[go: up one dir, main page]

WO2025103502A1 - Composés et méthodes de traitement de cancers - Google Patents

Composés et méthodes de traitement de cancers Download PDF

Info

Publication number
WO2025103502A1
WO2025103502A1 PCT/CN2024/132651 CN2024132651W WO2025103502A1 WO 2025103502 A1 WO2025103502 A1 WO 2025103502A1 CN 2024132651 W CN2024132651 W CN 2024132651W WO 2025103502 A1 WO2025103502 A1 WO 2025103502A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
membered heterocyclyl
optionally substituted
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/132651
Other languages
English (en)
Inventor
Jing Liu
Xiaoran HAN
Ting Yang
Ning Sun
Jing Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cullgen Shanghai Inc
Cullgen Inc
Original Assignee
Cullgen Shanghai Inc
Cullgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cullgen Shanghai Inc, Cullgen Inc filed Critical Cullgen Shanghai Inc
Publication of WO2025103502A1 publication Critical patent/WO2025103502A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • heterobifunctional compounds and methods useful for the modulation of certain cell cycle proteins via ubiquitination and/or targeted protein degradation are also provided.
  • pharmaceutically acceptable salts of such compounds are also provided, pharmaceutical compositions comprising such compounds and salts, and the uses thereof.
  • the ubiquitin (Ub) proteasome system plays a major role in the turnover of intracellular proteins and the maintenance of protein homeostasis, via the selective elimination of abnormally folded or damaged proteins.
  • UPS ubiquitin proteasome system
  • Cyclin-dependent kinases are a family of serine/threonine protein kinases that are critical for orchestrating signaling events, such as DNA replication and protein synthesis to ensure faithful cell division and proliferation.
  • the CDK catalytic units are activated by binding to regulatory subunits, known as cyclins, which can be divided into four general classes (G 1 , G 1 /S, S and M cyclins) whose expression levels vary at different points in the cell cycle.
  • Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6, and likely other cyclin/CDK heterodimers are important regulators of cell cycle progression.
  • CDK4/6-cyclin D and CDK2-cyclin E complexes control the G1/Scell cycle transition.
  • Progressive phosphorylation of retinoblastoma (Rb) by CDK4/6-cyclin D and subsequent CDK2-cyclin E releases the E2F family of transcription factors and promotes S-phase entry.
  • CDK4/6 inhibitors have been approved for human use, including palbociclib, ribociclib and abemaciclib in combination with endocrine therapy for HR + , HER2 - advanced or metastatic breast cancer, and trilaciclib to reduce chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer.
  • M. Zhang et al. CDK inhibitors in cancer therapy, an overview of recent developments, Am J Cancer Res (2021) , 11: 1913-1935; M.J. Mughal et al., CDK inhibitors from past to present: A new wave of cancer therapy, Semin Cancer Biol (2023) , 88: 106-122) .
  • CDK2 inhibitors are reportedly in early clinical development (e.g., PF-07104091, INCB123667, BLU-222 and INX-315) , but none have received regulatory approval. (International Publication No. WO 2020/157652; International Publication No. WO 2021/030537; International Publication No. WO 2021/072232; International Publication No. WO 2021/236650) .
  • Cyclin E (CCNE) amplification or overexpression can induce tumorigenesis through the CDK2 pathway and is associated with poor prognosis in human cancers, including ovarian cancer, breast cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, and lung cancer.
  • Cyclin E expression is a significant predictor of survival in advanced, suboptimally debulked ovarian epithelial cancers: a Gynecologic Oncology Group study, Cancer Res (2003) , 63: 1235-1241; X.
  • cyclin E1 CCNE1
  • CCNE2 cyclin E2
  • Targeted protein degraders that can modulate the activity of one or more cell cycle proteins may be useful for the treatment of abnormal cell proliferative disorders, in particular cancer.
  • Targeted protein degraders may offer advantages over small molecule inhibitors, for example by permitting the indirect targeting of proteins lacking an actionable binding site, or by offering enhanced selectivity, decreased potential for resistance, sustained duration of action, reduced dose or dosing frequency, or reduced toxicity.
  • heterobifunctional compounds of any of Formulae (I) - (XI-2) including sub-formulae thereof as further described herein, and pharmaceutically acceptable salts, pharmaceutical compositions, and uses thereof.
  • a heterobifunctional compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is N, Y is C, and ring is or X is C, Y is N, and ring is Z is CR 2 or N; Q and Q′are independently C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl; R 1 is independently H, D, halo, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 1a , SR 1a , NR 1b R 1c , C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, 4-7 membered heterocyclyl;
  • a heterobifunctional compound of Formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, wherein: X is N, Y is C, and ring is or X is C, Y is N, and ring is Z is CR 2 or N; Q is C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl; R 1 is independently H, D, halo, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 1a , SR 1a , NR 1b R 1c , C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, 4-7 membered heterocyclyl, wherein:
  • the compound of Formula (I) or (II-1) has the structure of any of Formulae (III-1) , (IV-1) , (V-1) , (VI-1) , or (VII-1)
  • the compound of Formula (I) or (II-2) has the structure of any of Formulae (III-2) , (IV-2) , (V-2) , (VI-2) , or (VII-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) or (II-1) has the structure of Formula (VIII-1) or (IX-1)
  • the compound of Formula (I) or (II-2) has the structure of Formula (VIII-2) or (IX-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (VIII-1) has the structure of Formula (X-1)
  • the compound of Formula (IX-1) has the structure of Formula (XI-1)
  • the compound of Formula (VIII-2) has the structure of Formula (X-2)
  • the compound of Formula (IX-2) has the structure of Formula (XI-2) : or a pharmaceutically acceptable salt thereof.
  • compositions or medicaments comprising the heterobifunctional compounds or salts of any of formulae provided herein, alone or in combination with one or more other therapeutic agents, such as additional anticancer agents.
  • FIG. 1A shows immunoblots of CDK2, CDK1, cyclin E1 and p-Rb proteins expressed by KURAMOCHI cells after treatment with a dose range of heterobifunctional compounds CPD-3, CPD-4, CPD-7, CPD-24, CPD-27, CPD-30, and CPD-39 for 24 hours.
  • FIG. 1B shows immunoblots of CDK2, CDK1, cyclin E1 and p-Rb proteins expressed by KURAMOCHI cells after treatment with a dose range of heterobifunctional compounds CPD-2, CPD-21, CPD-26, CPD-28, CPD-6, CPD-31, and CPD-38 for 24 hours.
  • FIG. 2 show graphs of KURAMOCHI and OVCAR3 ovarian cancer cell viability vs. concentrations of heterobifunctional compounds CPD-3, CPD-4, CPD-30, or CPD-39.
  • heterobifunctional compounds of any of Formulae (I) -(XI-2) described herein incorporate three moieties: (1) a cereblon E3 ligase binding moiety (CBM) , (2) a protein binding moiety (PBM) capable of binding to a CDK2 protein or an associated cyclin E, and (3) a bivalent linker (L) that covalently links the CBM to the PBM.
  • CBM cereblon E3 ligase binding moiety
  • PBM protein binding moiety
  • L bivalent linker
  • Amino refers to an “unsubstituted amino” radical of the form –NH 2 or a “substituted amino” radical of the form -NHR′or -N (R′) 2 as described herein and defined by the claims.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo (Br, Cl, F, I) substituents.
  • Haldroxy refers to the -OH radical.
  • Niro refers to the -NO 2 radical.
  • Oxa refers to the -O-radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon I and hydrogen (H) atoms, containing no unsaturation, having the specified number of carbon atoms.
  • an alkyl comprises from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl) .
  • an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl) .
  • an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl) .
  • an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl) . In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl) . In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl) . In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl) . In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl) .
  • the alkyl group is selected from methyl (Me) , ethyl (Et) , 1-propyl (n-propyl or n-Pr or n Pr) , 1-methylethyl (iso-propyl or i-Pr or i Pr) , 1-butyl (n-butyl or n-Bu or n Bu) , 1-methylpropyl (sec-butyl or s-Bu or s Bu) , 2-methylpropyl (iso-butyl or i-Bu or i Bu) , 1, 1-dimethylethyl (tert-butyl or t-Bu or t Bu) , or 1-pentyl (n-pentyl) .
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group (including an alkenyl or alkynyl group) may be optionally substituted by one or more substituent groups, as further defined by the claims and disclosure herein.
  • the total number of substituent groups may equal the total number of hydrogen atoms on the alkyl moiety, to the extent such substitution makes chemical sense.
  • Substituted alkyl groups typically contain from 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, or frequently 1 to 3 optional substituents.
  • Optional substituent groups are independently selected unless otherwise stated.
  • Alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. In certain embodiments, an alkenyl comprises from two to fifteen carbon atoms (e.g., C 2 -C 15 alkenyl) . In certain embodiments, an alkenyl comprises two to thirteen carbon atoms (e.g., C 2 -C 13 alkenyl) . In certain embodiments, an alkenyl comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenyl) . In other embodiments, an alkenyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkenyl) .
  • an alkenyl comprises two to four carbon atoms (e.g., C 2 -C 4 alkenyl) . In other embodiments, an alkenyl comprises two to three carbon atoms (e.g., C 2 -C 3 alkenyl) . Unless stated otherwise, alkenyl groups may be optionally substituted by one or more substituent groups, as further defined by the claims and disclosure herein.
  • Alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • an alkynyl comprises from two to fifteen carbon atoms (e.g., C 2 -C 15 alkynyl) .
  • an alkynyl comprises two to thirteen carbon atoms (e.g., C 2 -C 13 alkynyl) .
  • an alkynyl comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynyl) .
  • an alkynyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkynyl) . In other embodiments, an alkynyl comprises two to four carbon atoms (e.g., C 2 -C 4 alkynyl) . In other embodiments, an alkynyl comprises two to three carbon atoms (e.g., C 2 -C 3 alkynyl) . Unless stated otherwise, alkynyl groups may be optionally substituted by one or more substituent groups, as further defined by the claims and disclosure herein.
  • alkyl or alkylene moieties may be optionally further substituted with F, oxo, OH, alkoxy, amino, alkylamino or dialkylamino;
  • cycloalkyl or heterocyclyl moieties may be optionally further substituted with alkyl, F, oxo, OH, alkoxy, amino, alkylamino or dialkylamino;
  • aryl or heteroaryl moieties including the “aromatic” portion of arylalkyl and heteroarylalkyl groups
  • Alkylene refers to a straight or branched bivalent hydrocarbyl group having the specified number of carbon atoms, which can link two other groups together. Sometimes it refers to a straight chain group - (CH 2 ) t -where t is 1-10, and frequently t is 1-6. Examples include, e.g., methylene, ethylene, propylene, n-butylene, and the like.
