembodiments, In someembodiments, n some embodiment meembodiments, n some embodiment meembodiments, meembodiments, n some embodiment . In someembodiments, .

[0104] In somy one of the above, u is 1 to 3. In some embodiments, u is 1.In some embodiments, u is 2. In some embodiments, u is 3.

[0105] In some embodiments, Q is selected from:,some embodiments, n some embodiments meembodiments, Q is . In some embodiments, Q . In someembodiments, Q is . In some embodiments, Q . In someembodiments, Q . In some embodiments, Q . In someembodiments, Q i . In some embodiments, Q . In someembodiments, Q is . In some embodiments, Q . In someembodiments, Q is . In some embodiments, Q . In someembodiments, Q is . In some embodiments, Q . In someembodiments, Q . In some embodiments, Q . In some embodiments,Q i .[01bodiments, Q is selected from:, andeach RA is independently selected from H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R,-N(R)2, -C(O)R, -OC(O)R, -OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-,-N(R)C(S)S-, -N(R)C(O)S-, -N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2,-P(O)(OR)2, -P(O)(NR2)OR, -OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2,-OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and an optionally substituted C1-6 aliphatic; andu is 1 to 3.

[0107] In some embodiments, Q i . In some embodiments, Q is. In some embodiments, Q i . In some embodiments, Q is. In some embodiments, Q i . In some embodiments, Q ismbodiments of any one of the above, each RA is independently selected from H,halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -C(O)R, -OC(O)R, -OC(O)O-,-N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-, -N(R)C(S)S-, -N(R)C(O)S-, -N(R)C(S)O-,-N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2, -P(O)(OR)2, -P(O)(NR2)OR, -OP(O)(NR2)OR,-N(R)P(O)(NR2)OR, -P(O)(NR2)2, -OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and anoptionally substituted C1-6 aliphatic. In some embodiments, RA is H. In some embodiments, RA ishalogen. In some embodiments, RA is -CN. In some embodiments, RA is -OR. In someembodiments, RA is -SR. In some embodiments, RA is -S(O)R. In some embodiments, RA is-S(O)2R. In some embodiments, RA is -N(R)2. In some embodiments, RA is -C(O)R. In someembodiments, RA is -OC(O)R. In some embodiments, RA is -OC(O)O-. In some embodiments,RA is -N(R)C(O)N(R)-. In some embodiments, RA is -N(R)C(S)N(R)-. In some embodiments, RAis -N(R)C(O)O-. In some embodiments, RA is -N(R)C(S)S-. In some embodiments, RA is-N(R)C(O)S-. In some embodiments, RA is -N(R)C(S)O-. In some embodiments, RA is-N(R)C(O)R. In some embodiments, RA is -C(O)N(R)2. In some embodiments, RA is-OP(O)(OR)2. In some embodiments, RA is -P(O)(OR)2. In some embodiments, RA is-P(O)(NR2)OR. In some embodiments, RA is -OP(O)(NR2)OR. In some embodiments, RA is-N(R)P(O)(NR2)OR. In some embodiments, RA is -P(O)(NR2)2. In some embodiments, RA is-OP(O)(NR2)2. In some embodiments, RA is -Si(OH)2R. In some embodiments, RA is-Si(OH)(R)2. In some embodiments, RA is -Si(R)3. In some embodiments, RA is optionallysubstituted C1-6 aliphatic. In some embodiments, RA is an optionally substituted C1 aliphatic. Insome embodiments, RA is an optionally substituted C2 aliphatic. In some embodiments, RA is anoptionally substituted C3 aliphatic. In some embodiments, RA is an optionally substituted C4aliphatic. In some embodiments, RA is an optionally substituted C5 aliphatic. In someembodiments, RAis an optionally substituted C6 aliphatic.

[0109] In some embodiments of any one of the above, u is 1 to 3. In some embodiments, u is 1.In some embodiments, u is 2. In some embodiments, u is 3.

[0110] In some embodiments, Q is selected from:,, and. In some embodiments, Q . In some embodiments, Q is. In some embodiments, Q . In some embodiments, Q is. In some embodiments, Q is . In some embodiments, Q is. In some embodiments, Q i . In some embodiments, Q is. In some embodiments, Q i . In some embodiments, Q is.In some embodiments, Q i .

[0111] In some embodiments, L” is of the formula:wherein:each L11, L12, L13, L14, and L15is independently selected from a bond, –C1-20-alkylene–,–C(O)-C1-30-alkylene–, –N(R1)C(O)-C1-6-alkylene–, –C(O)N(R1)-C1-6-alkylene–,–N(R1)C1-6-alkylene–, –N(R1)C(O)N(R1)-C1-6-alkylene–, –N(R1)C(S)N(R1)-C1-6-alkylene–,–(monocyclic heterocycle)-C(O)-C1-6-alkylene–, –C1-30-alkylene-C(O)–, –C1-6-alkylene-C(O)N(R1)–, –C1-6-alkylene-N(R1)C(O)–, –C1-6-alkylene-N(R1)–, –C1-6-alkylene-N(R1)C(O)N(R1)–, –C1-6-alkylene-N(R1)C(S)N(R1)–, –C1-6-alkylene-C(O)-(monocyclicheterocycle)–, –O(CH2)g–, –(CH2)gO–, –(OCH2CH2)g–, –(CH2CH2O)g–, –N(R1)C(O)–,–C(O)N(R1)–, –N(R1)SO2–, –SO2N(R1)–, –CO–, –SO2–, –S(N)(O)–, –O–, –S–, monocyclicheteroaryl (e.g., triazole), monocyclic aryl, monocyclic heterocycle (e.g., piperidinyl, or piperazinyl), bicyclic heterocycle (e.g., spirocyclic), amino acid residue, –NH–, and –N(CH3)–; each R1is independently H or CH3; each g is independently 1, 2, 3, 4, 5, or 6; anda, b, c, d, and e are independently 1, 2, or 3.

[0112] In some embodiments, each L11, L12, L13, L14, and L15 is independently selected from abond, –C1-20-alkylene–, –C(O)-C1-30-alkylene–, –N(R1)C(O)-C1-6-alkylene–, –C(O)N(R1)-C1-6-alkylene–, –N(R1)C1-6-alkylene–, –N(R1)C(O)N(R1)-C1-6-alkylene–, –N(R1)C(S)N(R1)-C1-6-alkylene–, –(monocyclic heterocycle)-C(O)-C1-6-alkylene–, –C1-30-alkylene-C(O)–, –C1-6-alkylene-C(O)N(R1)–, –C1-6-alkylene-N(R1)C(O)–, –C1-6-alkylene-N(R1)–, –C1-6-alkylene-N(R1)C(O)N(R1)–, –C1-6-alkylene-N(R1)C(S)N(R1)–, –C1-6-alkylene-C(O)-(monocyclicheterocycle)–, –O(CH2)g–, –(CH2)gO–, –(OCH2CH2)g–, –(CH2CH2O)g–, –N(R1)C(O)–,–C(O)N(R1)–, –N(R1)SO2–, –SO2N(R1)–, –CO–, –SO2–, –S(N)(O)–, –O–, –S–, monocyclicheteroaryl (e.g., triazole), monocyclic aryl, monocyclic heterocycle (e.g., piperidinyl, or piperazinyl), bicyclic heterocycle (e.g., spirocyclic), amino acid residue, –NH–, and –N(CH3)–.In some embodiments, L11 is a bond. In some embodiments, L11 is –C1-20-alkylene–. In someembodiments, L11 is –C(O)-C1-30-alkylene–. In some embodiments, L11 is –C(O)-C1-25-alkylene–.In some embodiments, L11 is –C(O)-C1-20-alkylene–. In some embodiments, L11 is –C(O)-C1-15-alkylene–. In some embodiments, L11 is –C(O)-C1-10-alkylene–. In some embodiments, L11 is–C(O)-C1-6-alkylene–. In some embodiments, L11 is –N(R1)C(O)-C1-6-alkylene–. In someembodiments, L11 is –C(O)N(R1)-C1-6-alkylene–. In some embodiments, L11 is –N(R1)C1-6-alkylene–. In some embodiments, L11 is –N(R1)C(O)N(R1)-C1-6-alkylene–. In someembodiments, L11 is –N(R1)C(S)N(R1)-C1-6-alkylene–. In some embodiments, L11 is–(monocyclic heterocycle)-C(O)-C1-6-alkylene–. In some embodiments, L11 is –C1-30-alkylene-C(O)–. In some embodiments, L11 is –C1-25-alkylene-C(O)–. In some embodiments, L11 is –C1-20-alkylene-C(O)–. In some embodiments, L11 is –C1-15-alkylene-C(O)–. In some embodiments, L11is –C1-10-alkylene-C(O)–. In some embodiments, L11 is –C1-6-alkylene-C(O)–. In someembodiments, L11 is –C1-6-alkylene-C(O)N(R1)–. In some embodiments, L11 is –C1-6-alkylene-N(R1)C(O)–. In some embodiments, L11 is –C1-6-alkylene-N(R1)–. In some embodiments, L11 is–C1-6-alkylene-N(R1)C(O)N(R1)–. In some embodiments, L11 is –C1-6-alkylene-N(R1)C(S)N(R1)–. In some embodiments, L11 is –C1-6-alkylene-C(O)-(monocyclic heterocycle)–. In someembodiments, L11 is –O(CH2)g–. In some embodiments, L11 is –(CH2)gO–. In someembodiments, L11 is –(OCH2CH2)g–. In some embodiments, L11 is –(CH2CH2O)g–. In someembodiments, L11 is –N(R1)C(O)–. In some embodiments, L11 is –C(O)N(R1)–. In someembodiments, L11 is –N(R1)SO2–. In some embodiments, L11 is –SO2N(R1)–. In someembodiments, L11 is –CO–. In some embodiments, L11 is –SO2–. In some embodiments, L11 is–S(N)(O)–. In some embodiments, L11 is –O–. In some embodiments, L11 is –S–. In someembodiments, L11 is a monocyclic heteroaryl (e.g., triazole). In some embodiments, L11 is amonocyclic aryl. In some embodiments, L11 is a monocyclic heterocycle (e.g., piperidinyl orpiperazinyl). In some embodiments, L11 is a bicyclic heterocycle (e.g., spirocyclic). In someembodiments, L11 is an amino acid residue. In some embodiments, L11 is –NH–. In someembodiments, L11 is –N(CH3)–.

[0113] In some embodiments, L12 is a bond. In some embodiments, L12 is –C1-20-alkylene–. Insome embodiments, L12 is –C(O)-C1-30-alkylene–. In some embodiments, L12 is –C(O)-C1-25-alkylene–. In some embodiments, L12 is –C(O)-C1-20-alkylene–. In some embodiments, L12 is–C(O)-C1-15-alkylene–. In some embodiments, L12 is –C(O)-C1-10-alkylene–. In someembodiments, L12 is –C(O)-C1-6-alkylene–. In some embodiments, L12 is –N(R1)C(O)-C1-6-alkylene–. In some embodiments, L12 is –C(O)N(R1)-C1-6-alkylene–. In some embodiments, L12is –N(R1)C1-6-alkylene–. In some embodiments, L12 is –N(R1)C(O)N(R1)-C1-6-alkylene–. In someembodiments, L12 is –N(R1)C(S)N(R1)-C1-6-alkylene–. In some embodiments, L12 is–(monocyclic heterocycle)-C(O)-C1-6-alkylene–. In some embodiments, L12 is –C1-30-alkylene-C(O)–. In some embodiments, L12 is –C1-25-alkylene-C(O)–. In some embodiments, L12 is –C1-20-alkylene-C(O)–. In some embodiments, L12 is –C1-15-alkylene-C(O)–. In some embodiments, L12is –C1-10-alkylene-C(O)–. In some embodiments, L12 is –C1-6-alkylene-C(O)–. In someembodiments, L12 is –C1-6-alkylene-C(O)N(R1)–. In some embodiments, L12 is –C1-6-alkylene-N(R1)C(O)–. In some embodiments, L12 is –C1-6-alkylene-N(R1)–. In some embodiments, L12 is–C1-6-alkylene-N(R1)C(O)N(R1)–. In some embodiments, L12 is –C1-6-alkylene-N(R1)C(S)N(R1)–. In some embodiments, L12 is –C1-6-alkylene-C(O)-(monocyclic heterocycle)–. In someembodiments, L12 is –O(CH2)g–. In some embodiments, L12 is –(CH2)gO–. In someembodiments, L12 is –(OCH2CH2)g–. In some embodiments, L12 is –(CH2CH2O)g–. In someembodiments, L12 is –N(R1)C(O)–. In some embodiments, L12 is –C(O)N(R1)–. In someembodiments, L12 is –N(R1)SO2–. In some embodiments, L12 is –SO2N(R1)–. In someembodiments, L12 is –CO–. In some embodiments, L12 is –SO2–. In some embodiments, L12 is–S(N)(O)–. In some embodiments, L12 is –O–. In some embodiments, L12 is –S–. In someembodiments, L12 is a monocyclic heteroaryl (e.g., triazole). In some embodiments, L12 is amonocyclic aryl. In some embodiments, L12 is a monocyclic heterocycle (e.g., piperidinyl orpiperazinyl). In some embodiments, L12 is a bicyclic heterocycle (e.g., spirocyclic). In someembodiments, L12 is an amino acid residue. In some embodiments, L12 is –NH–. In someembodiments, L12 is –N(CH3)–.