  • an alkylene chain has from one to ten carbon atoms (C 1 -C 10 alkylene) , sometimes one to eight carbon atoms (e.g., C 1 -C 8 alkylene) , one to six carbon atoms (e.g., C 1 -C 6 alkylene) , one to four carbon atoms (e.g., C 1 -C 4 alkylene) , one to three carbon atoms (e.g., C 1 -C 3 alkylene) , one to two carbon atoms (e.g., C 1 -C 2 alkylene) , or one carbon atom (e.g., C 1 alkylene) .
  • an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene) , two to five carbon atoms (e.g., C 2 -C 5 alkylene) , or three to five carbon atoms (e.g., C 3 -C 5 alkylene) .
  • an alkylene can also be substituted by other groups and may include one or more degrees of unsaturation (i.e., an alkenylene or alkynylene chain) or rings. The open valences of an alkylene need not be at opposite ends of the chain.
  • substituents may include those typically present on alkyl groups as described herein and defined by the claims.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • thioalkoxy refers to a radical bonded through a sulfur atom of the formula –S-alkyl, where alkyl is an alkyl chain as defined above.
  • substituted alkyl groups of the indicated number of carbon atoms are specifically named by reference to the substituent group present on the alkyl moiety (e.g., alkoxyalkyl, aminoalkyl, arylalkyl, haloalkyl, hydroxyalkyl, and the like) .
  • An “alkoxyalkyl” refers to an alkyl group substituted by one or more alkoxy substituents, e.g., methoxymethyl (-CH 2 OMe) , ethoxymethyl (-CH 2 OEt) , or 2-ethoxyethyl (-CH 2 CH 2 OEt) .
  • aminoalkyl refers to an alkyl group substituted by one or more substituted or unsubstituted amino substituents, e.g., aminomethyl (-CH 2 NH 2 ) , aminoethyl (-CH 2 CH 2 NH 2 ) , N, N-dimethylaminoethyl (-CH 2 CH 2 N (Me) 2 ) or N-pyrrolidinylethyl (-CH 2 CH 2 -N-pyrrolidinyl) .
  • haloalkyl refers to an alkyl group substituted by one or more halogens.
  • haloalkyl groups include, e.g., fluoromethyl (-CH 2 F) , difluoromethyl (-CHF 2 ) , trifluoromethyl (-CF 3 ) , trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1, 2-dibromoethyl.
  • Fluoroalkyl refers to an alkyl radical specifically substituted by one or more fluoro radicals, e.g., fluoromethyl difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted as defined above for an alkyl group.
  • hydroxyalkyl refers to an alkyl group substituted by one or more hydroxy substituents, e.g., hydroxymethyl (-CH 2 OH) or 2-hydroxyethyl (-CH 2 CH 2 OH) .
  • Heteroalkyl refers to substituted or unsubstituted alkyl, alkenyl or alkynyl groups, in which one or more skeletal chain atoms is replaced by a heteroatom selected from O, N, S, P, or Si, or combinations thereof, wherein nitrogen, sulfur and phosphorus heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be substituted or quaternized.
  • heteroalkyl groups include the indicated number of chain atoms and one or more heteroatoms selected from -O-, -N (R") -, -S-, -S (O) -or -S (O) 2 -, where R"is H or C 1 -C 4 alkyl unless otherwise indicated.
  • R is H or C 1 -C 4 alkyl unless otherwise indicated.
  • a numerical range refers to the chain length in total, including both carbon and chain heteroatoms.
  • a 2-10 membered heteroalkyl has a chain length of 2 to 10 atoms, including both carbon and chain heteroatoms.
  • Such a heteroalkyl chain may be referred to herein as a “C 2 -C 10 heteroalkyl” .
  • Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain.
  • a heteroalkyl, heteroalkenyl, or heteroalkynyl group may be optionally substituted by one or more substituents such as those described herein as suitable for alkyl moieties.
  • Bivalent heteroalkyl, heteroalkenyl and heteroalkynyl moieties may be referred to respectively as heteroalkylene, heteroalkenylene or heteroalkynylene moieties of the indicated chain length.
  • heteroatoms i.e., -O-, -N (R") -, -S-, -S (O) -and -S (O) 2 -
  • a saturated or unsaturated heteroalkyl chain is limited to extent that such compounds are chemically stable (i.e., excluding peroxide moieties, disulfide moieties, and the like) .
  • Aryl or “aromatic” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. Bivalent aryl moieties may be referred to as arylene moieties.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon.
  • aryl groups may contain six to twenty carbon atoms ( “C 6 -C 20 ” aryl) , six to fourteen carbon atoms ( “C 6 -C 14 ” aryl) , six to twelve carbon atoms ( “C 6 -C 12 ” aryl) , or commonly six to ten carbon atoms ( “C 6 -C 10 ” aryl) as ring members, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • aryl groups include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.
  • aryl or the prefix "ar-" is meant to include aryl radicals optionally substituted by one or more substituents as defined in the claims and as further described below.
  • Arylalkyl or “aralkyl” refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • the number of carbon atoms in the alkyl and aryl portions of the arylalkyl moiety, respectively, may be indicated together or separately.
  • a benzyl group may be described as C 7 -arylalkyl or in the alternative as C 6 -aryl-C 1 -alkyl.
  • Carbocyclyl or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may be monocyclic, or include fused, spirocyclic or bridged ring systems, having from three to fifteen carbon atoms (e.g., a “C 3 -C 15 cycloalkyl” ) . Such a cycloalkyl ring systems may be referred to in the alternative as a 3-15 membered cycloalkyl.
  • a cycloalkyl ring comprises three to ten carbon atoms (e.g., a “C 3 -C 10 cycloalkyl” ) .
  • a cycloalkyl may comprise three to eight carbon atoms (e.g., a “C 3 -C 8 cycloalkyl” ) or five to seven carbon atoms (e.g., a “C 5 -C 7 cycloalkyl” ) .
  • the cycloalkyl may be attached to the rest of the molecule by a single bond or an exocyclic double bond.
  • a carbocyclyl may be fully saturated (i.e., containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds) .
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.
  • Partially unsaturated carbocyclyl rings may also be referred to as cycloalkenyl or cycloalkynyl moieties.
  • Bivalent cycloalkyl moieties may be referred to as cycloalkylene moieties.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl ( c Pr) , cyclobutyl ( c Bu) , cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, or cyclooctenyl.
  • bridged cycloalkyls examples include, e.g., adamantyl (i.e., tricyclo [3.3.1.1] decanyl) , norbornyl (i.e., bicyclo [2.2.1] heptanyl) , norbornenyl (i.e., bicyclo [2.2.1] hept-2-enyl) , or 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • fused cycloalkyls examples include, e.g., decalinyl, bicyclo [4.3.0] nonanyl, bicyclo [3.3.0] octanyl.
  • spirocyclic cycloalkyls examples include, e.g., spiro [3.3] heptanyl, spiro [3.4] octanyl or spiro [4.5] decanyl.
  • Carbocyclylalkyl or “cycloalkylalkyl” refers to a radical of the formula –R c -carbocyclyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the carbocyclyl radical are optionally substituted as defined above.
  • Heterocyclyl refers to a stable 3-to 20-membered non-aromatic ring radical that comprises two to fourteen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen or sulfur (i.e., N, O and S (O) z , where z is 0, 1 or 2) .
  • Such a ring system may be monocyclic, or include fused, spirocyclic or bridged ring systems.
  • the heterocyclyl ring system comprises 3-20 ring atoms (including both carbon and heteroatom ring atoms) , referred to herein as a 3-20 membered heterocyclyl.
  • the heterocyclyl ring system comprises 3-14 ring atoms, i.e., is a 3-14 membered heterocyclyl.
  • the heterocyclyl ring system comprises a 5-6 membered heterocyclyl, a 3-8 membered heterocyclyl, a 4-13 membered heterocyclyl, or a 4-10 membered heterocyclyl, wherein each such heterocyclyl typically contains from 1-3 heteroatoms.
  • Bivalent heterocycloalkyl moieties may be referred to as “heterocyclene” moieties. It will be understood that the number and location of heteroatoms in a heterocyclic ring is limited to extent that such compounds are chemically stable.
  • heterocyclyl radical is optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocyclyl radical is partially or fully saturated.
  • the heterocyclyl may be attached to the rest of the molecule through a C or N atom of the ring (s) .
  • heterocyclyl is meant to include heterocyclyl radicals that are optionally substituted by one or more substituents as defined in the claims and as further described below.
  • heterocyclyl radicals include, e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, quinuclidinyl,
  • Spirocyclic heterocyclyl radicals include, e.g., 2-azaspiro [3.3] heptan-6-yl, 2-azaspiro [3.3] heptan-6-yl, 2-azaspiro [4.4] nonan-6-yl, or azaspiro [4.5] decan-2-yl.
  • Cycloalkyl and heterocyclyl moieties described herein as optionally substituted may be substituted by one or more substituent groups, which are selected independently unless otherwise indicated.
  • the total number of substituent groups may equal the total number of hydrogen atoms on the cycloalkyl or heterocyclyl moiety, to the extent such substitution makes chemical sense.
  • Optionally substituted cycloalkyl or heterocyclyl groups typically contain from 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, sometimes 1 to 3 optional substituents, or frequently 1 to 2 optional substituents.
  • N-heterocyclyl or “N-linked heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-linked heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-linked heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-linked heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-linked heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-linked heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, 2-or 3-pyrrolidinyl, and the like.
  • Heteroaryl or “heteroaromatic” refers to a radical derived from a monocyclic, fused bicyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring atom, where at least one ring carbon atom has been replaced by N, O, or S, and wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the inclusion of heteroatoms permits aromaticity in 5-membered rings as well as 6-membered rings.
  • Heteroaryl groups may contain 5 to 20 ring atoms ( “5-20 membered heteroaryl” ) , sometimes 5 to 14 ring atoms ( “5-14 membered heteroaryl” ) , sometimes 5 to 12 ring atoms ( “5-12 membered heteroaryl” ) , and frequently 5 to 10 ring atoms ( “5-10 membered heteroaryl” ) or 5 to 6 ring atoms ( “5-6 membered heteroaryl” ) , in each case including both carbon and hetero-ring atoms.
  • Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained.
  • heteroaryl may be attached to the base molecule via a ring C atom
  • 5-membered heteroaryl rings may be attached to the base molecule via a ring C or N atom.
  • Bivalent heteroaryl moieties may be referred to as heteroarylene moieties.
  • heteroaryl or the prefix “heteroar-” (such as in “heteroaralkyl” ) is meant to include heteroaryl radicals optionally substituted by one or more substituents as defined in the claims and as further described below.
  • heteroarylalkyl moieties refers to a radical of the formula -R c -heteroaryl.
  • heteroaryl rings include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole (including 1, 2, 3-triazole and 1, 3, 4-triazole) , oxadiazole (including 1, 2, 3-oxadiazole, 1, 2, 4-oxadiazole, 1, 2, 5-oxadiazole, and 1, 3, 4-oxadiazole) , thiadiazole (including 1, 2, 3-thiadiazole, 1, 2, 4-thiadiazole, 1, 2, 5-thiadiazole, and 1, 3, 4-thiadiazole) , tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolopyridine (including pyrrolo [2,
  • 5-6 membered heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings.