[0114] In some embodiments, L13 is a bond. In some embodiments, L13 is –C1-20-alkylene–. Insome embodiments, L13 is –C(O)-C1-30-alkylene–. In some embodiments, L13 is –C(O)-C1-25-alkylene–. In some embodiments, L13 is –C(O)-C1-20-alkylene–. In some 13L is–C(O)-C1-15-alkylene–. In some embodiments, L13 is –C(O)-C1-10-alkylene–. In someembodiments, L13 is –C(O)-C1-6-alkylene–. In some embodiments, L13 is –N(R1)C(O)-C1-6-alkylene–. In some embodiments, L13 is –C(O)N(R1)-C1-6-alkylene–. In some embodiments, L13is –N(R1)C1-6-alkylene–. In some embodiments, L13 is –N(R1)C(O)N(R1)-C1-6-alkylene–. In someembodiments, L13 is –N(R1)C(S)N(R1)-C1-6-alkylene–. In some embodiments, L13 is–(monocyclic heterocycle)-C(O)-C1-6-alkylene–. In some embodiments, L13 is –C1-30-alkylene-C(O)–. In some embodiments, L13 is –C1-25-alkylene-C(O)–. In some embodiments, L13 is –C1-20-alkylene-C(O)–. In some embodiments, L13 is –C1-15-alkylene-C(O)–. In some embodiments, L13is –C1-10-alkylene-C(O)–. In some embodiments, L13 is –C1-6-alkylene-C(O)–. In someembodiments, L13 is –C1-6-alkylene-C(O)N(R1)–. In some embodiments, L13 is –C1-6-alkylene-N(R1)C(O)–. In some embodiments, L13 is –C1-6-alkylene-N(R1)–. In some embodiments, L13 is–C1-6-alkylene-N(R1)C(O)N(R1)–. In some embodiments, L13 is –C1-6-alkylene-N(R1)C(S)N(R1)–. In some embodiments, L13 is –C1-6-alkylene-C(O)-(monocyclic heterocycle)–. In someembodiments, L13 is –O(CH2)g–. In some embodiments, L13 is –(CH2)gO–. In someembodiments, L13 is –(OCH2CH2)g–. In some embodiments, L13 is –(CH2CH2O)g–. In someembodiments, L13 is –N(R1)C(O)–. In some embodiments, L13 is –C(O)N(R1)–. In someembodiments, L13 is –N(R1)SO2–. In some embodiments, L13 is –SO2N(R1)–. In someembodiments, L13 is –CO–. In some embodiments, L13 is –SO2–. In some embodiments, L13 is–S(N)(O)–. In some embodiments, L13 is –O–. In some embodiments, L13 is –S–. In someembodiments, L13 is a monocyclic heteroaryl (e.g., triazole). In some embodiments, L13 is amonocyclic aryl. In some embodiments, L13 is a monocyclic heterocycle (e.g., piperidinyl orpiperazinyl). In some embodiments, L13 is a bicyclic heterocycle (e.g., spirocyclic). In someembodiments, L13 is an amino acid residue. In some embodiments, L13 is –NH–. In someembodiments, L13 is –N(CH3)–.

[0115] In some embodiments, L14 is a bond. In some embodiments, L14 is –C1-20-alkylene–. Insome embodiments, L14 is –C(O)-C1-30-alkylene–. In some embodiments, L14 is –C(O)-C1-25-alkylene–. In some embodiments, L14 is –C(O)-C1-20-alkylene–. In some embodiments, L14 is–C(O)-C1-15-alkylene–. In some embodiments, L14 is –C(O)-C1-10-alkylene–. In someembodiments, L14 is –C(O)-C1-6-alkylene–. In some embodiments, L14 is –N(R1)C(O)-C1-6-alkylene–. In some embodiments, L14 is –C(O)N(R1)-C1-6-alkylene–. In some embodiments, L14is –N(R1)C1-6-alkylene–. In some embodiments, L14 is –N(R1)C(O)N(R1)-C1-6-alkylene–. In someembodiments, L14 is –N(R1)C(S)N(R1)-C1-6-alkylene–. In some embodiments, L14 is–(monocyclic heterocycle)-C(O)-C1-6-alkylene–. In some embodiments, L14 is –C1-30-alkylene-C(O)–. In some embodiments, L14 is –C1-25-alkylene-C(O)–. In some embodiments, L14 is –C1-20-alkylene-C(O)–. In some embodiments, L14 is –C1-15-alkylene-C(O)–. In some embodiments, L14is –C1-10-alkylene-C(O)–. In some embodiments, L14 is –C1-6-alkylene-C(O)–. In someembodiments, L14 is –C1-6-alkylene-C(O)N(R1)–. In some embodiments, L14 is –C1-6-alkylene-N(R1)C(O)–. In some embodiments, L14 is –C1-6-alkylene-N(R1)–. In some embodiments, L14 is–C1-6-alkylene-N(R1)C(O)N(R1)–. In some embodiments, L14 is –C1-6-alkylene-N(R1)C(S)N(R1)–. In some embodiments, L14 is –C1-6-alkylene-C(O)-(monocyclic heterocycle)–. In someembodiments, L14 is –O(CH2)g–. In some embodiments, L14 is –(CH2)gO–. In someembodiments, L14 is –(OCH2CH2)g–. In some embodiments, L14 is –(CH2CH2O)g–. In someembodiments, L14 is –N(R1)C(O)–. In some embodiments, L14 is –C(O)N(R1)–. In someembodiments, L14 is –N(R1)SO2–. In some embodiments, L14 is –SO2N(R1)–. In someembodiments, L14 is –CO–. In some embodiments, L14 is –SO2–. In some embodiments, L14 is–S(N)(O)–. In some embodiments, L14 is –O–. In some embodiments, L14 is –S–. In someembodiments, L14 is a monocyclic heteroaryl (e.g., triazole). In some embodiments, L14 is amonocyclic aryl. In some embodiments, L14 is a monocyclic heterocycle (e.g., piperidinyl orpiperazinyl). In some embodiments, L14 is a bicyclic heterocycle (e.g., spirocyclic). In someembodiments, L14 is an amino acid residue. In some embodiments, L14 is –NH–. In someembodiments, L14 is –N(CH3)–.

[0116] In some embodiments, L15 is a bond. In some embodiments, L15 is –C1-20-alkylene–. Insome embodiments, L15 is –C(O)-C1-30-alkylene–. In some embodiments, L15 is –C(O)-C1-25-alkylene–. In some embodiments, L15 is –C(O)-C1-20-alkylene–. In some embodiments, L15 is–C(O)-C1-15-alkylene–. In some embodiments, L15 is –C(O)-C1-10-alkylene–. In someembodiments, L15 is –C(O)-C1-6-alkylene–. In some embodiments, L15 is –N(R1)C(O)-C1-6-alkylene–. In some embodiments, L15 is –C(O)N(R1)-C1-6-alkylene–. In some embodiments, L15is –N(R1)C1-6-alkylene–. In some embodiments, L15 is –N(R1)C(O)N(R1)-C1-6-alkylene–. In someembodiments, L15 is –N(R1)C(S)N(R1)-C1-6-alkylene–. In some embodiments, L15 is–(monocyclic heterocycle)-C(O)-C1-6-alkylene–. In some embodiments, L15 is –C1-30-alkylene-C(O)–. In some embodiments, L15 is –C1-25-alkylene-C(O)–. In some embodiments, L15 is –C1-20-alkylene-C(O)–. In some embodiments, L15 is –C1-15-alkylene-C(O)–. In some embodiments, L15is –C1-10-alkylene-C(O)–. In some embodiments, L15 is –C1-6-alkylene-C(O)–. In someembodiments, L15 is –C1-6-alkylene-C(O)N(R1)–. In some embodiments, L15 is –C1-6-alkylene-N(R1)C(O)–. In some embodiments, L15 is –C1-6-alkylene-N(R1)–. In some embodiments, L15 is–C1-6-alkylene-N(R1)C(O)N(R1)–. In some embodiments, L15 is –C1-6-alkylene-N(R1)C(S)N(R1)–. In some embodiments, L15 is –C1-6-alkylene-C(O)-(monocyclic heterocycle)–. In someembodiments, L15 is –O(CH2)g–. In some embodiments, L15 is –(CH2)gO–. In someembodiments, L15 is –(OCH2CH2)g–. In some embodiments, L15 is –(CH2CH2O)g–. In someembodiments, L15 is –N(R1)C(O)–. In some embodiments, L15 is –C(O)N(R1)–. In someembodiments, L15 is –N(R1)SO2–. In some embodiments, L15 is –SO2N(R1)–. In someembodiments, L15 is –CO–. In some embodiments, L15 is –SO2–. In some embodiments, L15 is–S(N)(O)–. In some embodiments, L15 is –O–. In some embodiments, L15 is –S–. In someembodiments, L15 is a monocyclic heteroaryl (e.g., triazole). In some embodiments, L15 is amonocyclic aryl. In some embodiments, L15 is a monocyclic heterocycle (e.g., piperidinyl orpiperazinyl). In some embodiments, L15 is a bicyclic heterocycle (e.g., spirocyclic). In someembodiments, L15 is an amino acid residue. In some embodiments, L15 is –NH–. In someembodiments, L15 is –N(CH3)–.

[0117] In some embodiments of any one of the above, each R1 is independently H or CH3. Insome embodiments, R1 is H. In some embodiments, R1 is CH3.

[0118] In some embodiments of any one of the above, each g is independently 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. Insome embodiments, g is 4. In some embodiments, g is 5. In some embodiments, g is 6.

[0119] In some embodiments of any one of the above, a, b, c, d, and e are independently 1, 2, or3. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. Insome embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In someembodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3. In someembodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In someembodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3.

[0120] In some embodiments, L” comprises one or more groups selected from:,,

[0121] In some embodiments, L” comprises . In some embodiments, L” comprisesnts,someembodiments, L” comprise . In some embodiments, L”comprises . In some embodiments, L” comprises. In some embodiments, L” comprises.In some embodiments, L” comprise . In someembodiments, L” compris . In some embodiments, L” comprises. In some embodiments, L” comprises. In some embodiments, L” comprises. In some embodiments, L” comprises . In some embodiments, L” comprises . In some embodiments, L” comprisesIn some embodiments, L” comprises

[0122] In embodiments of any one of the above1, each m and n is independently from 1 to 30 In some embodiments, m is 1 . In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, in is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13 In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19. In some embodiments, m is 20. In some embodiments, m is 21. In some embodiments, m is 22. In some embodiments, m is 23. In some embodiments, m is 24. In some embodiments, m is 25 In some embodiments, m is 26. In some embodiments, m is 27. In some embodiments, m is 28 In some embodiments, m is 29. In some embodiments, m is 30. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11 . In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16 In some embodiments, n is 17 In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20. In some embodiments, n is 21. In some embodiments, n is 22. In some embodiments, n is 23. In some embodiments, n is 24. In some embodiments, n is 25. In some embodiments, n is 26. In some embodiments, n is 27. In some embodiments, n is 28. In some embodiments, n is 29. In some embodiments, n is 30.

[0123] In some embodiments, the CDK-BM is represented by Formula (I):(I)or a pharmaceutically acceptable sereof, wherein:R1is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted(C1-5)alkoxy, haloalkyl, halogen, OH, -CF3, -CF2H, -CFH2, -C2F5, -C2F4H, -C2F3H2, -C2F2H3,-C2FH4, and CN; R3 is selected from a divalent moiety that links to L’ or L”, H, alkyl, carbocycle,heterocycle, aryl, heteroaryl, alkylene-carbocycle, alkylene-heterocycle, alkylene-aryl, alkylene- heteroaryl, substituted versions thereof, and substituted versions thereof that are substituted witha divalent moiety that links to L’ or L”;L10 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-, -S-S-,-S(O)-, -S(O)2-, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, and -NHS(O)2-;Y4is N or CR4; R4is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN; 5, wherein:s a cyc c group se ected rom carbocyc y , eterocyclyl, aryl, heteroaryl, and substituted versions thereof; Z is selected from a bond, sulfonyl, sulfone, sulfoxide, sulfide, sulfonate ester, sulfonamide, sulfimide, sulfinamide, sulfenamide, sulfoximine, sulfonimidamide, sulfonate,sulfondiimine, sulfondiimidamide, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde,ester, alkoxy, nitrile, halogen, thiolactone, ether, urea, thiourea, and aliphatic group, or Z is adivalent moiety that links to L’ or L”;L1and L2are optional linkers; and * represents the point of attachment of R5to the nitrogen atom; ** represents a point of attachment of Z to L’ or L”; andR6is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN;wherein one of R3 and R5 comprises the divalent moiety that links to L’ or L”.

[0124] In some embodiments, R1 is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, -CF3, -CF2H, -CFH2, -C2F5, -C2F4H,-C2F3H2, -C2F2H3, -C2FH4, and CN. In some embodiments, R1 is H. In some embodiments, R1 is(C1-5)alkyl. In some embodiments, R1 is (C1)alkyl. In some embodiments, R1 is (C2)alkyl. Insome embodiments, R1is (C3)alkyl. In some embodiments, R1is (C4)alkyl. In someembodiments, R1 is (C5)alkyl. In some embodiments, R1 is substituted (C1-5)alkyl. In someembodiments, R1is substituted (C1)alkyl. In some embodiments, R1is substituted (C2)alkyl. In some embodiments, R1is substituted (C3)alkyl. In some embodiments, R1is substituted(C4)alkyl. In some embodiments, R1 is substituted (C5)alkyl. In some embodiments, R1 is (C1-5)alkoxy. In some embodiments, R1 is (C1)alkoxy. In some embodiments, R1 is (C2)alkoxy. Insome embodiments, R1is (C3)alkoxy. In some embodiments, R1is (C4)alkoxy. In someembodiments, R1 is (C5)alkoxy. In some embodiments, R1 is substituted (C1-5)alkoxy. In someembodiments, R1is substituted (C1)alkoxy. In some embodiments, R1is substituted (C2)alkoxy. In some embodiments, R1is substituted (C3)alkoxy. In some embodiments, R1is substituted (C4)alkoxy. In some embodiments, R1is substituted (C5)alkoxy. In some embodiments, R1ishaloalkyl. In some embodiments, R1 is halogen. In some embodiments, R1 is OH. In someembodiments, R1 is -CF3. In some embodiments, R1 is -CF2H. In some embodiments, R1 is-CFH2. In some embodiments, R1 is -C2F5. In some embodiments, R1 is -C2F4H. In someembodiments, R1 is -C2F3H2. In some embodiments, R1 is -C2F2H3. In some embodiments, R1 is-C2FH4. In some embodiments, R1 is CN.

[0125] In some embodiments, R3 is selected from a divalent moiety that links to L’ or L”, H,alkyl, carbocycle, heterocycle, aryl, heteroaryl, alkylene-carbocycle, alkylene-heterocycle, alkylene-aryl, alkylene-heteroaryl, substituted versions thereof, and substituted versions thereofthat are substituted with a divalent moiety that links to L’ or L”. In some embodiments, R3 is adivalent moiety that links to L’ or L”. In some embodiments, R3 is H. In some embodiments, R3is alkyl. In some embodiments, R3 is carbocycle. In some embodiments, R3 is heterocycle. Insome embodiments, R3 is aryl. In some embodiments, R3 is heteroaryl. In some embodiments, R3is alkylene-carbocycle. In some embodiments, R3 is alkylene-heterocycle. In some embodiments,R3 is alkylene-aryl. In some embodiments, R3 is alkylene-heteroaryl. In some embodiments, anyof the preceding R3 is a substituted version thereof. In some embodiments, any of the precedingR3 is a substituted version thereof that is substituted with a divalent moiety that links to L’ or L”.

[0126] In some embodiments, L10 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-,-N(R)-, -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, and-NHS(O)2-. In some embodiments, L10 is a bond. In some embodiments, L10 is -C(R)2-. In someembodiments, L10 is -Si(R)2-. In some embodiments, L10 is -N(R)-. In some embodiments, L10 is-O-. In some embodiments, L10 is -S-. In some embodiments, L10 is -S-S-. In some embodiments,L10 is -S(O)-. In some embodiments, L10 is -S(O)2-. In some embodiments, L10 is -C(O)-. In someembodiments, L10 is -C(O)NH-. In some embodiments, L10 is -NHC(O)-. In some embodiments,L10 is -S(O)2NH-. In some embodiments, L10 is -NHS(O)2-.

[0127] In some embodiments, Y4 is N or CR4. In some embodiment, Y4 is N. In someembodiment, Y4 is CR4.

[0128] In some embodiments, R4 is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN. In some embodiment, R4 isH. In some embodiments, R4 is (C1-5)alkyl. In some embodiments, R4 is (C1)alkyl. In someembodiments, R4 is (C2)alkyl. In some embodiments, R4 is (C3)alkyl. In some embodiments, R4is (C4)alkyl. In some embodiments, R4 is (C5)alkyl. In some embodiments, R4 is substituted (C1-5)alkyl. In some embodiments, R4 is substituted (C1)alkyl. In some embodiments, R4 issubstituted (C2)alkyl. In some embodiments, R4 is substituted (C3)alkyl. In some embodiments,R4 is substituted (C4)alkyl. In some embodiments, R4 is substituted (C5)alkyl. In someembodiments, R4 is (C1-5)alkoxy. In some embodiments, R4 is (C1)alkoxy. In some embodiments,R4 is (C2)alkoxy. In some embodiments, R4 is (C3)alkoxy. In some embodiments, R4 is(C4)alkoxy. In some embodiments, R4 is (C5)alkoxy. In some embodiments, R4 is substituted (C1-5)alkoxy. In some embodiments, R4 is substituted (C1)alkoxy. In some embodiments, R4 issubstituted (C2)alkoxy. In some embodiments, R4 is substituted (C3)alkoxy. In someembodiments, R4 is substituted (C4)alkoxy. In some embodiments, R4 is substituted (C5)alkoxy.In some embodiments, R4 is haloalkyl. In some embodiments, R4 is halogen. In someembodiments, R4 is OH. In some embodiments, R4 is CN.

[0129] In some embodiments, R5 is or . In somembodiments, R5e is . In some embodiments, R5 is .

[0130] In some emclic group selected from carbaryl,heteroaryl, and substituted versions thereof. In some embodiments, A is a cyclic group. In someembodiments, A is carbocyclyl. In some embodiments, A is heterocyclyl. In some embodiments,A is aryl. In some embodiments, A is heteroaryl. In some embodiments, any one of the precedingA is a substituted version thereof.

[0131] In some embodiments, Z is selected from a bond, sulfonyl, sulfone, sulfoxide, sulfide,sulfonate ester, sulfonamide, sulfimide, sulfinamide, sulfenamide, sulfoximine, sulfonimidamide, sulfonate, sulfondiimine, sulfondiimidamide, carboxamide, carboxy, hydroxy, hydroxyalkyl,aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, ether, urea, thiourea, and aliphatic group, orZ is a divalent moiety that links to L’ or L”. In some embodiments, Z is a bond. In someembodiments, Z is sulfonyl. In some embodiments, Z is sulfone. In some embodiments, Z issulfoxide. In some embodiments, Z is sulfide. In some embodiments, Z is sulfonate ester. Insome embodiments, Z is sulfonamide. In some embodiments, Z is sulfonate. In someembodiments, Z is sulfinamide. In some embodiments, Z is sulfenamide. In some embodiments,Z is sulfoximine. In some embodiments, Z is sulfonimidamide. In some embodiments, Z issulfondiimine. In some embodiments, Z is sulfondiimidamide. In some embodiments, Z iscarboxamide. In some embodiments, Z is carboxy. In some embodiments, Z is hydroxy. In someembodiments, Z is hydroxyalkyl. In some embodiments, Z is aldehyde. In some embodiments, Zis ester. In some embodiments, Z is alkoxy. In some embodiments, Z is nitrile. In someembodiments, Z is halogen. In some embodiments, Z is thiolactone. In some embodiments, Z isether. In some embodiments, Z is urea. In some embodiments, Z is thiourea. In someembodiments, Z is an aliphatic group. In some embodiments, Z is a divalent moiety that links toL’ or L”.

[0132] In some embodiments, L1 and L2 are optional linkers. In some embodiments, L1 is anoptional linker. In some embodiments, L2 is an optional linker.

[0133] In some embodiments, R6 is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN. In some embodiment, R6 isH. In some embodiments, R6 is (C1-5)alkyl. In some embodiments, R6 is (C1)alkyl. In someembodiments, R6 is (C2)alkyl. In some embodiments, R6 is (C3)alkyl. In some embodiments, R6is (C4)alkyl. In some embodiments, R6 is (C5)alkyl. In some embodiments, R6 is substituted (C1-5)alkyl. In some embodiments, R6 is substituted (C1)alkyl. In some embodiments, R6 issubstituted (C2)alkyl. In some embodiments, R6 is substituted (C3)alkyl. In some embodiments,R6 is substituted (C4)alkyl. In some embodiments, R6 is substituted (C5)alkyl. In someembodiments, R6 is (C1-5)alkoxy. In some embodiments, R6 is (C1)alkoxy. In some embodiments,R6 is (C2)alkoxy. In some embodiments, R6 is (C3)alkoxy. In some embodiments, R6 is(C4)alkoxy. In some embodiments, R6 is (C5)alkoxy. In some embodiments, R6 is substituted (C1-5)alkoxy. In some embodiments, R6 is substituted (C1)alkoxy. In some embodiments, R6 issubstituted (C2)alkoxy. In some embodiments, R6 is substituted (C3)alkoxy. In someembodiments, R6 is substituted (C4)alkoxy. In some embodiments, R6 is substituted (C5)alkoxy.In some embodiments, R6 is haloalkyl. In some embodiments, R6 is halogen. In someembodiments, R6 is OH. In some embodiments, R6 is CN.

[0134] In some embodiments, one of R3 and R5 comprises the divalent moiety that links to L’ orL”. In some embodiments, R3 comprises the divalent moiety that links to L’ or L”. In someembodiments, R5 comprises the divalent moiety that links to L’ or L”.

[0135] In some embodiments of Formula (I), the CDK-BM is of Formula (IA) or Formula (IB):In some embodiments, the CDK-BM is of Formula (IA). In some embodiments, the CDK-BM isof Formula (IB).

[0136] In some embodiments of Formula (I), Formula (IA), or Formula(IB), the CDK-BM is ofFormula (IIA) or Formula (IIB):wherein:Y6 to Y10 are independently C-Z, CR12, or N; andeach R12is independently selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, and CN.

[0137] In some embodiments, Y6 to Y10 are independently C-Z, CR12, or N. In someembodiments, Y6 is C-Z. In some embodiments, Y6 is CR12. In some embodiments, Y6 is N. Insome embodiments, Y7is C-Z. In some embodiments, Y7is CR12. In some embodiments, Y7isN. In some embodiments, Y8 is C-Z. In some embodiments, Y8 is CR12. In some embodiments,Y8 is N. In some embodiments, Y9 is C-Z. In some embodiments, Y9 is CR12. In someembodiments, Y9 is N. In some embodiments, Y10 is C-Z. In some embodiments, Y10 is CR12. Insome embodiments, Y10is N.