  • Aryl and heteroaryl moieties described herein as optionally substituted may be substituted by one or more substituent groups, which are selected independently unless otherwise indicated.
  • the total number of substituent groups may equal the total number of hydrogen atoms on the aryl or heteroaryl moiety, to the extent such substitution makes chemical sense and aromaticity is maintained.
  • Optionally substituted aryl or heteroaryl groups typically contain from 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, sometimes 1 to 3 optional substituents, or frequently from 1 to 2 optional substituents.
  • Exemplary groups suitable as optional substituent groups on an aryl or heteroaryl moiety include: alkyl, fluoroalkyl alkenyl, alkynyl, halo, cyano, nitro, trimethylsilanyl, R a , -R b -OR a , -R b -SR a , -R b -OC (O) -R a , -R b -N (R a ) 2 , -R b -C (O) R a , -R b -C (O) OR a , -R b -C (O) N (R a ) 2 , -R b -N (R a ) C (O) OR a , -R b -OC (O) N (R a ) 2 , -R b -N (R a ) C (O) R a , -R b -OC (
  • N-heteroaryl or “N-linked heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a N atom in the heteroaryl radical.
  • An N-linked heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl or “C-linked heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-linked heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • the compounds disclosed herein contain one or more asymmetric centers and may give rise to enantiomers, diastereomers, racemates, or other stereoisomeric forms or mixtures thereof, which in some embodiments are defined in terms of absolute stereochemistry as (R) -or (S) -.
  • the stereoisomers are enantiomers
  • the chiral purity may be reported as the enantiomeric excess (e.e. ) , typically as a percentage.
  • chiral purity may be reported as the diastereomeric excess (d. e. ) , typically as a percentage.
  • Bonds of compounds containing asymmetric centers may be depicted using a solid line a solid wedge or a dotted wedge
  • a solid line to depict a bond to an asymmetric center is meant to indicate that the stereochemistry is undefined, and all possible stereoisomers (e.g., specific isomers, racemic mixtures, etc. ) at the stereocenter, or mixtures thereof, are included.
  • the use of a solid or dotted wedge to depict a bond to an asymmetric center is meant to indicate that the relative or absolute stereochemistry at the asymmetric center (s) is defined. Where defined, the absolute configuration may be indicated Ian (R) -or (S) -designation (e.g., in the chemical name or specified in the chemical structure) .
  • formula (1) represents any mixture of the four possible stereoisomers at the two asymmetric centers
  • formula (2) represents any mixture of the two cis diastereomers (including, e.g., a racemic mixture)
  • formula (3) represents the indicated stereoisomer in substantially pure form:
  • the compounds disclosed herein may also include geometric isomers, atropisomers, other conformational isomers and/or tautomeric forms.
  • the compounds described herein contain alkenyl groups, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans) of an alkene double bond, unless otherwise indicated.
  • Positional isomers e.g., structural isomers such as ortho-, meta-, and para-isomers around a benzene ring
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms, which are otherwise identical to those recited in one of the formulae provided, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • compounds having the present structures except for the replacement of one or more hydrogen atoms by a deuterium ( 2 H) or tritium ( 3 H) , or the replacement of a carbon atom by 13 C-or 14 C-enriched carbon.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, chlorine, bromine, or iodine.
  • Isotopic substitution with 2 H, 3 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are contemplated.
  • the compounds described herein may include isotopic forms enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • isotopically labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Substitution with heavier isotopes, such as deuterium, i.e., 2 H, may also afford certain therapeutic advantages such as greater metabolic stability, increased in vivo half-life, increased duration of action, or reduced dosage requirements. In some embodiments, a compound is deuterated in at least one position.
  • a compound disclosed herein has some or all the 1 H atoms replaced with 2 H atoms.
  • Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Methods for the synthesis for deuterium-containing compounds are known and include, by way of non-limiting example only, the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • references to compounds herein include references to salts (including pharmaceutically acceptable salts) , solvates (including hydrates) , and complexes thereof, as well as to solvates and complexes of the salts thereof, and isotopically labelled versions of the foregoing.
  • the term “substantially pure” means the compound or salt has a purity, measured as %area HPLC, of about 95%or more (i.e., contains less than about 5%of other organic components, such as starting materials, intermediates or by-products) . In some embodiments, the compound or salt has a purity, measured as %area HPLC, of about 99%or more (i.e., contains less than about 1%of other such components) . In some embodiments, the compound or salt has a purity, measured as %area HPLC, of about 99.5%or more (i.e., contains less than about 0.5%of other such components) .
  • salts refers to inorganic or organic salts of a compound herein. Such salts may be prepared in situ during the isolation and purification of a compound, or by separately treating the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. Unless otherwise indicated, salts may include pharmaceutically acceptable salts or non-pharmaceutically acceptable salts. Non-pharmaceutically acceptable salts, including salts of chiral acids, may be useful for synthesis, isolation, purification, chiral resolution, and the like.
  • “Pharmaceutically acceptable salts” are salts that retain the biological effectiveness and properties of the free base compound that are suitable for administration to a subject.
  • Reference to “a pharmaceutically acceptable salt” of a compound described herein is intended to encompass any pharmaceutically suitable salt, including pharmaceutically acceptable acid addition salts or base addition salts. (see, e.g., S.M. Berge et al., Pharmaceutical Salts, J Pharm Sci (1977) , 66: 1-19) .
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Salts can be prepared according to methods known in the art, for example by mixing a solution of the basic or acidic compound and the desired acid or base, respectively.
  • the resulting salt form may be isolated by precipitation and filtration or may be recovered by evaporation of the solvent.
  • Compounds existing in free base form having a basic functionality may be converted to the acid addition salts by treating with a stoichiometric excess of the appropriate acid.
  • Such acid addition salts may be reconverted to the corresponding free base by treating with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent at a temperature between about 0°C and 100°C.
  • the free base form may be isolated by conventional means, such as extraction into an organic solvent.
  • Acid addition salts may be interchanged by taking advantage of differential solubilities of the salts, volatilities or acidities of the acids, or by treating with an appropriately loaded ion exchange resin.
  • the interchange may be affected by the reaction of a salt with a slight stoichiometric excess of an acid of a lower pK than the acid component of the starting salt.
  • Such interconversions are typically carried out at a temperature between about 0°C and the boiling point of the solvent being used as the medium for the procedure.
  • Similar exchanges are possible with base addition salts, typically via the intermediacy of the free base form.
  • solvate refers to a molecular complex comprising a compound or salt and one or more solvent molecules.
  • the solvate may include one or more pharmaceutically acceptable solvents, such as water or ethanol.
  • hydrate is use when said solvent is water. Hydrates may be classified as isolated site, channel, or metal-ion coordinated hydrates.
  • solvent or water molecules are tightly bound, the complex may have a well-defined stoichiometry independent of humidity.
  • solvent or water molecules are weakly bound, the solvent or water content may be non-stoichiometric and depend on humidity or drying conditions.
  • multi-component complexes other than salts and solvates
  • the compound of any of the formulate provided herein and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • complexes include clathrates (i.e., drug-host inclusion complexes) and co-crystals, which typically are crystalline complexes wherein the constituents are bound together through non-covalent interactions.
  • a “prodrug” refers to a masked compound that functions as a drug precursor, which may itself have little or no pharmacological activity, that releases the active drug in vivo following administration via a chemical or physiological process (e.g., due to exposure to physiological pH or through enzymatic action) .
  • a chemical or physiological process e.g., due to exposure to physiological pH or through enzymatic action.
  • heterobifunctional compounds of any of Formulae (I) - (XI-2) in each case including subformulae thereof) , or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts.
  • heterobifunctional compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above.
  • the compound of Formula (I) has the structure of Formula (I-A) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) has the structure of Formula (I-B) : or a pharmaceutically acceptable salt thereof.
  • Q′ is C 6 -C 10 aryl or 5-10 membered heteroaryl. In some such embodiments, Q′is phenyl or 5-6 membered heteroaryl. In some embodiments of Formula (I) , (I-A) or (I-B) , Q′is C 6 -C 10 aryl. In some such embodiments, Q′is phenyl. In some embodiments of Formula (I) , (I-A) or (I-B) , Q′is 5-10 membered heteroaryl. In some such embodiments, Q′is 5-6 membered heteroaryl.
  • Q′ is C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl. In some such embodiments, Q′is C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl. In some embodiments of Formula (I) , (I-A) or (I-B) , Q′is C 3 -C 10 cycloalkyl. In some such embodiments, Q′is C 3 -C 6 cycloalkyl. In some such embodiments, Q′selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Q′ is 4-10 membered heterocyclyl. In some such embodiments, Q′is 4-6 membered heterocyclyl. In some such embodiments, Q′is selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl.
  • the moiety has the structure of formula: wherein: q is an integer selected from 0, 1 or 2; and r is an integer selected from 0, 1 or 2.
  • Z is CR 2 or N. In some embodiments, Z is CR 2 . In other embodiments, Z is N.
  • the compound of Formula (I) has the structure of Formula (II-1) or (II-2) .
  • heterobifunctional compound of Formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, as described above.
  • the compound has the structure of Formula (II-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (II-2) , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II-1) has the structure of Formula (II-A-1) or (II-B-1)
  • the compound of Formula (II-2) has the structure of Formula (II-A-2) or (II-B-2) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein for Formula (II-1) are applicable to Formulae (II-A-1) or (II-B-1) , to the extent they are not inconsistent.
  • the embodiments described herein for Formula (II-2) are applicable to Formulae (II-A-2) or (II-B-2) , to the extent they are not inconsistent.
  • the compound has the structure of Formula (II-A-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (II-A-2) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (II-B-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (II-B-2) , or a pharmaceutically acceptable salt thereof.
  • Z is CR 2 or N. In some such embodiments, Z is CR 2 . In other such embodiments, Z is N.
  • the compound of Formula (I) or (II-1) has the structure of Formula (III-1)
  • the compound of Formula (I) or (II-2) has the structure of Formula (III-2) : or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (III-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (III-2) , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (III-1) has the structure of Formula (III-A-1) or (III-B-1)
  • the compound of Formula (III-2) has the structure of Formula (III-A-2) or (III-B-2) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein for Formula (III-1) are applicable to compounds of Formula (III-A-1) or (III-B-1) , to the extent they are not inconsistent.
  • the embodiments described herein for Formula (III-2) are applicable to compounds of Formulae (III-A-2) or (III-B-2) , to the extent they are not inconsistent.
  • the compound has the structure of Formula (III-A-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (III-A-2) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (III-B-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (III-B-2) , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) or (II-1) has the structure of Formula (IV-1)
  • the compound of Formula (I) or (II-2) has the structure of Formula (IV-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (IV-1) has the structure of Formula (IV-A-1) or (IV-B-1)
  • the compound of Formula (IV-2) has the structure of Formula (IV-A-2) or (IV-B-2) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein for Formula (IV-1) are applicable to compounds of Formula (IV-A-1) or (IV-B-1) , to the extent they are not inconsistent.