[0138] In some embodiments, each R12 is independently selected from H, (C1-5)alkyl, substituted(C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, and CN. In some embodiment,R12 is H. In some embodiments, R12 is (C1-5)alkyl. In some embodiments, R12 is (C1)alkyl. Insome embodiments, R12 is (C2)alkyl. In some embodiments, R12 is (C3)alkyl. In someembodiments, R12 is (C4)alkyl. In some embodiments, R12 is (C5)alkyl. In some embodiments,R12 is substituted (C1-5)alkyl. In some embodiments, R12 is substituted (C1)alkyl. In someembodiments, R12 is substituted (C2)alkyl. In some embodiments, R12 is substituted (C3)alkyl. Insome embodiments, R12 is substituted (C4)alkyl. In some embodiments, R12 is substituted(C5)alkyl. In some embodiments, R12 is (C1-5)alkoxy. In some embodiments, R12 is (C1)alkoxy. Insome embodiments, R12 is (C2)alkoxy. In some embodiments, R12 is (C3)alkoxy. In someembodiments, R12 is (C4)alkoxy. In some embodiments, R12 is (C5)alkoxy. In someembodiments, R12 is substituted (C1-5)alkoxy. In some embodiments, R12 is substituted(C1)alkoxy. In some embodiments, R12 is substituted (C2)alkoxy. In some embodiments, R12 issubstituted (C3)alkoxy. In some embodiments, R12 is substituted (C4)alkoxy. In someembodiments, R12 is substituted (C5)alkoxy. In some embodiments, R12 is halogen. In someembodiments, R12 is OH. In some embodiments, R12 is CN.

[0139] In some embodiments of Formula (IIA) or Formula (IIB), one and only one of Y6 to Y10is C-Z. In some embodiments, Y6 is C-Z. In some embodiments, Y7 is C-Z. In someembodiments, Y8 is C-Z. In some embodiments, Y9 is C-Z. In some embodiments, Y10 is C-Z.

[0140] In some embodiments of Formula (IIA) or Formula (IIB), one or two of Y6, Y7, Y8, Y9, orY10 is N. In some embodiments, Y6 is N. In some embodiments, Y7 is N, In some embodiments,Y8 is N. In some embodiments, Y9 is N. In some embodiments, Y10 is N. In some embodimentsY6and Y7are N. In some embodiments Y6and Y8are N. In some embodiments Y6and Y9are N.In some embodiments Y6 and Y10 are N. In some embodiments Y7 and Y8 are N. In someembodiments Y7 and Y9 are N. In some embodiments Y7 and Y10 are N. In some embodimentsY8 and Y9 are N. In some embodiments Y8 and Y10 are N. In some embodiments Y9 and Y10 areN.

[0141] In some embodiments of Formula (IIA) or Formula (IIB), four of Y6 to Y10 are CR12. Insome embodiments Y6, Y7, Y8, and Y9 are CR12. In some embodiments Y6, Y7, Y8, and Y10 areCR12. In some embodiments Y6, Y7, Y9, and Y10 are CR12. In some embodiments Y6, Y8, Y9, andY10 are CR12. In some embodiments Y7, Y8, Y9, and Y10 are CR12. In some embodiments, eachR12is H.

[0142] In some embodiments of Formula (IIA) or Formula (IIB), the CDK-BM is of one ofFormula (IIIB) to Formula (IIIJ):wherein R12is H, () y , ( ) y , ( ) y, (C1-5)alkoxy, halogen, OH, or CN.

[0143] In some embodiment, R12 is H. In some embodiments, R12 is (C1-5)alkyl. In someembodiments, R12 is (C1)alkyl. In some embodiments, R12 is (C2)alkyl. In some embodiments,R12 is (C3)alkyl. In some embodiments, R12 is (C4)alkyl. In some embodiments, R12 is (C5)alkyl.In some embodiments, R12 is substituted (C1-5)alkyl. In some embodiments, R12 is substituted(C1)alkyl. In some embodiments, R12 is substituted (C2)alkyl. In some embodiments, R12 issubstituted (C3)alkyl. In some embodiments, R12 is substituted (C4)alkyl. In some embodiments,R12 is substituted (C5)alkyl. In some embodiments, R12 is (C1-5)alkoxy. In some embodiments,R12 is (C1)alkoxy. In some embodiments, R12 is (C2)alkoxy. In some embodiments, R12 is(C3)alkoxy. In some embodiments, R12 is (C4)alkoxy. In some embodiments, R12 is (C5)alkoxy.In some embodiments, R12 is substituted (C1-5)alkoxy. In some embodiments, R12 is substituted(C1)alkoxy. In some embodiments, R12 is substituted (C2)alkoxy. In some embodiments, R12 issubstituted (C3)alkoxy. In some embodiments, R12 is substituted (C4)alkoxy. In someembodiments, R12 is substituted (C5)alkoxy. In some embodiments, R12 is halogen. In someembodiments, R12 is OH. In some embodiments, R12 is CN.

[0144] In some embodiments of Formula (I), Formula (IA), or Formula (IB), the CDK-BM is ofFormula (IIC) or Formula (IID):wherein:each R11 is independently selected from H, (C1-5)alkyl, substituted (C1-5)alkyl,(C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, and CN; and i is from 0 to 9.

[0145] In some embodiments, each R11 is independently selected from H, (C1-5)alkyl, substituted(C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, and CN. In some embodiment,R11 is H. In some embodiments, R11 is (C1-5)alkyl. In some embodiments, R11 is (C1)alkyl. Insome embodiments, R11 is (C2)alkyl. In some embodiments, R11 is (C3)alkyl. In someembodiments, R11 is (C4)alkyl. In some embodiments, R11 is (C5)alkyl. In some embodiments,R11 is substituted (C1-5)alkyl. In some embodiments, R11 is substituted (C1)alkyl. In someembodiments, R11 is substituted (C2)alkyl. In some embodiments, R11 is substituted (C3)alkyl. Insome embodiments, R11 is substituted (C4)alkyl. In some embodiments, R11 is substituted(C5)alkyl. In some embodiments, R11 is (C1-5)alkoxy. In some embodiments, R11 is (C1)alkoxy. Insome embodiments, R11 is (C2)alkoxy. In some embodiments, R11 is (C3)alkoxy. In someembodiments, R11 is (C4)alkoxy. In some embodiments, R11 is (C5)alkoxy. In someembodiments, R11 is substituted (C1-5)alkoxy. In some embodiments, R11 is substituted(C1)alkoxy. In some embodiments, R11 is substituted (C2)alkoxy. In some embodiments, R11 issubstituted (C3)alkoxy. In some embodiments, R11 is substituted (C4)alkoxy. In someembodiments, R11 is substituted (C5)alkoxy. In some embodiments, R11 is halogen. In someembodiments, R11 is OH. In some embodiments, R11 is CN.

[0146] In some embodiments, i is from 0 to 9. In some embodiments, i is 0. In someembodiments, i is 1. In some embodiments, i is 2. In some embodiments, i is 3. In someembodiments, i is 4. In some embodiments, i is 5. In some embodiments, i is 6. In someembodiments, i is 7. In some embodiments, i is 8. In some embodiments, i is 9.

[0147] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),R3is selected from (C1-5)alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, (C1-3)alkylene- cycloalkyl, (C1-3)alkylene-heterocycle, (C1-3)alkylene-phenyl, (C1-3)alkylene-heteroaryl, andsubstituted versions thereof. In some embodiments, R3 is optionally substituted (C1-5)alkyl. Insome embodiments, R3 is optionally substituted (C1)alkyl. In some embodiments, R3 isoptionally substituted (C2)alkyl. In some embodiments, R3 is optionally substituted (C3)alkyl. Insome embodiments, R3 is optionally substituted (C4)alkyl. In some embodiments, R3 isoptionally substituted (C5)alkyl. In some embodiments, R3 is optionally substituted cycloalkyl. Insome embodiments, R3 is optionally substituted heterocycle. In some embodiments, R3 isoptionally substituted aryl. In some embodiments, R3 is optionally substituted heteroaryl. Insome embodiments, R3 is optionally substituted (C1-3)alkylene-cycloalkyl. In some embodiments,R3 is optionally substituted (C1)alkylene-cycloalkyl. In some embodiments, R3 is optionallysubstituted (C2)alkylene-cycloalkyl. In some embodiments, R3 is optionally substituted(C3)alkylene-cycloalkyl. In some embodiments, R3 is optionally substituted (C1-3)alkylene-heterocycle. In some embodiments, R3 is optionally substituted (C1)alkylene-heterocycle. Insome embodiments, R3 is optionally substituted (C2)alkylene-heterocycle. In some embodiments,R3 is optionally substituted (C3)alkylene-heterocycle. In some embodiments, R3 is optionallysubstituted (C1-3)alkylene-phenyl. In some embodiments, R3 is optionally substituted(C1)alkylene-phenyl. In some embodiments, R3 is optionally substituted (C2)alkylene-phenyl. Insome embodiments, R3 is optionally substituted (C3)alkylene-phenyl. In some embodiments, R3is optionally substituted (C1-3)alkylene-heteroaryl. In some embodiments, R3 is optionallysubstituted (C1)alkylene-heteroaryl. In some embodiments, R3 is optionally substituted(C2)alkylene-heteroaryl. In some embodiments, R3 is optionally substituted (C3)alkylene-heteroaryl.

[0148] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),L10 is -O-. In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ), L10 is a bond. In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or(IIIA)-(IIIJ), L10 is -CH2-.[014 nts of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),L10 is -O-; and R3 is –(CH2)k-cycloalkyl (e.g., cyclohexyl or cyclopentyl), wherein k is 1, or 2. Insome embodiments, L10 is -O-; and R3 is –(CH2)-cycloalkyl. In some embodiments, L10 is -O-;and R3 is –(CH2)2-cycloalkyl.

[0150] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),R1is CF3.

[0151] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),R6is H.

[0152] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),Y4is N.

[0153] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),Y4is CH.

[0154] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),L1and L2are absent.

[0155] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ), Zis or comprises a group selected from sulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine,sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof. In some embodiments, Z is orcomprises a sulfonyl. In some embodiments, Z is or comprises a sulfone. In some embodiments,Z is or comprises a sulfonamide. In some embodiments, Z is or comprises a sulfimide. In someembodiments, Z is or comprises a sulfoximine. In some embodiments, Z is or comprises asulfonimidamide. In some embodiments, Z is or comprises a sulfonate. In some embodiments, Zis or comprises a carboxamide. In some embodiments, Z is or comprises a carboxy. In someembodiments, Z is or comprises a hydroxy. In some embodiments, Z is or comprises ahydroxyalkyl. In some embodiments, Z is or comprises an aldehyde. In some embodiments, Z isor comprises an ester. In some embodiments, Z is or comprises an alkoxy. In some embodiments,Z is or comprises a nitrile. In some embodiments, Z is or comprises a halogen. In someembodiments, Z is or comprises a thiolactone.

[0156] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ), Zis alkylsulfoximine, cycloalkylsulfoximine, heterocyclylsulfoximine, sulfonamide, oralkylsulfonamide. In some embodiments, Z is alkylsulfoximine. In some embodiments, Z iscycloalkylsulfoximine. In some embodiments, Z is heterocyclylsulfoximine. In someembodiments, Z is sulfonamide. In some embodiments, Z is alkylsulfonamide.

[0157] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),-L2-Z or Z is of one of Formula (Z1) to Formula (Z6):3),);wherein:Y11 is absent, -O-, -NR9-, -(C1-6)alkylene-O-, or -(C1-6)alkylene-NR9-;X11is O or NH; R51 is selected from halogen, R8, and -NR9R10;R8 is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substitutedversion thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl, a sulfone, or a thiolactone; R52is H, optionally substituted (C1-6)alkyl, optionally substituted aryl, or optionally substituted heterocyclyl;h is 0, 1 or 2; andp, q, s, and t are independently 0, 1, 2, 3, 4, 5, or 6.

[0158] In some embodiments, Y11 is absent, -O-, -NR9-, -(C1-6)alkylene-O-, or -(C1-6)alkylene-NR9-. In some embodiments, Y11 is absent. In some embodiments, Y11 is -O-. In someembodiments, Y11 is -NR9-. In some embodiments, Y11 is -(C1-6)alkylene-O-. In someembodiments, Y11 is -(C1)alkylene-O-. In some embodiments, Y11 is -(C2)alkylene-O-. In someembodiments, Y11 is -(C3)alkylene-O-. In some embodiments, Y11 is -(C4)alkylene-O-. In someembodiments, Y11 is -(C5)alkylene-O-. In some embodiments, Y11 is -(C6)alkylene-O-. In someembodiments, Y11 is -(C1-6)alkylene-NR9. In some embodiments, Y11 is -(C1)alkylene-NR9. Insome embodiments, Y11 is -(C2)alkylene-NR9. In some embodiments, Y11 is -(C3)alkylene-NR9.In some embodiments, Y11 is -(C4)alkylene-NR9. In some embodiments, Y11 is -(C5)alkylene-NR9. In some embodiments, Y11 is -(C6)alkylene-NR9.

[0159] In some embodments, X11 is O or NH. In some embodiments, X11 is O. In someembodiments, X11 is NH.

[0160] In some embodiments, R51 is selected from halogen, R8, and -NR9R10. In someembodiments, R51 is halogen. In some embodiments, R51 is R8. In some embodiments, R51 is -NR9R10.

[0161] In some embodiments, R8 is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl,heterocyclyl, or a substituted version thereof. In some embodiments, R8 is optionally substituted(C1-6)alkyl. In some embodiments, R8 is optionally substituted (C1)alkyl. In some embodiments,R8 is optionally substituted (C2)alkyl. In some embodiments, R8 is optionally substituted(C3)alkyl. In some embodiments, R8 is optionally substituted (C4)alkyl. In some embodiments,R8 is optionally substituted (C5)alkyl. In some embodiments, R8 is optionally substituted(C6)alkyl. In some embodiments, R8 is optionally substituted (C2-6)alkenyl. In someembodiments, R8 is optionally substituted (C2)alkenyl. In some embodiments, R8 is optionallysubstituted (C3)alkenyl. In some embodiments, R8 is optionally substituted (C4)alkenyl. In someembodiments, R8 is optionally substituted (C5)alkenyl. In some embodiments, R8 is optionallysubstituted (C6)alkenyl. In some embodiments, R8 is optionally substituted (C2-6)alkynyl. In someembodiments, R8 is optionally substituted (C2)alkynyl. In some embodiments, R8 is optionallysubstituted (C3)alkynyl. In some embodiments, R8 is optionally substituted (C4)alkynyl. In someembodiments, R8 is optionally substituted (C5)alkynyl. In some embodiments, R8 is optionallysubstituted (C6)alkynyl. In some embodiments, R8 is optionally substituted cycloalkyl. In someembodiments, R8 is optionally substituted heterocyclyl.

[0162] In some embodiments, R9 is H or optionally substituted (C1-6)alkyl. In someembodiments, R9 is H. In some embodiments, R9 is optionally substituted (C1-6)alkyl. In someembodiments, R9 is optionally substituted (C1)alkyl. In some embodiments, R9 is optionallysubstituted (C2)alkyl. In some embodiments, R9 is optionally substituted (C3)alkyl. In someembodiments, R9 is optionally substituted (C4)alkyl. In some embodiments, R9 is optionallysubstituted (C5)alkyl. In some embodiments, R9 is optionally substituted (C6)alkyl.

[0163] In some embodiments, R10 is H, optionally substituted (C1-6)alkyl, optionally substituted(C3-8)cycloalkyl, optionally substituted heterocyclyl, a sulfone, or a thiolactone. In someembodiments, R10 is H. In some embodiments, R10 is optionally substituted (C1-6)alkyl. In someembodiments, R10 is optionally substituted (C1)alkyl. In some embodiments, R10 is optionallysubstituted (C2)alkyl. In some embodiments, R10 is optionally substituted (C3)alkyl. In someembodiments, R10 is optionally substituted (C4)alkyl. In some embodiments, R10 is optionallysubstituted (C5)alkyl. In some embodiments, R10 is optionally substituted (C6)alkyl. In someembodiments, R10 is optionally substituted (C3-8)cycloalkyl. In some embodiments, R10 isoptionally substituted (C3)cycloalkyl. In some embodiments, R10 is optionally substituted(C4)cycloalkyl. In some embodiments, R10 is optionally substituted (C5)cycloalkyl. In someembodiments, R10 is optionally substituted (C6)cycloalkyl. In some embodiments, R10 isoptionally substituted (C7)cycloalkyl. In some embodiments, R10 is optionally substituted(C8)cycloalkyl. In some embodiments, R10 is optionally substituted heterocyclyl. In someembodiments, R10 is a sulfone. In some embodiments, R10 is a thiolactone.

[0164] In some embodiments, R52 is H, optionally substituted (C1-6)alkyl, optionally substitutedaryl, or optionally substituted heterocyclyl. In some embodiments, R52 is H. In someembodiments, R52 is optionally substituted (C1-6)alkyl. In some embodiments, R52 is optionallysubstituted (C1)alkyl. In some embodiments, R52 is optionally substituted (C2)alkyl. In someembodiments, R52 is optionally substituted (C3)alkyl. In some embodiments, R52 is optionallysubstituted (C4)alkyl. In some embodiments, R52 is optionally substituted (C5)alkyl. In someembodiments, R52 is optionally substituted (C6)alkyl. In some embodiments, R52 is optionallysubstituted aryl. In some embodiments, R10 is optionally substituted heterocyclyl.

[0165] In some embodiments, h is 0, 1 or 2. In some embodiments, h is 0. In some embodiments,h is 1. In some embodiments, h is 2.

[0166] In some embodiments, p, q, s, and t are independently 0, 1, 2, 3, 4, 5, or 6. In someembodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In someembodiments, p is 6. In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In someembodiments, q is 5. In some embodiments, q is 6. In some embodiments, s is 0. In someembodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In someembodiments, s is 4. In some embodiments, s is 5. In some embodiments, s is 6. In someembodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. In some embodiments, t is 6.

[0167] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),-L2-Z or Z is of Formula (Z1) and is of one of the following structures:);wherein R10 is H, optionally s- y , y bstituted (C3-8)cycloalkyl, oroptionally substituted heterocyclyl.

[0168] In some embodiments, R10 is H. In some embodiments, R10 is optionally substituted(C1-6)alkyl. In some embodiments, R10 is optionally substituted (C1)alkyl. In some embodiments,R10 is optionally substituted (C2)alkyl. In some embodiments, R10 is optionally substituted(C3)alkyl. In some embodiments, R10 is optionally substituted (C4)alkyl. In some embodiments,R10 is optionally substituted (C5)alkyl. In some embodiments, R10 is optionally substituted(C6)alkyl. In some embodiments, R10 is optionally substituted (C3-8)cycloalkyl. In someembodiments, R10 is optionally substituted (C3)cycloalkyl. In some embodiments, R10 isoptionally substituted (C4)cycloalkyl. In some embodiments, R10 is optionally substituted(C5)cycloalkyl. In some embodiments, R10 is optionally substituted (C6)cycloalkyl. In someembodiments, R10 is optionally substituted (C7)cycloalkyl. In some embodiments, R10 isoptionally substituted (C8)cycloalkyl. In some embodiments, R10 is optionally substitutedheterocyclyl.

[0169] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),-L2-Z or Z is ; and R8 is optionally substituted (C3-7)cycloalkyl, optionally substituted(C2-6)heteroca divalent moiety that links to L’ or L”. In some embodiments of any oneof Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),-L2-Z or Z is ; and R8 is optionally substituted (C3-7)cycloalkyl, or optionallysubstituted (C2-6)heterocyclyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C3-7)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C3)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C4)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C5)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C6)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C7)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 isoptionally substituted (C2-6)heterocyclyl. In some embodiments, -L2-Z or Z ; and R8is optionally substituted (C2)heterocyclyl. In some embodiments, -L2-Z or Z i ; and R8is optionally substituted (C3)heterocyclyl. In some embodiments, -L2-Z or Zis ; and R8is optionally substituted (C4)heterocyclyl. In some embodiments, -L2-Z or Z is ; and R8is optionally substituted (C5)heterocyclyl. In some embodiments, -L2-Z or Z i ; and R8is optionally substituted (C6)heterocyclyl. In some embodiments, -L2-Z or Z i ; and R8is a divalent moiety that links to L’ or L”.

[0170] In some embodiments, -L2-Z or Z i ; and R8 is (C3-4)cycloalkyl, (C2-4)heterocyclyl, or a divalent moiety that linor L”. In some embodiments, -L2-Z or Z is; and R8 is (C3-4)cycloalkyl or (C2-4)heterocyclyl. In some embodiments, -L2-Z or Z is;and R8 is (C3-4)cycloalkyl. In some embodiments, -L2-Z or Z ; and R8 is(C3)cycloalkyl. In some embodiments, -L2-Z or Z is ; and R8 is (C4)cycloalkyl. In someembodiments, -L2-Z or Z is ; and R8 is (C2-4)heterocyclyl. In some embodiments, -L2-Zor Z is ; and R8 is (C2)heterocyclyl. In some embodiments, -L2-Z or Z ; andR8 is (C3)heterocyclyl. In some embodiments, -L2-Z or Z i ; and R8 is(C4)heterocyclyl. In some embodiments, -L2-Z or Z i ; and R8 is a divalent moiety thatlinks to L’ or L”.

[0171] In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),-L2-Z or Z is ; R9 is H; and R10 is H, optionally substituted (C1-6)alkyl, or a divalentmoiety that lr L”. In some embodiments of any one of Formula (I), (IA)-(IB), (IIA)-(IID), or (IIIA)-(IIIJ),-L2-Z or Z is ; R9 is H; and R10 is H or optionally substituted (C1-6)alkyl. In someembodiments, -L2-Z or Z i ; R9 is H; and R10 is H. In some embodiments, -L2-Z or Zis ; R9 is H; and R10 is optionally substituted (C1-6)alkyl. In some embodiments, -L2-Z or Z is ; R9 is H; and R10 is optionally substituted (C1)alkyl. In some embodiments,-L2-Z or Z is ; R9 is H; and R10 is optionally substituted (C2)alkyl. In someembodiments, -L2-Z or Z i ; R9 is H; and R10 is optionally substituted (C3)alkyl. Insome embodiments, -L2-Z or Z i 9 10; R is H; and R is optionally substituted(C4)alkyl. In some embodiments, -L2-Z or Z i 9 10; R is H; and R is optionallysubstituted (C5)alkyl. In some embodiments, -L2-Z or Z ; R9 is H; and R10 isoptionally substituted (C6)alkyl. In some embodiments, -L2-Z or Z ; R9 is H; andR10 is a divalent moiety that links to L’ or L”.

[0172] In some embodiments of any one of Formula (Z1) to Formula (Z6), Formula (Z1B), orFormula (Z1C), X11 is O.

[0173] In some embodiments of any one of Formula (Z1) to Formula (Z6), Formula (Z1B), orFormula (Z1C), X11 is NH.

[0174] In some embodiments, the CDK-BM is of the structure:.

[0175] Examples of compounds described herein include those listed in Tables and exemplifiedherein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the present disclosure comprises a compound selected from thosedepicted in Table 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture ofstereoisomers thereof.

[0176] In some embodiments, a compound of the present disclosure is selected from Table 1, ora pharmaceutically acceptable salt thereof. Table 1. Compounds of the present disclosure3.3. Pharmaceutical Compositions

[0177] Pharmaceutical compositions of the present disclosure comprise at least one compound ofFormula (I), or a tautomer, stereoisomer, or a mixture of stereoisomers, or a pharmaceuticallyacceptable salt, or hydrate, or deuterated derivative thereof formulated together with one or morepharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal,topical, buccal, and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous)administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

[0178] Formulations suitable for oral administration may be presented in discrete units, such ascapsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step ofbringing into association at least one compound of the present disclosure as the active compoundand a carrier or excipient (which may constitute one or more accessory ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the at least one active compound. Other pharmacologically active substances may also be present including other compounds. The formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.

[0179] For solid compositions, conventional nontoxic solid carriers include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can be prepared by, for example, dissolving or dispersing, at leastone active compound of the present disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulationsmay be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free- flowing form, such as a powder or granules, which may be optionally mixed with a binder,lubricant, inert diluent, and / or surface active / dispersing agent(s). Molded tablets may be made bymolding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.

[0180] Compounds of the present disclosure can be prepared and administered in a wide varietyof oral, parenteral, and topical dosage forms. Thus, the compounds of the present disclosure can be administered by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). In some embodiments, compounds of the present disclosure are administered orally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present disclosure can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer compounds of the disclosure. Accordingly, the present disclosure also provides pharmaceutical compositions comprising pharmaceutically acceptable carrier or excipient and one or more compounds of the disclosure.

[0181] For preparing pharmaceutical compositions from the compounds of the presentdisclosure, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0182] In powders, the carrier is finely divided solid in a mixture with the finely divided activecomponent. In tablets, the active component is mixed with the carrier having the necessarybinding properties in suitable proportions and compacted in the shape and size desired.