  • the embodiments described herein for Formula (IV-2) are applicable to compounds of Formula (IV-A-2) or (IV-B-2) , to the extent they are not inconsistent.
  • the compound has the structure of Formula (IV-A-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (IV-A-2) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (IV-B-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (IV-B-2) , or a pharmaceutically acceptable salt thereof.
  • q is an integer selected from 0, 1 or 2. In some embodiments, q is an integer selected from 0 or 1. In some embodiments, q is the integer 1. In some embodiments, q is the integer 0.
  • r is an integer selected from 0, 1 or 2. In some embodiments, r is an integer selected from 0 or 1. In some embodiments, r is the integer 1. In some embodiments, r is the integer 0.
  • q is an integer selected from 0 or 1 and r is an integer selected from 0 or 1. In some such embodiments, q is the integer 1 and r is the integer 1. In some such embodiments, q is the integer 1 and r is the integer 0. In some such embodiments, q is the integer 0 and r is the integer 1. In some such embodiments, q is the integer 0 and r is the integer 0.
  • the compound of Formula (II-1) has the structure of Formula (V-1) , (V-A-1) or (V-B-1)
  • the compound of Formula (II-2) has the structure of Formula (V-2) , (V-A-2) or (V-B-2) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein for Formula (V-1) are applicable for compounds of Formula (V-A-1) or (V-B-1) , to the extent they are not inconsistent.
  • the embodiments described herein for Formula (V-2) are applicable for compounds of Formula (V-A-2) or (V-B-2) , to the extent they are not inconsistent.
  • Z is CR 2 or N. In some such embodiments, Z is CR 2 . In other such embodiments, Z is N.
  • the compound has the structure of Formula (V-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (V-2) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (V-A-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (V-A-2) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (V-B-1) , or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (V-B-2) , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II-1) has the structure of Formula (VI-1) , (VI-A-1) or (VI-B-1)
  • the compound of Formula (II-2) has the structure of Formula (VI-2) , (VI-A-2) or (VI-B-2) : or a pharmaceutically acceptable salt thereof.
  • the compound has the structure of Formula (VI-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (VI-2) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (VI-A-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (VI-A-2) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (VI-B-1) , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (VI-B-2) , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (VI-A-1) has the structure of Formula (VI-a2) or (VI-a3)
  • the compound of Formula (VI-B-1) has the structure of Formula (VI-b2) or (VI-b3) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein as applicable for Formulae (VI-1) are applicable for compounds of any of Formulae (VI-A-1) , (V1-B-1) , (VI-a2) , (VI-a3) , (VI-b2) or (VI-b3) , to the extent they are not inconsistent.
  • the embodiments described herein as applicable for Formula (VI-2) are applicable for compounds of any of Formulae (VI-A-2) or (V1-B-2) , to the extent they are not inconsistent.
  • the compound of Formula (II-1) has the structure of Formula (VII-1) , (VII-A-1) or (VII-B-1)
  • the compound of Formula (II-2) has the structure of Formula (VII-2) , (VII-A-2) or (VII-B-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (VII-A-1) has the structure of Formula (VII-a2) or (VII-a3)
  • the compound of Formula (VII-B-1) has the structure of (VII-b2) or (VII-b3) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein as applicable for Formula (VII-1) are applicable for any of Formulae (VII-A-1) , (VI1-B-1) , (VII-a2) , (VII-a3) , (VII-b2) or (VII-b3) , to the extent they are not inconsistent.
  • the embodiments described herein as applicable for Formula (VII-2) are applicable for any of Formulae (VII-A-2) or (VI1-B-2) , to the extent they are not inconsistent.
  • the compound of Formula (VI-1) has the structure of Formula (VIII-1) , (VIII-A-1) or (VIII-B-1)
  • the compound of Formula (VI-2) has the structure of Formula (VIII-2) , (VIII-A-2) or (VIII-B-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (VIII-A-1) has the structure of Formula (VIII-a2) or (VIII-a3)
  • the compound of Formula (VIII-B-1) has the structure of Formula (VIII-b2) or (VIII-b3) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein as applicable for Formula (VIII-1) are applicable for any of Formulae (VIII-A-1) , (VII1-B-1) , (VIII-a2) , (VIII-a3) , (VIII-b2) or (VIII-b3) , to the extent they are not inconsistent.
  • the embodiments described herein as applicable for Formula (VIII-2) are applicable for any of Formulae (VIII-A-2) or (VII1-B-2) , to the extent they are not inconsistent.
  • the compound of Formula (VII-1) has the structure of Formula (IX-1) , (IX-A-1) or (IX-B-1)
  • the compound of Formula (VII-2) has the structure of Formula (IX-2) , (IX-A-2) or (IX-B-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (IX-A-1) has the structure of Formula (IX-a2) or (IX-a3)
  • the compound of Formula (IX-B-1) has the structure of Formula (IX-b2) or (IX-b3) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein as applicable for Formula (IX-1) are applicable for any of Formulae (IX-A-1) , (IX-B-1) , (IX-a2) , (IX-a3) , (IX-b2) or (IX-b3) , to the extent they are not inconsistent.
  • the embodiments described herein as applicable for Formula (IX-2) are applicable for any of Formulae (IX-A-2) or (IX-B-2) , to the extent they are not inconsistent.
  • the compound of Formula (VIII-1) has the structure of Formula (X-1) , (X-A-1) or (X-B-1)
  • the compound of Formula (VIII-2) has the structure of Formula (X-2) , (X-A-2) or (X-B-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (X-A-1) has the structure of Formula (X-a2) or (X-a3)
  • the compound of Formula (X-B-1) has the structure of Formula (X-b2) or (X-b3) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein as applicable for Formula (X-1) are applicable for any of Formulae (X-A-1) , (X-B-1) , (X-a2) , (X-a3) , (X-b2) or (X-b3) , to the extent they are not inconsistent.
  • the embodiments described herein as applicable for Formula (X-2) are applicable for any of Formulae (X-A-2) or (X-B-2) , to the extent they are not inconsistent.
  • the compound of Formula (IX-1) has the structure of Formula (XI-1) , (XI-A-1) or (XI-B-1)
  • the compound of Formula (IX-2) has the structure of Formula (XI-2) , (XI-A-2) or (XI-B-2) : or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (XI-A-1) has the structure of Formula (XI-a2) or (XI-a3)
  • the compound of Formula (XI-B-1) has the structure of Formula (XI-b2) or (XI-b3) : or a pharmaceutically acceptable salt thereof.
  • the embodiments described herein as applicable for Formula (XI-1) are applicable for any of Formulae (XI-A-1) , (XI-B-1) , (XI-a2) , (XI-a3) , (XI-b2) or (XI-b3) , to the extent they are not inconsistent.
  • the embodiments described herein as applicable for Formula (XI-2) are applicable for any of Formulae (XI-A-2) or (XI-B-2) , to the extent they are not inconsistent.
  • R 1 is independently H, D, halo, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 1a , SR 1a , NR 1b R 1c , C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, 4-7 membered heterocyclyl-C 1 -C 4 alkyl, phenyl-C 1 -C 4 alkyl, or 5-6 membered heteroaryl-C 1 -C 4 alkyl, wherein each said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 1 -C 4 alkyl is optionally substituted by one
  • R 1 is independently H, C 1 -C 6 alkyl, OR 1a , SR 1a , NR 1b R 1c , 4-7 membered heterocyclyl, or phenyl, wherein each said C 1 -C 6 alkyl is optionally substituted by one or more R 1A , and each said 4-7 membered heterocyclyl or phenyl is optionally substituted by one or more R 1R .
  • R 1 is NR 1b R 1c .
  • R 1 is NR 1b R 1c and R 1b and R 1c are independently selected from H or C 1 -C 6 alkyl, or R 1b and R 1c are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl.
  • R 1 is NR 1b R 1c , and R 1b and R 1c are independently selected from H, Me or iPr, or R 1b and R 1c are taken together with the nitrogen atom to which they are attached to form an N-linked azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl ring.
  • R 1 is NHMe, NH i Pr, NMe 2 , or N-linked azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.
  • R 1 is independently H or OR 1a .
  • R 1 is OR 1a and R 1a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 7 cycloalkyl.
  • R 1 is OR 1a and R 1a is C 1 -C 6 alkyl.
  • R 1 is OR 1a and R 1a is C 1 -C 6 haloalkyl.
  • R 1 is OR 1a and R 1a is C 3 -C 7 cycloalkyl. In some embodiments, R 1 is OEt, O i Pr, O c Bu, or OCH 2 CF 3 . In some embodiments, R 1 is OR 1a and R 1a is Et, i Pr, c Bu, or CH 2 CF 3 . In some embodiments, R 1 is OR 1a and R 1a is Et. In some embodiments, R 1 is OR 1a and R 1a is iPr. In some embodiments, R 1 is OR 1a and R 1a is c Bu. In some embodiments, R 1 is OR 1a and R 1a is CH 2 CF 3 .
  • each R 1a , R 1b and R 1c is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, 4-7 membered heterocyclyl-C 1 -C 4 alkyl, phenyl-C 1 -C 4 alkyl, or 5-6 membered heteroaryl-C 1 -C 4 alkyl, wherein each said C 1 -C 6 alkyl or C 1 -C 4 alkyl moiety is optionally substituted by one or more R 1A , and each said C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is
  • each R 1a , R 1b and R 1c is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, C 3- C 7 cycloalkyl-C 1 -C 4 alkyl, or 4-7 membered heterocyclyl-C 1 -C 4 alkyl, wherein each said C 1 -C 6 alkyl or C 1 -C 4 alkyl moiety is optionally substituted by one or more R 1A , and each said C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, or phenyl is optionally substituted by one or more R 1R .
  • each R 1a , R 1b and R 1c is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 7 cycloalkyl.
  • R 1b and R 1c are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl optionally substituted by one or more R 1R .
  • R 1 is OR 1a and R 1a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 7 cycloalkyl.
  • R 1 is OR 1a and R 1a is Et, iPr, cBu, or CH 2 CF 3 .
  • each R 1A is independently D, halo, OH, oxo, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 ; and each R 1R is independently D, halo, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 , where each C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally substituted by one or more D, halo, OH, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 .
  • R 2 is independently H, D, halo, CN, C 1 -C 4 alkyl, OR 2a , NR 2b R 2c or C 3 -C 7 cycloalkyl, wherein each said C 1 -C 4 alkyl is optionally substituted by one or more R 2A , and each said C 3 -C 7 cycloalkyl is optionally substituted by one or more R 2R .
  • R 2 is H or halo.
  • R 2 is H or F.
  • R 2 is H.
  • each R 2a , R 2b and R 2c is independently H, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; or R 2b and R 2c are takentogether with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl optionally substituted by one or more R 2R .
  • R 2 is independently H, halo, C 1 -C 4 alkyl, OR 2a or NR 2b R 2c .