[0183] Formulations suitable for buccal (sub-lingual) administration include lozengescomprising at least one compound of the present disclosure in a flavored base, usually sucroseand acacia or tragacanth, and pastilles comprising the at least one compound in an inert basesuch as gelatin and glycerin or sucrose and acacia.

[0184] Formulations of the present disclosure suitable for parenteral administration comprisesterile aqueous preparations of at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosuremay contain from 0.1% to 5% w / w of the active compound.

[0185] Formulations suitable for rectal administration are presented as unit-dose suppositories.These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0186] Formulations suitable for topical application to the skin may take the form of anointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound (i.e., at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof) is generally present at aconcentration of from 0.1% to 15% w / w of the composition, for example, from 0.5% to 2%.3.3.1. Effective Dosages

[0187] Pharmaceutical compositions provided by the present disclosure include compositionswherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, whenadministered in methods to treat cancer, such compositions will contain an amount of activeingredient effective to achieve the desired result (e.g., inhibiting and / or degrading CDK2 and / or decreasing an amount of CDK2 in a subject).

[0188] The dosage and frequency (single or multiple doses) of compound administered can varydepending upon a variety of factors, including route of administration; size, age, sex, health,body weight, body mass index, and diet of the recipient; nature and extent of the symptoms ofthe disease being treated (e.g., the disease responsive treatment); and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the disclosure.

[0189] For any provided compound or test agent, the therapeutically effective amount can beinitially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing CDK2 expressed in a subject.

[0190] Therapeutically effective amounts for use in humans may be determined from animalmodels. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring biomarkers associated with cancer and adjusting the dosage upwards or downwards, as described above.

[0191] Dosages may be varied depending upon the requirements of the patient and thecompound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.

[0192] In some embodiments, a compound of the disclosure or a pharmaceutical compositioncomprising the same is provided as a unit dose.

[0193] The amount of active compound administered may be dependent on the subject beingtreated, the subject’s weight, the manner of administration, and the judgment of the prescribingphysician. For example, a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of 1 µg to 1000 mg. In another embodiment, intermittent administration, such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed. Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect. In accordance with standard dosing regimens, physicians will readily determine optimumdosages and will be able to readily modify administration to achieve such dosages.

[0194] A therapeutically effective amount of a compound or composition disclosed herein can bemeasured by the therapeutic effectiveness of the compound. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration. Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.

[0195] Toxicity and therapeutic efficacy can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50.

[0196] Data obtained from the cell culture assays or animal studies can be used in formulating arange of dosage for use in humans. Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factorsknown in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966)and Table 2 below for Equivalent Surface Area Dosage Factors). Table 2. Equivalent Surface Area Dosage Factors.To: Mouse Rat Monkey Dog Human

[0197] The dosage of such compounds lies, for example, within a range of circulatingconcentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject’s age, condition, andgender, as well as the severity of the medical condition in the subject. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0198] In some embodiments, the disclosure provides a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formula (I), or a tautomer, stereoisomer ora mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuteratedderivative thereof, and one or more of a pharmaceutically acceptable carrier, a pharmaceuticallyacceptable vehicle, a pharmaceutically acceptable excipient, or combinations thereof.

[0199] The compounds of the disclosure can be administered alone or can be co-administered tothe subject. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0200] In some embodiments, a compound as described herein can be incorporated into apharmaceutical composition for administration by methods known to those skilled in the art and described herein for provided compounds. 3.3.2. Methods of Treatment

[0201] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or amixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, is administered to treat cancer in a subject in need thereof. In someembodiments, the cancer is a CDK2-associated cancer. In some embodiments, the CDK2-associated cancer is chosen from breast cancer, breast invasive ductal carcinoma, lung cancer,lung adenocarcinoma, pancreatic cancer, small bowel cancer, colon adenocarcinoma, colorectalcancer, gall bladder cancer, thyroid cancer, liver cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer. In some embodiments, the cancer is breast cancer. In some embodiments, thecancer is breast invasive ductal carcinoma. In some embodiments, the cancer is lung cancer. Insome embodiments, the cancer is lung adenocarcinoma. In some embodiments, the lung cancer isnon-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer. In someembodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, thecancer is small bowel cancer. In some embodiments, the cancer is colon adenocarcinoma. Insome embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gallbladder cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, thecancer is liver cancer. In some embodiments, the cancer is bile duct cancer. In someembodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrialcancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer isbladder cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, thecancer is esophageal cancer. In some embodiments, the cancer is blood cancer. In someembodiments, the therapeutic treatment is for the treatment of diseases and conditions associatedwith CDK2.

[0202] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or amixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, is administered as a pharmaceutical composition.

[0203] In some embodiments, the disclosure provides for methods for treating cancer in a subject(e.g., patient) in need thereof, comprising (a) determining that the cancer is associated with aCDK2; and (b) administering to the subject a therapeutically effective amount of at least onecompound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or apharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, or apharmaceutical composition comprising at least one compound of Formula (I) or a tautomer,stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof.

[0204] In some embodiments, the disclosure provides for methods for treating a cancerassociated with CDK2 in a subject (e.g., patient) in need thereof, comprising administering to thesubject a therapeutically effective amount of at least one compound of Formula (I) or a tautomer,stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, or a pharmaceutical composition comprising at least onecompound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, or apharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof. In certain of suchembodiments, the cancer has been determined to be associated with CDK2 and / or the patient hasbeen diagnosed as suffering from a cancer associated with CDK2.

[0205] In some embodiments, the disclosure provides for methods for inhibiting and / ordegrading CDK2 in a cell, comprising contacting the cell with at least one compound of Formula(I) or a tautomer, stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptablesalt, or hydrate, or deuterated derivative thereof, or a pharmaceutical composition comprising atleast one compound of Formula (I) or a tautomer, stereoisomer or a mixture of stereoisomers, ora pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof.

[0206] In some embodiments, the disclosure provides for methods for degrading CDK2 in a cell,comprising contacting the cell in which degradation of CDK2 is desired with an effective amountof a compound of Formula (I), pharmaceutically acceptable salts thereof, or pharmaceuticalcompositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0207] As used herein, the term “contacting” refers to the bringing together of indicated moietiesin an in vitro system or an in vivo system. For example, “contacting” CDK2 with a compoundprovided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having CDK2, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing CDK2.

[0208] In some embodiments, a cell in which degradation of CDK2 is desired is contacted withan effective amount of a compound of Formula (I) to negatively modulate CDK2. In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I) may be used.

[0209] By negatively modulating CDK2 (e.g., by degradation), the methods described herein aredesigned to halt undesired cellular proliferation resulting from enhanced CDK2 presence withinthe cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of CDK2.

[0210] The concentration and route of administration to the patient will vary depending on thecancer to be treated.

[0211] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or amixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, is administered in combination with another therapeutic agent, e.g.,chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0212] In some embodiments, a compound of Formula (I), or a tautomer, stereoisomer or amixture of stereoisomers, or a pharmaceutically acceptable salt, or hydrate, or deuterated derivative thereof, is administered with an additional anti-cancer agent. In some embodiments,the compound of Formula (I) and / or the pharmaceutical composition comprising the compoundof Formula (I), and the additional anti-cancer agent are administered concomitantly. In someembodiments, the compound of Formula (I) and / or the pharmaceutical composition comprisingthe compound of Formula (I), and the additional anti-cancer agent are administered sequentially.

[0213] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable saltor solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0214] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable saltor solvate / hydrate thereof, or a pharmaceutical composition thereof, as defined herein, for use inthe treatment of cancer.

[0215] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable saltor solvate thereof, for use in the inhibition and / or degradation of CDK2.

[0216] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable saltor solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in thetreatment of a CDK2-associated disease or disorder.

[0217] Also provided herein is the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for thetreatment of cancer.

[0218] Also provided herein is a use of a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for theinhibition of activity and / or degradation of CDK2.

[0219] Also provided herein is the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a CDK2-associated disease or disorder.

[0220] One skilled in the art will recognize that both in vivo and in vitro trials using suitable,known, and generally accepted cell and / or animal models are predictive of the ability of a testcompound to treat or prevent a given disorder.4. EXAMPLES

[0221] The examples and preparations provided below further illustrate and exemplify thecompounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.

[0222] The chemical entities described herein can be synthesized according to one or moreillustrative schemes herein and / or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within atemperature range from -10° C to 200 °C. Further, except as otherwise specified, reaction timesand conditions are intended to be approximate, e.g., taking place at atmospheric pressure within atemperature range of -10° C to 200 °C over a period that can be, for example, 1 to 24 hours;reactions left to run overnight in some embodiments can average a period of 16 hours.

[0223] Isolation and purification of the chemical entities and intermediates described herein canbe effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3rdEd., 1990 New York: Plenum Press; Mundy et al., NameReaction and Reagents in Organic Synthesis, 2nd Ed., 2005 Hoboken, NJ: J. Wiley & Sons.Specific illustrations of suitable separation and isolation procedures are given by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

[0224] In all of the methods, it is well understood that protecting groups for sensitive or reactivegroups may be employed where necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0225] When desired, the (R)- and (S)-isomers of the nonlimiting exemplary compounds, ifpresent, can be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallization; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallization, gas- liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

[0226] The compounds described herein can be optionally contacted with a pharmaceuticallyacceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.

[0227] In some embodiments, disclosed compounds can generally be synthesized by anappropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted startingcompounds and other reactants are commercially available, e.g., from Millipore Sigma, or can bereadily prepared by those skilled in the art using commonly employed synthetic methodology.

[0228] The discussion below is offered to illustrate certain of the diverse methods available foruse in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein. The skilled artisan will understand that standard atom valences apply to all compounds disclosed herein ingenus or named compound form unless otherwise specified.

[0229] Synthesis of 4-(cyclohexylmethoxy)-N-(4-(hex-5-yn-1-ylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine[

[0231] TEA (2.6 m, . , . . red solution of 4-nitrobenzenethiol (1.2 g, 7.73 mmol, 1 equiv.) and 5-iodopent-1-yne (1.5 g, 7.73 mmol, 1 equiv.)in DCM (20 mL) under nitrogen atmosphere at 0 °C. The resulting mixture was allowed to stir atroom temperature (RT) for another 14 h. The starting material was consumed and a non-polarspot was formed in TLC. The crude was diluted with water and extracted with DCM. The obtained organic part was washed sequentially with aqueous NaHCO3 and with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure to obtain (4-nitrophenyl)(pent-4-yn-1-yl)sulfane (1.5 g, 6.72 mmol, 87% yield) as yellow solid. It was used as such for the nextstep without further purification. The product had no ionization in LCMS.

[0232] Step-2: Synthesis of 1-nitro-4-(pent-4-yn-1-ylsulfonyl)benzene:

[0233] HCl (37%) (10 µL, 0.18 mmol, 0.03 equiv.), TiCl3 (20 mg, 0.12 mmol, 0.02 equiv.), andH2O2 (0.75 mL, 24.43 mmol, 4.0 equiv.) were sequentially added to a stirred solution of (4- nitrophenyl)(pent-4-yn-1-yl)sulfane (1.35 g, 6.11 mmol, 1 equiv.) in MeOH (15 mL) under aninert atmosphere at 0 °C. The resulting mixture was allowed to reflux for 3 h. After completeconversion of the starting material, the reaction mixture was cooled to 0 °C and then quenchedwith water and kept for 16 h. White solid precipitation was observed, which was filtered over asintered funnel, dried, and triturated with pentane to furnish the desired 1-nitro-4-(pent-4-yn-1-ylsulfonyl)benzene (1.5 g, 5.9 mmol, 97% yield) as off white solid. LC-MS: 312.1 (M+OAc)-.

[0234] Step-3: Synthesis of 4-(pent-4-yn-1-ylsulfonyl)aniline:

[0235] Ammon.1mmol, 12 equiv.)were added sequentially to a stirred solution of 1-nitro-4-(pent-4-yn-1-ylsulfonyl)benzene (1.5 g,5.93 mmol, 1 equiv.) in 9:1 EtOH-water (20 mL) under ice cooled condition. The resultingmixture was allowed to stir for another 16 h at RT. The reaction was monitored by TLC andLCMS. The reaction mixture was filtered over celite pad and repeatedly washed with EtOH. Theobtained filtrate was evaporated under reduced pressure to furnish a yellowish crude. It was diluted with EtOAc and washed sequentially with water and brine. The obtained organic layerwas dried over sodium sulfate, filtered, and evaporated under reduced pressure to furnish 4-(pent-4-yn-1-ylsulfonyl)aniline (940 mg, 4.21 mmol, 71% yield) as off white solid. LC-MS:224.0 (M+H)+.