  • each R 2a , R 2b and R 2c is independently H, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; or R 2b and R 2c are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl optionally substituted by one or more R 2R .
  • each R 2A is independently D, halo, OH, oxo, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 .
  • each R 2R is independently D, halo, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 , where each C 1 -C 4 alkyl is optionally substituted by one or more D, halo, OH, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 .
  • n is an integer selected from 0, 1, 2, 3 or 4. In some embodiments, n is the integer 0, 1 or 2. In some embodiments, n is the integer 0 or 1. In some embodiments, n is the integer 1 or 2. In some embodiments, n is the integer 0. In some embodiments, n is the integer 1. In some embodiments, n is the integer 2.
  • n is an integer selected from 0, 1, 2, 3 or 4. In some embodiments, n is the integer 0, 1 or 2. In some embodiments, n is the integer 0 or 1. In some embodiments, n is the integer 0. In some embodiments, n is the integer 1.
  • n is an integer selected from 0, 1, 2, 3 or 4. In some embodiments, n is the integer 0, 1 or 2. In some embodiments, n is the integer 1 or 2. In some embodiments, n is the integer 1. In some embodiments, n is the integer 2.
  • n is an integer selected from 1, 2, 3 or 4, and n-1 is an integer selected from 0, 1, 2 or 3.
  • n is the integer 1 or 2
  • n-1 is the integer 0 or 1.
  • n is the integer 1
  • n-1 is the integer 0.
  • n is the integer 2
  • n-1 is the integer 1.
  • each R 3 is independently D, halo, CN, C 1 -C 4 alkyl, oxo, OH, C 1 -C 4 alkoxy, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 , and C 3 -C 4 cycloalkyl, wherein each C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally substituted by one or more R 3A , andeach said C 3 -C 4 cycloalkyl is optionally substituted by one or more R 3R ; or two R 3 are taken together with the atom (s) to which they are attached to form a C 3 -C 12 cycloalkyl or a 4-12 membered heterocyclyl, each optionally substituted by one or more R 3R .
  • each R 3 is independently halo, C 1 -C 4 alkyl or OH. In some such embodiments, each R 3 is independently F, CH 3 or OH. In some embodiments, n is the integer 1 and R 3 is halo, C 1 -C 4 alkyl or OH. In some embodiments, n is the integer 1 and R 3 is F, CH 3 or OH. In some embodiments, n is the integer 1 and R 3 is CH 3 . In some embodiments, n is the integer 2 and each R 3 is independently halo, C 1 -C 4 alkyl or OH In some embodiments, n is the integer 2 and each R 3 is independently F, CH 3 or OH .
  • each R 3A is independently D, halo, OH, oxo, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 .
  • R 3 is C 1 -C 4 alkyl optionally substituted by one or more R 3A
  • eachR 3A is halo.
  • each R 3R is independently D, halo, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 , wherein each C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally substituted by one or more D, halo, OH, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 .
  • p is an integer selected from 0, 1, 2, 3 or 4. In some embodiments, p is an integer selected from 0, 1 or 2. In some such embodiments, p is an integer selected from 1 or 2. In some such embodiments, p is an integer selected from 0 or 1. In some such embodiments, p is the integer 0. In some such embodiments, p is the integer 1. In some such embodiments, p is the integer 2.
  • each R 4 is independently selected from halo, CN, C 1 -C 6 alkyl, OR 4a , NR 4b R 4c or C 3 -C 7 cycloalkyl, wherein each said C 1 -C 6 alkyl is optionally substituted by one or more R 4A , and each said C 3 -C 7 cycloalkyl is optionally substituted by one or more R 4R .
  • each R 4 is independently selected from halo, C 1 -C 6 alkyl or NR 4b R 4c .
  • each R 4 is independently selected from halo, C 1 -C 3 alkyl or NH 2 . In some embodiments, each R 4 is independently selected from CH 3 or NH 2 . In some such embodiments, each R 4 is independently selected from C 1 -C 3 alkyl. In some embodiments, each R 4 is CH 3 .
  • each R 4a , R 4b and R 4c is independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl-C 1 -C 4 alkyl, 4-7 membered heterocyclyl-C 1 -C 4 alkyl, phenyl-C 1 -C 4 alkyl, or 5-6 membered heteroaryl-C 1 -C 4 alkyl, wherein each said C 1 -C 6 alkyl or C 1 -C 4 alkyl moiety is optionally substituted by one or more R 4A , and each said C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted by one or more R 4R ;
  • each R 4a , R 4b and R 4c is independently selected from H or C 1 -C 6 alkyl, wherein each said C 1 -C 6 alkyl is optionally substituted by one or more R 4A ; and each R 4A is halo.
  • p is an integer selected from 0 or 1.
  • each R 4A is independently D, halo, OH, oxo, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 ; and each R 4R is independently D, halo, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 , where each C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally substituted by one or more D, halo, OH, C 1 -C 4 alkoxy, CN, NH 2 , NH (C 1 -C 4 alkyl) or N (C 1 -C 4 alkyl) 2 .
  • X is C
  • Y is N
  • ring is
  • Z is CR 2 or N. In some embodiments of any of Formulae (I) , (II-1) , (II-2) , (V-1) or (V-2) , Z is CR 2 . In some embodiments of any of Formulae (I) , (II-1) , (II-2) , (V-1) or (V-2) , Z is CH or CF. In some embodiments of any of Formulae (I) , (II-1) , (II-2) , (V-1) or (V-2) , Z is CH. In some embodiments of any of Formulae (I) , (II-1) , (II-2) , (V-1) or (V-2) , Z is N.
  • Q is C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclyl. In some embodiments, Q is 5-10 membered heteroaryl. In some such embodiments, Q is 5-6 membered heteroaryl. In some such embodiments, Q is pyrazolyl or imidazolyl. In some such embodiments, Q is pyrazolyl, more preferably 1H-pyrazol-4-yl.
  • CBM cereblon E3 ligase binding moiety
  • CBM is a cereblon binding moiety of Formula (Z) : wherein: Z"is a bond, -C (O) -, -CR za R zb -, -NR zc -, -O-, -C (O) -NR zc -, -NR zc -C (O) -, -C (O) -CR za R zb -NR zc -, -C (O) -CR za R zb -NR zc -, -C (O) - CR za R zb -O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkyl or 4-12 membered heterocyclyl, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene
  • R zf and R zg are taken together with the nitrogen atom to which they are attached to form a 4-6 membered heterocyclyl;
  • R z2 is H or C 1 -C 3 alkyl; and
  • R z3 is H, D, F, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • Ar is a moiety selected from: wherein V 1 , W 1 , X 1 and Y 1 are defined as for Formulae (A) , (B) , (C) or (D) ; U 2 , V 2 , W 2 , X 2 , Y 2 , T 1 , T 2 , are defined as for Formulae (E) , (F) , (G) , (H) , (I) , (J) , (K) , (M) , (N) , (O) or (P) ; U 3 , V 3 , W 3 and X 3 are defined as for Formulae (Q) , (R) , (S) , (T) , (U) , (V) , (W) , (X) or (Y) ; U 4 , V 4 , W 4 , X 4 and Y 4 are defined as for Formulae (AA) , (AB) or (AC) ;
  • L z is a bond. In some embodiments of Formula (Z) , L z is -NH-. In some embodiments of Formula (Z) , L z is -C (O) NH-.
  • X z is N. In some embodiments of Formula (Z) , X z is CR z3 . In some embodiments of Formula (Z) , X z is CR z3 ; and R z3 is H, D, or F (i.e., X z is CH, CD or CF) . In some embodiments of Formula (Z) , X z is CR z3 ; and R z3 is H (i.e., X z is CH) .
  • Z" is a bond, -C (O) -, -CR za R zb -, -NR zc -, -O-, -C (O) -NR zc -, -NR zc -C (O) -, -C (O) -CR za R zb -NR zc -, -C (O) -CR za R zb -O-, C 2 -C 10 alkylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkyl or 4-12 membered heterocyclyl.
  • Z" is a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -NH-, -NH-C (O) -, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 10 alkylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkyl or 4-12 membered heterocyclyl.
  • Z" is a bond, C 3 -C 12 cycloalkyl or 4-12 membered heterocyclyl. In some embodiments of Formula (Z) , Z"is a bond. In some embodiments of Formula (Z) , Z"is C 3 -C 12 cycloalkyl.
  • Z" is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl or spiro [5.5] undecanyl.
  • Z" is 4-12 membered heterocyclyl.
  • Z" is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyranyl, dioxanyl, azaspiro [2.3] -hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl, diazaspiro [3.5] nonanyl, diazaspiro [4.4] nonanyl, diazaspiro [4.5] decanyl, azaspiro [5.5]
  • CBM is a moiety selected from the group consisting of: (i) Formulae (A) , (B) , (C) and (D) : wherein: V 1 , W 1 and X 1 are independently CR C 6 or N; Y 1 is C (O) or CR C 7a R C 7b ; R C 5a is H, D, F, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; R C 5b is H or C 1 -C 3 alkyl; each R C 6 is independently H, D, halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, OR C 6a , NR C 6b R C 6c , CN or NO 2 , wherein each C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered
  • CBM is a CRBN E3 ligase binding moiety of Formula (A) , (B) , (C) or (D) :
  • V 1 , W 1 and X 1 are independently CR C 6 , and each R C 6 is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or C 2 -C 4 haloalkoxy.
  • V 1 , W 1 and X 1 are independently CR C 6 , and each R C 6 is independently H or halo.
  • V 1 , W 1 and X 1 are independently CR C 6 , and each R C 6 is independently H or F.
  • V 1 , W 1 and X 1 are independently CR 6 , and each R C 6 is H (i.e., V 1 , W 1 and X 1 are each CH) .
  • Y 1 is C (O) or CR C 7a R C 7b . In some embodiments of any of Formulae (A) , (B) , (C) or (D) , Y 1 is C (O) or CH 2 . In some embodiments of any of Formulae (A) , (B) , (C) or (D) , Y 1 is C (O) . In some embodiments of any of Formulae (A) , (B) , (C) or (D) , Y 1 is CR C 7a R C 7b .
  • R C 7a and R C 7b are independently H, D, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • Y 1 is CR C 7a R C 7b
  • each ofR C 7a and R C 7b is H (i.e., Y 1 is CH 2 ) .
  • R C 5a is H, D, F, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments of any of Formulae (A) , (B) , (C) or (D) , R C 5a is H.
  • R C 5b is H or C 1 -C 3 alkyl. In some embodiments of any of Formulae (A) , (B) , (C) or (D) , R C 5b is H.
  • the CBM moiety of Formula (A) , (B) , (C) or (D) has the structure of Formula (A") , (B") , (C") or (D") , respectively: wherein R C 6 , Y 1 and Z 1 are defined as for Formulae (A) , (B) , (C) or (D) .
  • CBM is a CRBN E3 ligase binding moiety of Formula (A") , (B") , (C") or (D") .
  • CBM is a moiety of Formula (A") .
  • CBM is a moiety of Formula (B") .
  • CBM is a moiety of Formula (C") .
  • CBM is a moiety of Formula (D") .
  • Y 1 and Z 1 described herein for CBM moieties of Formula (A) , (B) , (C) or (D) are applicable to CBM moieties of Formula (A") , (B") , (C") or (D") , to the extent they are not inconsistent.
  • Z 1 is a bond, -C (O) -, -CR C 8a R C 8b -, -NR C 8c -, -O-, -C (O) NR C 8c -, -NR C 8c C (O) -, -C (O) CR C 8a R C 8b NR C 8c -, -C (O) CR C 8a R C 8b O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene is optionally substituted
  • Z 1 is selected from the group consisting of a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -NH-, -NH-C (O) -, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene and 4-12 membered heterocyclene, optionally substituted as described.
  • Z 1 is selected from the group consisting of a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 6 alkylene, C 2 alkynylene, C 3 -C 6 cycloalkylene and 4-6 membered heterocyclene, optionally substituted as described.
  • Z 1 is a bond.
  • Z 1 is -C (O) -.
  • Z 1 is -CR C 8a R C 8b -.
  • R 8a and R 8b are H, such that Z 1 is -CH 2 - (i.e., methylene) .
  • Z 1 is -NR C 8c -.
  • R 8c is H, such that Z 1 is -NH-.
  • Z 1 is -O-.
  • Z 1 is -C (O) -CH 2 -NH-.
  • Z 1 is -C (O) -CH 2 -O-.
  • Z 1 is C 2 -C 10 alkylene (e.g., ethylene, propylene, or butylene) .
  • Z 1 is C 2 -C 10 alkenylene or C 2 -C 10 alkynylene (e.g., ethenylene or ethynylene) . In some such embodiments, Z 1 is C 2 alkynylene.
  • Z 1 is C 3 -C 12 cycloalkylene. In some such embodiments, Z 1 is C 3 -C 6 cycloalkylene.
  • Z 1 is a bivalent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, or octahydropentalenyl moiety.
  • Z 1 is 4-12 membered heterocyclene. In some such embodiments, Z 1 is 4-6 membered heterocyclene. In some such embodiments, Z 1 a bivalent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaspiro [2.3] hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] -octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl, diazas
  • CBM is a CRBN E3 ligase binding moiety of Formula (A) , (B) , (C) or (D) selected from the group consisting of:
  • CBM is a CRBN E3 ligase binding moiety of Formula (E) , (F) , (G) , (H) , (I′) , (J) , (K) , (ZA) , (ZB) , (ZC) , (M) , (N) , (O) and (P) :
  • CBM is a moiety of Formula (E) . In some embodiments, CBM is a moiety of Formula (F) . In some embodiments, CBM is a moiety of Formula (G) . In some embodiments, CBM is a moiety of Formula (H) . In some embodiments, CBM is a moiety of Formula (I′) . In some embodiments, CBM is a moiety of Formula (J) . In some embodiments, CBM is a moiety of Formula (K) . In some embodiments, CBM is a moiety of Formula (ZA) . In some embodiments, CBM is a moiety of Formula (ZB) .
  • U 2 , V 2 , W 2 and X 2 are independently CR C 10 , and each R C 10 is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 2 -C 4 haloalkoxy.
  • U 2 , V 2 , W 2 and X 2 are independently CR C 10 , and each R C 10 is H (i.e., U 2 , V 2 , W 2 and X 2 are each CH) .
  • U 2 , V 2 , W 2 and X 2 are independently CR C 10 , and at least one R C 10 is F (i.e., at least one of U 2 , V 2 , W 2 and X 2 is CF) .
  • Y 2 is CR C 11a R C 11b , NR C 11c or O. In some embodiments of Formula (E) , (F) , (H) , (M) or (N) , Y 2 is CR C 11a R C 11b . In some such embodiments, R C 11a and R C 11b are independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl.
  • R C 11a and R C 11b are independently H, D or C 1 -C 4 alkyl. In some such embodiments, R C 11a and R C 11b are independently H.
  • Y 2 is CH 2 , NH, NCH 3 or O. In some embodiments of Formula (E) , (F) or (H) , Y 2 is CH 2 . In some embodiments of Formula (E) , (F) , (H) , (M) or (N) , Y 2 is NR C 11c .
  • R C 11c is independently H, D, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In some such embodiments, R C 11c is independently H or methyl. In some such embodiments, R C 11c is independently methyl. In some frequent embodiments of Formula (E) , (F) , (H) , (M) or (N) , Y 2 is NCH 3 . In some embodiments of Formula (E) , (F) , (H) , (M) or (N) , Y 2 is O.
  • Y 3 is CR C 11d or N. In some embodiments of Formula (G) , Y 3 is CR C 11d . In some such embodiments, R C 11d is independently H, D, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl. In some such embodiments, R C 11d is independently H or C 1 -C 4 alkyl. In some such embodiments, R C 11d is independently H or methyl. In some such embodiments, R C 11d is H. In some embodiments of Formula (G) , Y 3 is N.
  • T 1 is NR C 11e or O.
  • T 1 is NR C 11e .
  • R C 11e is independently H, D, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl.
  • R C 11e is independently H or methyl. In some such embodiments, R C 11e is independently methyl.
  • T 1 is NCH 3 .
  • T 1 is O.
  • T 2 is CR C 11f or N.
  • T 2 is CR C 11f .
  • R C 11f is independently H, D, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl.
  • R C 11f is independently H or methyl. In some such embodiments, R C 11f is independently H.
  • T 2 is CH. In some embodiments of Formula (I′) , (J) , (K) , (ZA) , (ZB) , (ZC) , (O) or (P) , T 2 is N.
  • R C 9a is H, D, F, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments of any of Formulae (E) , (F) , (G) , (H) , (ZA) , (ZB) , (ZC) , (M) or (N) , R C 9a is H.
  • R C 9b is H or C 1 -C 3 alkyl.
  • R C 9b is H.
  • s is an integer selected from 0, 1, 2 or 3; and t is an integer selected from 0, 1, 2 or 3.
  • s is an integer selected from 0, 1, 2 or 3; and t is an integer selected from 0, 1, 2 or 3; with the proviso that the sum of s and t is an integer selected from 2, 3 or 4.
  • the sum of s and t is an integer selected from 2 or 3.
  • the sum of s and t is 2.
  • the sum of s and t is 3.
  • s is 1; and t is 1. In some such embodiments, s is 1; and t is 2. In some such embodiments, s is 2; and t is 1.
  • CBM is a CRBN E3 ligase binding moiety of Formula (E") , (F") , (G") , (H") , (I") , (J") , (K") , (M”) , (N") , (O") or (P") .
  • CBM is a moiety of Formula (E” ) .
  • CBM is a moiety of Formula (F") .
  • CBM is a moiety of Formula (G”) .
  • CBM is a moiety of Formula (H”) .
  • CBM is a moiety of Formula (I") . In some embodiments, CBM is a moiety of Formula (J") . In some embodiments, CBM is a moiety of Formula (K") . In some embodiments, CBM is a moiety of Formula (M”) . In some embodiments, CBM is a moiety of Formula (N") . In some embodiments, CBM is a moiety of Formula (O”) . In some embodiments, CBM is a moiety of Formula (P”) .
  • R C 10 , Y 2 , Y 3 , Z 2 , Z 4 , T 1 and T 2 described herein for CBM moieties of Formula (E) , (F) , (G) , (H) , (I′) , (J) , (K) , (ZA) , (ZB) , (ZC) , (M) , (N) , (O) and (P) are applicable to CBM moieties of Formula (E") , (F") , (G") , (H") , (I") , (J") , (K”) , (M”) , (N") , (O") and (P) to the extent they are not inconsistent.
  • Z 2 is a bond, -C (O) -, -CR C 12a R C 12b -, -NR C 12c -, -O-, -C (O) -NR C 12c -, -NR C 12c -C (O) -, -C (O) -CR C 12a R C 12b -NR C 12c -, -C (O) -CR C 12a R C 12b -O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkylene, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene
  • Z 2 is selected from the group consisting of a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -NH-, -NH-C (O) -, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene and 4-12 membered heterocyclene, optionally substituted as described.
  • Z 2 is selected from the group consisting of a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 6 alkylene, C 2 alkynylene, C 3 -C 6 cycloalkyl and 4-6 membered heterocyclyl, optionally substituted as described.
  • Z 2 is a bond.
  • Z 2 is -C (O) -.
  • Z 2 is -CR C 12a R C 12b -.
  • R C 12a and R C 12b are H, such that Z 2 is -CH 2 - (i.e., methylene) .
  • Z 2 is -NR C 12c -.
  • R C 12c is H, such that Z 2 is -NH-.
  • Z 2 is -O-.
  • Z 2 is -C (O) -CH 2 -NH-.
  • Z 2 is -C (O) -CH 2 -O-.
  • Z 2 is C 2 -C 10 alkylene (e.g., ethylene, propylene, or butylene) .
  • Z 2 is C 2 -C 10 alkenylene or C 2 -C 10 alkynylene (e.g., ethenylene or ethynylene) . In some such embodiments, Z 2 is C 2 alkynylene.
  • Z 2 is C 3 -C 12 cycloalkylene.
  • Z 2 is a bivalent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, or octahydropentalenyl.
  • Z 2 is C 3 -C 6 cycloalkylene.
  • Z 2 is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • Z 2 is 4-12 membered heterocyclene.
  • Z 2 is a bivalent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaspiro [2.3] hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] -octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl, diazaspiro [3.5] nonanyl, diazaspiro [4.4] nonanyl, diazaspiro [4.5] decanyl, diazaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diaza
  • Z 2 is 4-6 membered heterocyclene.
  • Z 2 is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.
  • Z 4 is selected from a bond, C (O) , CR C 21a R C 21b , C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene is optionally substituted by one or more R C 21c ; where R C 21a , R C 21b and R C 21c are as further defined herein.
  • Z 4 is C (O) .
  • Z 4 is CR C 21a R C 21b .
  • R C 21a and R C 21b are H, such that Z 4 is -CH 2 - (i.e., methylene) .
  • Z 4 is C 2 -C 10 alkylene (e.g., ethylene, propylene, or butylene) .
  • Z 4 is C 2 -C 10 alkenylene or C 2 -C 10 alkynylene (e.g., ethenylene or ethynylene) .
  • Z 4 is C 3 -C 12 cycloalkylene.
  • Z 4 is a bivalent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, or octa
  • Z 4 is C 3 -C 6 cycloalkylene. In some such embodiments, Z 4 is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • Z 4 is 4-12 membered heterocyclene.
  • Z 4 is a bivalent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaspiro [2.3] hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] -octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl, diazaspiro [3.5] nonanyl, diazaspiro [4.4] non
  • Z 4 is 4-6 membered heterocyclene. In some such embodiments, Z 4 is azetidinyl, pyrrolidinyl or piperidinyl.