[0236] Step-4: Synthesis of 4-chloro-N-(4-(hex-5-yn-1-ylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine:

[0237] ZnBr2 (406 mg, 1.81 mmol, 3 equiv.) was added to a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (130 mg, 0.6 mmol, 1 equiv.) in DCE-tBuOH (1:1) (5 mL) at 0 °Cunder nitrogen atmosphere and allowed to stir for 30 min. 4-(hex-5-yn-1-ylsulfonyl)aniline (130mg, 0.54 mmol, 0.9 equiv.) and Et3N (180 µL, 1.32 mmol. 2.2 equiv.) were added sequentially tothe reaction mixture under same condition. The reaction mixture was then allowed to stir at RTfor another 20 h. The reaction mixture was filtered over celite, diluted with ethyl acetate, andwashed sequentially with water and brine. The obtained organic layer was dried over sodiumsulfate, filtered, and evaporated under reduced pressure to furnish a yellowish crude. The crudewas purified by CombiFlash chromatography using 5-15 % EA-DCM gradient to obtain 4-chloro-N-(4-(hex-5-yn-1-ylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (120 mg,0.29 mmol, 48% yield) as yellowish solid. LC-MS: 416.1 (M-H)-.

[0238] Step-5: Synthesis of 4-(cyclohexylmethoxy)-N-(4-(hex-5-yn-1-ylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine:[0(215 mg, 0.52 mmol, 1 equiv.) was portion-wise added to a stirred solution of sodium tert-butoxide (250 mg. 2.57 mmol, 5 equiv.) in cyclohexylmethanol (1.5 mL) at 0 °C under an inertatmosphere. The resulting mixture was allowed to stir at RT for 16 h. The reaction mixture wasdiluted with ethyl acetate and washed sequentially with saturated ammonium chloride solutionand brine solution. The obtained organic layer was dried over sodium sulfate, filtered, andevaporated under reduced pressure to furnish a yellowish crude. The crude was purified byCombiFlash chromatography using 5-10 % EA-DCM gradient to obtain 4-(cyclohexylmethoxy)-N-(4-(hex-5-yn-1-ylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.31 mmol,59% yield) as off white solid. LC-MS: 496.2 (M-H)-.

[0240] Synthesis of 5-(4-(2-azidoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione[

[0242] To a solutionmol, 1 equiv.) and 3-aminopiperidine-2,6-dione (2.7 g, 16.3 mmol, 1 equiv.) in acetic acid (20 mL) was added sodiumacetate (2.7 g, 32.6 mmol, 2 equiv.) at RT under an inert atmosphere. The reaction mixture wasstirred for 18 h under refluxing condition. After completion of the reaction, as monitored byLCMS, the reaction mixture was poured onto ice water to observe precipitation. It was filteredover a sintered funnel, the solid residue washed sequentially with water and diethyl ether, anddried under high vacuum to furnish 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (3.5 g, 11.9 mmol, 73% yield) as a light brown solid. LC-MS: 312.1 (M+NH4)+.

[0243] Step-7: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate:

[0244] To asolution of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (3 g, 10.2mmol, 1 equiv.) in DMSO (20 mL) were added tert-butyl piperazine-1-carboxylate (2.3 g, 12.2mmol, 1.2 equiv.) and DIPEA (33.37 mL, 20.4 mmol, 2 equiv.) at RT in a sealed tube. Thereaction mixture was stirred at 110 °C for 18 h. After completion of the reaction, as monitored byLCMS, the reaction mixture was poured onto ice-water, extracted with ethyl acetate (twice), thecombined organic layer washed with water and brine solution, dried over Na2SO4, filtered, andconcentrated under reduced pressure to furnish a reddish crude. This crude compound waspurified by CombiFlsah chromatography eluting with 10-30% EtOAc-hexane gradient to affordtert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (4.2 g, 9.01 mmol, 89% yield) as light greenish solid. LC-MS: 478.0 (M+NH4)+.

[0245] Step-8: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione:

[0246] To3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (1 g, 1.8 mmol,1.0 equiv.)) in dioxane (5 mL) wasadded 4.0 M HCl in dioxane solution (5 mL) at 0 °C. The reaction mixture was stirred at roomtemperature for 16 h. The reaction was monitored by crude LCMS. Volatiles were evaporatedunder reduced pressure and the obtained yellowish crude was triturated with ether (2 x 20 mL) toafford 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (650 g,crude, 99% yield) as a brown solid. LC-MS: 361.3 (M+H)+.

[0247] Step-9: Synthesis of 5-(4-(2-azidoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0248] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (300 mg, 0.83 mmol) and 1-azido-2-bromoethane (190 g, 1.25 mmol) in DMF (2 mL) was added DIPEA (0.6 mL, 3.33 mmol) and the reaction was stirred at 70 °C for 18h. After completion, the residue was diluted with EtOAc, sequentially washed with water andbrine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a reddishresidue which was purified by silica gel chromatography (Teledyne ISCO, 10-30% EtOAc-DCM) to afford 5-(4-(2-azidoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (90 mg, 25%) as a light yellow solid: MS (ES): m / z = 430.1 (M+H)+.

[0249] Step-6: Synthesis of Synthesis of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (10):

[0250] Toxylate (8)(3.0 g, 10.8 mmol, 1.0 equiv.) and 3-bromopiperidine-2,6-dione (9) (6.2 g, 32.4 mmol, 3.0equiv.) in DMF (10mL) was added DIPEA (4.8 mL, 27 mmol, 2.5 equiv.) and the reaction wasstirred at 70 °C for 18 h. After completion the crude was diluted with ethyl acetate, sequentiallywashed with water and brine, dried over Na2SO4, filtered, and concentrated under reducedpressure to obtain a reddish crude. Crude was purified by CombiFlash column chromatographyusing 10-20% EA-DCM gradient to afford tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (10) (3.0 g, 8.2 mmol, 76% yield) as brownsolid. LC-MS: 390.3 (M+H)+.

[0251] Step-7: Synthesis of 3-((6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione (11):

[0252] To a stirred solution of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl) amino) pyridin-2-yl)piperazine-1-carboxylate (10) (2.3 g, 5.9 mmol,1.0 equiv.) in dioxane (10 mL) was added 4.0 MHCl in dioxane solution (10 mL) at 0 °C. The reaction mixture was stirred at room temperaturefor 6 h. The reaction was monitored by crude LCMS. Volatiles were evaporated under reducedpressure and the obtained yellowish crude was triturated with ether (2 x 20 mL) to afford 3-((6-(piperazin-1-yl) pyridin-3-yl) amino) piperidine-2,6-dione [HCl salt] (11) (1.7 g, crude, 99%yield) as a brown solid. LC-MS: 290.3 (M+H)+.

[0253] Step-8: Synthesis of 3-((6-(4-(1-azidopropyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione:[0254-dione[HCl salt] (400 mg, 1.38 mmol, 1.0 equiv.) and 1-azido-3-bromopropane (1.2 g, 6.9 mmol, 5.0equiv.) in DMF (5 mL) was added DIPEA (2.4 mL, 1.38 mmol, 10 equiv.) and the reaction wasstirred at 70 °C for 18 h. After completion, the crude was diluted with ethyl acetate, sequentiallywashed with water and brine, dried over Na2SO4, filtered, and concentrated under reducedpressure to obtain a reddish crude. The crude was purified by CombiFlash columnchromatography using 10-30% EA-hexane gradient to afford 3-((6-(4-(1-azidopropyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione (150 mg, 0.4 mmol, 29% yield) as a brown solid.LC-MS: 373.2 (M+H)+.

[0255] Note: 1-azido-3-bromopropanewas prepared from 1,3-dibromopropane (1 equiv.) andsodium azide (0.9 equiv.) in DMF under the condition [50 °C, 48 h]. The obtained crude wasused as such for the next step without further purification

[0256] Step 9: Synthesis of 3-((6-(4-(3-(4-(4-((4-((4-(cyclohexylmethoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)butyl)-1H-1,2,3-triazol-1- yl)propyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione:

[0257] Cof 4-(cyclohexylmethoxy)-N-(4-(hex-5-yn-1-ylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine (25 mg, 0.051 mmol, 1 equiv.) and 3-((6-(4-(1-azidopropyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione (19 mg, 0.051 mmol, 1 equiv.) in 4:1 mixture of DMF-water (1.5mL). After 15 min, sodium ascorbate (10 mg, 0.051 mmol, 1 equiv.) was added and the resultingmixture was allowed to stir for 2 days at RT. The crude reaction mixture was subjected to RPprep HPLC purification to furnish 3-((6-(4-(3-(4-(4-((4-((4-(cyclohexylmethoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)sulfonyl)butyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione (5 mg, 11% yield) as an offwhite solid. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.62 (s, 1H), 8.62 (s, 1H), 8.02-7.99 (m, 2H), 7.82—7.76 (m, 3H), 7.70-7.69 (m, 1H), 7.06-7.03 (m, 1H), 6.66 (d, J = 9.2 Hz,1H), 5.40 (d, J = 7.6 Hz, 1H), 4.32-4.28 (m, 4H) , 4.26-4.15 (m, 1H), 3.26-3.23 (m, 5H), 2.59-2.50 (m, 4H), 2.41-2.38 (m, 4H), 2.24-2.21 (m, 2H), 2.15-2.05 (m, 1H), 1.95-1.92 (m, 2H), 1.78- 1.54 (m, 11H), 1.26-1.05 (m, 6H). LC-MS: 868.48 (M+H)+.

[0258] Table 3. Biological activity of compounds of the present disclosure.CompoundHiBit LD 293T.2 HiBit LD 293T.2CompoundHiBit LD 293T.2 HiBit LD 293T.2Number CDK2-HiBiT Degradation CDK2-HiBiT 24 h r Dm x % 24 h r Dm x %CompoundHiBit LD 293T.2 HiBit LD 293T.2Number CDK2-HiBiT Degradation CDK2-HiBiT 24 h r Dm x % 24 h r Dm x %

[0259] 5. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0260] While aspects of this disclosure have been particularly shown and described withreference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the scope of the disclosure.

[0261] Accordingly, the preceding merely illustrates the principles of the disclosure. It will beappreciated that those skilled in the art will be able to devise various arrangements which,although not explicitly described or shown herein, embody the principles of the disclosure andare included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the disclosure and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions.Moreover, all statements herein reciting principles, aspects, and embodiments of the disclosure as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims.

[0262] In at least some of the previously described embodiments, one or more elements used inan embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0263] The scope of the present disclosure, therefore, is not intended to be limited to theexemplary embodiments shown and described herein. Rather, the scope and spirit of presentdisclosure is embodied by the appended claims. In the claims, 35 U.S.C. § 112(f) or 35 U.S.C. §112(6) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" or the exact phrase "step for" is recited at the beginning of such limitation in the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112 (f) or 35 U.S.C. §112(6) is not invoked.

[0264] All references, issued patents, and patent applications cited within the body of the instantspecification are hereby incorporated by reference in their entirety, for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A compound, wherein the compound is represented by Formula (X):(X) or is a pharmaceuticallyCDK-BM is a cyclin-dependent kinase (CDK) binding moiety; L’ is a divalent moiety (e.g., linker) that connects CDK-BM to UBM; andUBM is an E3 ubiquitin ligase binding moiety.

2. The compound according to claim 1, wherein:the CDK-BM is capable of binding one or more of CDK2, CDK4, and CDK6; andthe UBM is a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligasebinding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety.