  • CBM is a CRBN E3 ligase binding moiety of any of Formula (E) , (F) , (G) , (H) , (I′) , (J) , (K) , (ZA) , (ZB) , or (ZC) is selected from the group consisting of:
  • CBM is a CRBN E3 ligase binding moiety of Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) or (Y) :
  • CBM is a moiety of Formula (Q) . In some embodiments, CBM is a moiety of Formula (R) . In some embodiments, CBM is a moiety of Formula (S) . In some embodiments, CBM is a moiety of Formula (T) . In some embodiments, CBM is a moiety of Formula (ZD) . In some embodiments, CBM is a moiety of Formula (ZE) . In some embodiments, CBM is a moiety of Formula (U) . In some embodiments, CBM is a moiety of Formula (V) . In some embodiments, CBM is a moiety of Formula (W) . In some embodiments, CBM is a moiety of Formula (X) . In some embodiments, CBM is a moiety of Formula (Y) .
  • Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) or (Y) , U 3 , V 3 , W 3 and X 3 are independently CR C 14 , and each R C 14 is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl C 1 -C 4 alkoxy or C 2 -C 4 haloalkoxy.
  • Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) or (Y) , U 3 , V 3 , W 3 and X 3 are independently CR C 14 , and each R C 14 is independently H or halo.
  • Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) or (Y) U 3 , V 3 , W 3 and X 3 are independently CR C 14 , and each R C 14 is independently H or F.
  • U 3 , V 3 , W 3 and X 3 are independently CR C 14 , and each R C 14 is H (i.e., U 3 , V 3 , W 3 and X 3 are each CH) .
  • U 3 , V 3 , W 3 and X 3 are independently CR C 14 , and at least one R C 14 is F (i.e., at least one of U 3 , V 3 , W 3 and X 3 is CF) .
  • R C 13a is H, D, F, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments of any of Formulae (Q) , (R) , (ZD) , (ZE) , (U) , (V) , (W) or (Y) , R C 13a is H or C 1 -C 3 alkyl. In some embodiments of any of (Q) , (R) , (ZD) , (ZE) , (U) , (V) , (W) or (Y) , R C 13a is H.
  • R C 13b is H or C 1 -C 3 alkyl.
  • R C 13b is H or methyl.
  • R C 13b is H.
  • s is an integer selected from 0, 1, 2 or 3; and t is an integer selected from 0, 1, 2 or 3.
  • s is an integer selected from 0, 1, 2 or 3; and t is an integer selected from 0, 1, 2 or 3; with the proviso that the sum of s and t is an integer selected from 2, 3 or 4.
  • the sum of s and t is an integer selected from 2 or 3.
  • the sum of s and t is the integer 2.
  • the sum of s and t is 3.
  • s is the integer 1; and t is the integer 1.
  • s is the integer 2; and t is the integer 1.
  • the CBM moieties of Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) and (Y) has the structure of Formulae (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′) , (U′) , (V′) , (W′) , (X′) and (Y′) , respectively: wherein R C 13a and R C 13b are defined as for Formulae (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) and (Y) ; Z 3 is defined as for Formulae (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V)
  • CBM is a CRBN E3 ligase binding moiety of Formula (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′) , (U′) , (V′) , (W′) , (X′) or (Y′) .
  • CBM is a moiety of Formula (Q′) .
  • CBM is a moiety of Formula (R′) .
  • CBM is a moiety of Formula (S′) .
  • CBM is a moiety of Formula (T′) .
  • CBM is a moiety of Formula (ZD′) . In some embodiments, CBM is a moiety of Formula (ZE′) . In some embodiments, CBM is a moiety of Formula (U′) . In some embodiments, CBM is a moiety of Formula (V′) . In some embodiments, CBM is a moiety of Formula (W′) . In some embodiments, CBM is a moiety of Formula (X′) . In some embodiments, CBM is a moiety of Formula (Y′) .
  • R C 13a and R C 13b described herein for CBM moieties of Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) and (Y) are applicable to CBM moieties of Formula (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′) , (U′) , (V′) , (W′) , (X′) and (Y′) to the extent they are not inconsistent.
  • the embodiments Z 3 described herein for CBM moieties of Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) and (V) are applicable to CBM moieties of Formula (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′) , (U′) and (V′) to the extent they are not inconsistent.
  • the embodiments Z 4 , s and t described herein for CBM moieties of Formula (W) , (X) and (Y) are applicable to CBM moieties of Formula (W′) , (X′) and (Y′) to the extent they are not inconsistent.
  • each R C 14a , R C 14b , R C 14c or R C 14d is independently H, D, halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, OR C 15a , NR C 15b R C 15c or CN, wherein each C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more halo, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, 4-6 member
  • each R C 14a , R C 14b , R C 14c or R C 14d is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or OR C 15a , where R C 15a is H, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • each R C 14a , R C 14b , R C 14c or R C 14d is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or OR C 15a , where R C 15a is H, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • each R C 14a , R C 14b and R C 14c is H and R C 14d is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or OR C 15a , where R C 15a is H, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • each R C 14a , R C 14b and R C 14c is H and R C 14d is OR C 15a , where R C 15a is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • each R C 14a , R C 14b and R C 14c is H and R C 14d is OCH 3 , OCHF 2 , OCF 3 .
  • each R C 14a , R C 14b and R C 14c is H and R C 14d is OCH 3 .
  • each R C 14a , R C 14b , R C 14c and R C 14d is H.
  • each R C 14a , R C 14b and R C 14c is H and R C 14d is halo.
  • each R C 14a , R C 14b and R C 14c is H and R C 14d is F or Cl.
  • each R C 14b and R C 14c is H and R C 14a and R C 14d are independently H or halo.
  • each R C 14b and R C 14c is H and R C 14a and R C 14d are halo.
  • each R C 14b and R C 14c is H and R C 14a and R C 14d are independently F or Cl. In some such embodiments, each R C 14b and R C 14c is H and R C 14a and R C 14d are F.
  • the CBM moieties of Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) and (Y) has the structure of Formulae (Q") , (R") , (S”) , (T") , (ZD”) , (ZE") , (U") , (V") , (W”) , (X”) and (Y”) , respectively: wherein R C 14a and R C 14d is defined as for Formulae (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′) , (U′) , (V′) , (W′) , (X′) or (Y′) ; Z 3 is defined as for Formulae (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′)
  • CBM is a CRBN E3 ligase binding moiety of Formula (Q") , (R") , (S") , (T") , (ZD") , (ZE") , (U") , (V") , (W”) , (X”) or (Y”) .
  • CBM is a moiety of Formula (Q") .
  • CBM is a moiety of Formula (R") .
  • CBM is a moiety of Formula (S”) .
  • CBM is a moiety of Formula (T”) .
  • CBM is a moiety of Formula (ZD”) .
  • CBM is a moiety of Formula (ZE") . In some embodiments, CBM is a moiety of Formula (U") . In some embodiments, CBM is a moiety of Formula (V") . In some embodiments, CBM is a moiety of Formula (W”) . In some embodiments, CBM is a moiety of Formula (X”) . In some embodiments, CBM is a moiety of Formula (Y”) .
  • R C 14d described herein for CBM moieties of Formula (Q′) , (R′) , (S′) , (T′) , (ZD′) , (ZE′) , (U′) , (V′) , (W′) , (X′) or (Y′) are applicable to CBM moieties of Formula (Q") , (R") , (S”) , (T”) , (ZD”) , (ZE”) , (U”) , (V”) , (W”) , (X”) or (Y”) to the extent they are not inconsistent.
  • Z 3 is a bond, -C (O) -, -CR C 16a R C 16b -, -NR C 16c -, -O-, -C (O) -NR C 16c -, -NR C 16c -C (O) -, -C (O) -CR C 16a R C 16b -NR C 16c -, -C (O) -CR C 16a R C 16b -O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 6 cycloalkylene or 4-6 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 6 cycloalkylene or 4-6 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C
  • Z 3 is selected from the group consisting of a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -NH-, -NH-C (O) -, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene and 4-12 membered heterocyclene, optionally substituted as described.
  • Z 3 is selected from the group consisting of a bond, -C (O) -, -CH 2 -, -NH-, -O-, -C (O) -CH 2 -NH-, -C (O) -CH 2 -O-, C 2 -C 6 alkylene, C 2 alkynylene, C 3 -C 6 cycloalkylene and 4-6 membered heterocyclene, optionally substituted as described.
  • Z 3 is a bond.
  • Z 3 is -CR C 16a R C 16b -.
  • R C 16a and R C 16b are H, such that Z 3 is -CH 2 - (i.e., methylene) .
  • Z 3 is -NR C 16c -.
  • R C 16c is H, such that Z 3 is -NH-.
  • Z 3 is -C (O) -CH 2 -NH-.
  • Z 3 is -C (O) -CH 2 -O-.
  • Z 3 is C 2 -C 10 alkylene (e.g., ethylene, propylene, or butylene) .
  • Z 3 is C 2 -C 10 alkenylene or C 2 -C 10 alkynylene (e.g., ethenylene or ethynylene) .
  • Z 2 is C 2 alkynylene.
  • Z 3 is C 3 -C 12 cycloalkylene.
  • Z 3 is a bivalent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl
  • Z 3 is C 3 -C 6 cycloalkylene.
  • Z 3 is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • Z 3 is 4-12 membered heterocyclene.
  • Z 3 is a bivalent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaspiro [2.3] hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] -octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl,
  • Z 3 is 4-6 membered heterocyclene.
  • Z 3 is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.
  • Z 4 is selected from a bond, C (O) , CR C 21a R C 21b , C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene is optionally substituted by one or more R C 21c ; where R C 21a , R C 21b and R C 21c are as further defined herein.
  • Z 4 is CR C 21a R C 21b .
  • R C 21a and R C 21b are H, such that Z 4 is -CH 2 - (i.e., methylene) .
  • Z 4 is C 2 -C 10 alkylene (e.g., ethylene, propylene, or butylene) .
  • Z 4 is C 2 -C 10 alkenylene or C 2 -C 10 alkynylene (e.g., ethenylene or ethynylene) .
  • Z 4 is C 3 -C 12 cycloalkylene.
  • Z 4 is a bivalent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, or octahydropentaleny
  • Z 4 is C 3 -C 6 cycloalkylene. In some such embodiments, Z 4 is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • Z 4 is 4-12 membered heterocyclene.
  • Z 4 a bivalent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaspiro [2.3] hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] -octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl, diazaspiro [3.5] nonanyl, diazaspiro [4.4] nonanyl, diazaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diaza
  • Z 4 is 4-6 membered heterocyclene. In some such embodiments, Z 4 is azetidinyl, pyrrolidinyl or piperidinyl.
  • the CBM is a CRBN E3 ligase binding moiety of Formula (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) or (Y) selected from the group consisting of:
  • CBM is a CRBN E3 ligase binding moiety of Formulae (AA) , (AB) or (AC) :
  • CBM is a moiety of Formula (AA) . In some embodiments, CBM is a moiety of Formula (AB) . In some embodiments, CBM is a moiety of Formula (AC) .