3. The compound according to claim 2, wherein the UBM is a cereblon E3 ubiquitin ligasebinding moiety represented by Formula (Xa): a)or is a pharmaceuticallyp ,X1 is a divalent moiety selected from a covalent bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-,-S-S-, -S(O)-, -S(O)2-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, anX2is C or Si;X3 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-, -S-S-;L” is a divalent moiety selected from a bond or an optionally substituted saturated orpartially unsaturated, straight or branched aliphatic C1-150 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independentlyselected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-,-P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-;Q is a divalent moiety selected from a bond or an optionally substituted saturated or partially unsaturated, straight or branched aliphatic C1-10 hydrocarbon chain, wherein one or more carbon atoms of the chain are optionally replaced by a divalent group independentlyselected from -O-, -NR-, -S-, -S(O)-, -S(NR)-, -S(O)2-, -S(O)(NR)-, -S(NR)2-, -P(O)R-,-P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, and -CyA-;each CyA is independently an optionally substituted ring system selected from a 3- to 12-membered saturated or partially unsaturated carbocyclene; a phenylene; a 3- to 12-memberedsaturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 5- to 6- or 8- to 12-membered heteroarylene having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a combination of any of these ring systems including variants thereof; R1 is H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -C(O)R, -OC(O)R,-OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-, -N(R)C(S)S-, -N(R)C(O)S-,-N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2, -P(O)(OR)2, -P(O)(NR2)OR,-OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2, -OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2,-Si(R)3, or an optionally substituted C1-6aliphatic; and each R is independently hydrogen, deuterium, or an optionally substituted straight,branched, or cyclic group selected from C1-6 aliphatic, phenyl, a 4- to 7-membered saturated orpartially unsaturated heterocyclyl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and a 5- to 6-membered heteroaryl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

4. The compound according to claim 3, wherein Q is represented by the structure:wherein: Q1is N or CRA; Q2is N or C; Q3is N or C; Q4is N or CRA; Q5is N or CRA; Q6is N or CRA; Z1 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2;Z2 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2;Z3 is N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2;Z4 is a bond, N, NRA, C, O, S, CRA, C(=O), C(=NRA), or C(RA)2; andeach RA is independently selected from H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R,-N(R)2, -C(O)R, -OC(O)R, -OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-,-N(R)C(S)S-, -N(R)C(O)S-, -N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2,-P(O)(OR)2, -P(O)(NR2)OR, -OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2,-OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and an optionally substituted C1-6 aliphatic.

5. The compound according to claim 3 or 4, wherein Q is selected from:,6. The compound according to any one of claims 3-5, wherein Q is selected from:,7. The compound according to claim 3, wherein Q is selected from:nd;each RA is independently selected from H, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R,-N(R)2, -C(O)R, -OC(O)R, -OC(O)O-, -N(R)C(O)N(R)-, -N(R)C(S)N(R)-, -N(R)C(O)O-,-N(R)C(S)S-, -N(R)C(O)S-, -N(R)C(S)O-, -N(R)C(O)R, -C(O)N(R)2, -OP(O)(OR)2,-P(O)(OR)2, -P(O)(NR2)OR, -OP(O)(NR2)OR, -N(R)P(O)(NR2)OR, -P(O)(NR2)2,-OP(O)(NR2)2, -Si(OH)2R, -Si(OH)(R)2, -Si(R)3, and an optionally substituted C1-6 aliphatic; andu is 1 to 3.

8. The compound according to claim 3 or 7, wherein Q is selected from:nd9.The compound according to any one of the preceding claims, wherein L is of theformula:wherein: each L11, L12, L13, L14, and L15is independently selected from a bond, –C1-20-alkylene–,–C(O)-C1-30-alkylene–, –N(R1)C(O)-C1-6-alkylene–, –C(O)N(R1)-C1-6-alkylene–, –N(R1)C1-6-alkylene–, –N(R1)C(O)N(R1)-C1-6-alkylene–, –N(R1)C(S)N(R1)-C1-6-alkylene–, –(monocyclicheterocycle)-C(O)-C1-6-alkylene–, –C1-30-alkylene-C(O)–, –C1-6-alkylene-C(O)N(R1)–, –C1-6-alkylene-N(R1)C(O)–, –C1-6-alkylene-N(R1)–, –C1-6-alkylene-N(R1)C(O)N(R1)–, –C1-6-alkylene-N(R1)C(S)N(R1)–, –C1-6-alkylene-C(O)-(monocyclic heterocycle)–, –O(CH2)g–, –(CH2)gO–,–(OCH2CH2)g–, –(CH2CH2O)g–, –N(R1)C(O)–, –C(O)N(R1)–, –N(R1)SO2–, –SO2N(R1)–, –CO–,–SO2–, –S(N)(O)–, –O–, –S–, monocyclic heteroaryl (e.g., triazole), monocyclic aryl,monocyclic heterocycle (e.g., piperidinyl, or piperazinyl), bicyclic heterocycle (e.g., spirocyclic), amino acid residue, –NH–, and –N(CH3)–; each R1 is independently H or CH3;each g is independently 1, 2, 3, 4, 5, or 6; anda, b, c, d, and e are independently 1, 2, or 3.

10. The compound according to claim 9, wherein L” comprises one or more groups selectedfrom: ,nd11. The compound according to any one of the preceding claims, wherein:X1 is a divalent moiety selected from a covalent bond, -C(R)2-, -N(R)-, -O-, -S-, -C(O)-,;X3 is a divalent moiety selected from a bond, -C(R)2-, -N(R)-, -O-, and -S-.

12. The compound according to any one of the preceding claims, wherein the CDK-BM isrepresented by Formula (I): (I)or a pharmaceutically acceptable sa, so va e, o p o ug ereof, wherein:R1is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted(C1-5)alkoxy, haloalkyl, halogen, OH, -CF3, -CF2H, -CFH2, -C2F5, -C2F4H, -C2F3H2, -C2F2H3, -C2FH4, and CN; R3 is selected from a divalent moiety that links to L’ or L”, H, alkyl, carbocycle,heterocycle, aryl, heteroaryl, alkylene-carbocycle, alkylene-heterocycle, alkylene-aryl, alkylene-heteroaryl, substituted versions thereof, and substituted versions thereof that are substituted witha divalent moiety that links to L’ or L”;L10 is a divalent moiety selected from a bond, -C(R)2-, -Si(R)2-, -N(R)-, -O-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, and -NHS(O)2-;Y4is N or CR4; R4is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN; R5 is or , wherein:ocyclyl, aryl, heteroaryl, and substituted versions thereof; Zis selected from a bond, sulfonyl, sulfone, sulfoxide, sulfide, sulfonate ester,sulfonamide, sulfimide, sulfinamide, sulfenamide, sulfoximine, sulfonimidamide, sulfonate, sulfondiimine, sulfondiimidamide, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, ether, urea, thiourea,and aliphatic group, or Z is a divalent moiety that links to L’ or L”;L1and L2are optional linkers; and * represents the point of attachment of R5to the nitrogen atom; ** represents a point of attachment of Z to L’ or L”; andR6is selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, haloalkyl, halogen, OH, and CN;wherein one of R3 and R5 comprises the divalent moiety that links to L’ or L”.

13. The compound according to claim 11 or 12, wherein the CDK-BM is of Formula (IA) orFormula (IB):

14. The compound athe CDK-BM is ofFormula (IIA) or Formula (IIB):wherein: Y6 to Y10 are independently C-Z, CR12, or N; andeach R12is independently selected from H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, and CN.

15. The compound according to claim 14, wherein one and only one of Y6 to Y10 is C-Z.

16. The compound according to claim 14, wherein Y7 is C-Z.

17. The compound according to claim 14, wherein Y8 is C-Z.

18. The compound according to any one of claims 14-17, wherein one or two of Y6, Y7, Y8,Y9, or Y10is N.

19. The compound according to any one of claims 14-18, wherein four of Y6 to Y10 are CR12.

20. The compound according to claim 18 or 19, wherein each R12 is H.

21. The compound according to any one of claims 14-20, wherein the CDK-BM is of one ofFormula (IIIB) to Formula (IIIJ):( ) ( );wherein R12is H, (C1-5)alkyl, substituted (C1-5)alkyl, (C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, or CN.

22. The compound according to any one of claims 11-13, wherein the CDK-BM is ofFormula (IIC) or Formula (IID):wherein:each R11 is independently selected from H, (C1-5)alkyl, substituted (C1-5)alkyl,(C1-5)alkoxy, substituted (C1-5)alkoxy, halogen, OH, and CN; and iis from 0 to 9.

23. The compound according to any one of claims 12-22, wherein R3 is selected from(C1-5)alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, (C1-3)alkylene-cycloalkyl, (C1-3)alkylene- heterocycle, (C1-3)alkylene-phenyl, (C1-3)alkylene-heteroaryl, and substituted versions thereof.

24. The compound according to claim 22, wherein R3 is optionally substituted (C1-3)alkylene-cycloalkyl.

25. The compound according to any one of claims 12-23, wherein L10 is -O-.

26. The compound according to any one of claims 12-23, wherein L10 is a bond.

27. The compound according to any one of claims 12-23, wherein L10 is -CH2-.

28. The compound according to claim 23, wherein:L10 is -O-; andR3 is –(CH2)k-cycloalkyl (e.g., cyclohexyl or cyclopentyl), wherein k is 1, or 2.

29. The compound according to any one of claims 12-28, wherein R1 is CF3.

30. The compound according to any one of claims 12-29, wherein R6 is H.

31. The compound according to any one of claims 12-30, wherein Y4 is N.

32. The compound according to any one of claims 12-30, wherein Y4 is CH.

33. The compound according to any one of claims 12-32, wherein L1 and L2 are absent.

34. The compound according to any one of claims 12-33, wherein Z is selected fromsulfonyl, sulfone, sulfonamide, sulfimide, sulfoximine, sulfonimidamide, sulfonate, carboxamide, carboxy, hydroxy, hydroxyalkyl, aldehyde, ester, alkoxy, nitrile, halogen, thiolactone, and any combination thereof.

35. The compound according to any one of claims 12-34, wherein Z is alkylsulfoximine,cycloalkylsulfoximine, heterocyclylsulfoximine, sulfonamide, or alkylsulfonamide.

36. The compound according to any one of claims 12-34, wherein -L2-Z or Z is of one ofFormula (Z1) to Formula (Z6): 6);wherein:Y11 is absent, -O-, -NR9-, -(C1-6)alkylene-O-, or -(C1-6)alkylene-NR9-;X11is O or NH; R51 is selected from halogen, R8, and -NR9R10;R8 is (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, cycloalkyl, heterocyclyl, or a substitutedversion thereof; R9is H or optionally substituted (C1-6)alkyl; R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, optionally substituted heterocyclyl, a sulfone, or a thiolactone; R52is H, optionally substituted (C1-6)alkyl, optionally substituted aryl, or optionally substituted heterocyclyl;h is 0, 1, or 2; andp, q, s, and t are independently 0, 1, 2, 3, 4, 5, or 6.

37. The compound according to claim 36, wherein -L2-Z or Z is of Formula (Z1) and is ofone of the following structures: (Z1B) or ); wherein:R10is H, optionally substituted (C1-6)alkyl, optionally substituted (C3-8)cycloalkyl, or optionally substituted heterocyclyl.

38. The compound according to claim 37, wherein:2 dd (C3-7)cycloalkyl, or optionally substituted (C2-6)heterocyclyl.

39. The compound according to claim 38, wherein R8 is (C3-4)cycloalkyl or(C2-4)heterocyclyl.

40. The compound according to claim 37, wherein:;R is H; andR10 is H or optionally substituted (C1-6)alkyl.

41. The compound according to any one of claims 36-40, wherein X11 is O.

42. The compound according to any one of claims 36-40, wherein X11 is NH.

43. The compound according to claim 12 or 21, wherein the CDK-BM is of the structure:.

44. The compound accordingompound is selected from Table 1.

45. A pharmaceutical composition comprising a compound according to any one of claims 1-44 and a pharmaceutically acceptable excipient.

46. A method according to degrading a cyclin-dependent kinase (CDK), the methodcomprising contacting a biological sample containing the CDK with an amount of a compoundaccording to any one of claims 1-44 effective to degrade the CDK.

47. A method according to degrading a CDK in a subject, the method comprisingadministering to a subject a compound of any one of claims 1-44, or a pharmaceuticalcomposition according to claim 45, to degrade the CDK in the subject.

48. The method according to claim 46 or 47, wherein the CDK is CDK2.

49. The method according to claim 46 or 47, wherein the CDK is CDK4.

50. A method according to treating a disease or disorder associated with CDK in a subject,the method comprising administering to the subject in need thereof a dose of a compoundaccording to any one of claims 1-44, or a pharmaceutical composition according to claim 45.

51. The method according to claim 50, wherein the disease or disorder is associated withCDK2.

52. The method according to claim 50, wherein the disease or disorder is associated withCDK4.

53. The method according to any one of claims 50-52, wherein the disease or disorderassociated with CDK is cancer.

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