  • U 4 , V 4 , W 4 and X 4 are independently CR C 18 , and each R C 18 is independently H, D, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl C 1 -C 4 alkoxy or C 2 -C 4 haloalkoxy.
  • U 4 , V 4 , W 4 and X 4 are independently CR C 10 , and each R C 10 is independently H or halo.
  • U 4 , V 4 , W 4 and X 4 are independently CR C 10 , and each R C 10 is independently H or F.
  • U 4 , V 4 , W 4 and X 4 are independently CR C 10 , and each R C 10 is H (i.e., U 4 , V 4 , W 4 and X 4 are each CH) .
  • U 4 , V 4 , W 4 and X 4 are independently CR C 10 , and at least one R C 10 is F (i.e., at least one of U 4 , V 4 , W 4 and X 4 is CF) .
  • Y 4 is C (O) or CR C 20a R C 20b . In some embodiments of any of Formulae (AA) , (AB) or (AC) , Y 4 is C (O) or CH 2 . In some embodiments of any of Formulae (AA) , (AB) or (AC) , Y 4 is C (O) . In some embodiments of any of Formulae (AA) , (AB) or (AC) , Y 4 is CR C 20a R C 20b . In some such embodiments, R C 20a and R C 20b are independently H, D, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl. Preferably, when Y 4 is CR C 20a R C 20b , each ofR C 20a and R C 20b is H (i.e., Y 4 is CH 2 ) .
  • R C 17a is H, D, F, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In some embodiments, R C 17a is H.
  • R C 17b is H or C 1 -C 3 alkyl. In some embodiments, R C 17b is H.
  • s is an integer selected from 0, 1, 2 or 3; and t is an integer selected from 0, 1, 2 or 3.
  • s is an integer selected from 0, 1, 2 or 3; and t is an integer selected from 0, 1, 2 or 3; with the proviso that the sum of s and t is an integer selected from 2, 3 or 4.
  • the sum of s and t is an integer selected from 2 or 3.
  • the sum of s and t is the integer 2.
  • the sum of s and t is 3.
  • s is the integer 1; and t is the integer 1.
  • s is the integer 2; and t is the integer 1.
  • the CBM moieties of Formula (AA) , (AB) or (AC) has the structure of Formulae (AA") , (AB") or (AC") , respectively: wherein: R C 17a , R C 17b , Y 4 and Z 4 are defined as for Formulae (AA) , (AB) or (AC) ; each R C 18a , R C 18b , R C 18c , and R C 18d is independently H, D, halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, OR C 19a , NR C 19b R C 19c , CN or NO 2 , wherein each C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more halo, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1
  • CBM is a CRBN E3 ligase binding moiety of Formula (AA") , (AB") or (AC") .
  • CBM is a moiety of Formula (AA") .
  • CBM is a moiety of Formula (AB”) .
  • CBM is a moiety of Formula (AC”) .
  • R C 17a , R C 17b , Y 4 and Z 4 described herein for CBM moieties of Formula ( (AA) , (AB) or (AC) are applicable to CBM moieties of Formula ( (AA") , (AB") or (AC") to the extent they are not inconsistent.
  • each R C 18a , R C 18b , R C 18c and R C 18d is independently H, D, halo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, OR C 19a , NR C 19b R C 19c , CN or NO 2 , wherein each C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more halo, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, NH 2 , NH (C 1 -C 4 alkyl) , N (C 1 -C 4 alkyl) 2 or CN.
  • R C 19a , R C 19b and R C 19c are independently H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 4 cycloalkyl.
  • each R C 18a , R C 18b , R C 18c or R C 18d is independently H or halo.
  • each R C 18a , R C 18b , R C 18c or R C 18d is H.
  • at least one of R C 18a , R C 18b , R C 18c or R C 18d is halo.
  • At least one of R C 18a , R C 18b , R C 18c or R C 18d is F or Cl. In some embodiments, at least one of R C 18a , R C 18b , R C 18c or R C 18d is F.
  • Z 4 is selected from a bond, C (O) , CR C 21a R C 21b , C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene, wherein each said C 2 -C 10 alkylene, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, C 3 -C 12 cycloalkylene or 4-12 membered heterocyclene is optionally substituted by one or more R C 21c ; where R C 21a , R C 21b and R C 21c are as further defined herein.
  • Z 4 is a bond.
  • Z 4 is C (O) .
  • Z 4 is CR C 21a R C 21b .
  • R C 21a and R C 21b are H, such that Z 4 is -CH 2 - (i.e., methylene) .
  • Z 4 is C 2 -C 10 alkylene (e.g., ethylene, propylene, or butylene) .
  • Z 4 is C 2 -C 10 alkenylene or C 2 -C 10 alkynylene (e.g., ethenylene or ethynylene) .
  • Z 4 is C 3 -C 12 cycloalkylene.
  • Z 4 is a bivalent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [2.5] octanyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [5.5] undecanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, or octahydropentaleny
  • Z 4 is C 3 -C 6 cycloalkylene. In some such embodiments, Z 4 is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.
  • Z 4 is 4-12 membered heterocyclene.
  • Z 4 a bivalent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaspiro [2.3] hexanyl, azaspiro [2.4] heptanyl, azaspiro [2.5] octanyl, azaspiro [3.3] heptanyl, azaspiro [3.4] -octanyl, azaspiro [3.5] nonanyl, azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diazaspiro [3.3] heptanyl, diazaspiro [3.4] octanyl, diazaspiro [3.5] nonanyl, diazaspiro [4.4] nonanyl, diazaspiro [4.5] decanyl, azaspiro [5.5] undecanyl, diaza
  • Z 4 is 4-6 membered heterocyclene. In some such embodiments, Z 4 is azetidinyl, pyrrolidinyl or piperidinyl.
  • CBM is a CRBN E3 ligase binding moiety of Formula (AA”) , (AB”) or (AC”) selected from the group consisting of:
  • Z 1 , Z 2 , or Z 3 is selected from: where the dashed line indicates the point of attachment to the linker.
  • Z 4 is selected from: where the dashed line indicates the point of attachment to the linker.
  • Z 1 , Z 2 , Z 3 , or Z 4 is selected from: where the dashed line indicates the point of attachment to the linker.
  • Z 1 , Z 2 , Z 3 , or Z 4 is selected from: where the dashed line indicates the point of attachment to the linker.
  • Z 1 , Z 2 , or Z 3 is selected from: where the dashed line indicates the point of attachment to the linker.
  • Z 4 is selected from: where the dashed line indicates the point of attachment to the linker.
  • Z 1 , Z 2 , Z 3 , or Z 4 is selected from:
  • Z 1 , Z 2 , Z 3 , or Z 4 is selected from: Linkers:
  • the linker L is covalently attached to a protein binding moiety (PBM) that binds to CDK4, CDK6 or CDK2.
  • PBM protein binding moiety
  • Formula (L) may be represented as Formula (L-1) : wherein each L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 and L 10 is independently defined as for L x .
  • m is an integer selected from 1 to 5
  • Formula (L) may be represented as Formula (L-2) : wherein each L 1 , L 2 , L 3 , L 4 and L 5 is independently defined as for L x .
  • m is an integer selected from 1 to 4, and Formula (L) may be represented as Formula (L-3) : wherein each L 1 , L 2 , L 3 and L 4 is independently defined as for L x .
  • m is an integer selected from 1 to 3
  • Formula (L) may be represented as Formula (L-4) : wherein each L 1 , L 2 and L 3 is independently defined as for L x .
  • m is an integer selected from 1 to 2
  • Formula (L) may be represented as Formula (L-5) : wherein each L 1 and L 2 is independently defined as for L x .
  • Formula (L) may be represented as Formula (L-6) : wherein L 1 is independently defined as for L x .
  • L is a bivalent linker of Formula (L) .
  • L is a bivalent linker of Formula (L-1) .
  • L is a bivalent linker of Formula (L-2) .
  • L is a bivalent linker of Formula (L-3) .
  • L is a bivalent linker of Formula (L-4) .
  • L is a bivalent linker of Formula (L-5) . In some embodiments of any of Formulae (I) - (XI-2) , L is a bivalent linker of Formula (L-6) .
  • L is a bivalent linker of any of Formulae (L) , (L-1) , (L-2) , (L-3) , (L-4) , (L-5) or (L-6) , wherein at least one L x is R L r , wherein R L r may be monocyclic, fused, bridged or spirocyclic C 3 -C 12 cycloalkylene or 3-12 membered heterocyclene, or monocyclic or fused C 6 -C 12 arylene or 5-13 membered heteroarylene, each optionally substituted as described.
  • R L r is C 3 -C 12 cycloalkylene or 3-12 membered heterocyclene, each optionally substituted by one or more R 24a . In some such embodiments, R L r is C 6 -C 10 arylene or 5-10 membered heteroarylene, each optionally substituted by one or more R 24b .
  • Examples of ring moieties R L r suitable for inclusion in linkers any of Formulae (L) , (L-1) , (L-2) , (L-3) , (L-4) , (L-5) or (L-6) include the moieties of formula (L-a) , formula (L-b) , formula (L-c) , formula (L-d) and formula (L-e) , and embodiments thereof described herein.
  • L is a bivalent linker of any of Formulae (L) , (L-1) , (L-2) , (L-3) , (L-4) , (L-5) or (L-6) comprising one or more rings selected from the group consisting of formula (L-a) , formula (L-b) , formula (L-c) , formula (L-d) and formula (L-e) : wherein: X R ’a nd Y R ’a re independently selected from N or CR R b ; A R 1 , B R 1 , C R 1 and D R 1 , at each occurrence, are independently selected from a bond, O, CO, SO, SO 2 , C (O) NR R b , S (O) 2 NR R b , NR R b or CR R b R R c ; A R 2 , B R 2 , C R 2 , D R 2
  • L is a bivalent linker of any of Formulae (L) , (L-1) , (L-2) , (L-3) , (L-4) , (L-5) or (L-6) comprising one or more R L r moieties selected from the group consisting of formula (L-a) , formula (L-b) , formula (L-c) , formula (L-d) and formula (L-e) .
  • L is a bivalent linker of any of Formulae (L) , (L-1) , (L-2) , (L-3) , (L-4) , (L-5) or (L-6) comprising one or more R L r moieties selected from the group consisting of:
  • L is a bivalent linker selected from the group consisting of: -C (O) -C 1 -C 10 alkylene, -C (O) -C 2 -C 10 heteroalkylene, -C (O) -C 1 -C 10 alkylene-C 1 -C 10 alkylene, -C (O) -C 1 -C 10 alkylene-C 2 -C 10 heteroalkylene, -C (O) -C 2 -C 10 heteroalkylene-C 1 -C 10 alkylene and -C (O) -C 2 -C 10 heteroalkylene-C 2 -C 10 heteroalkylene.
  • L is a bivalent linker selected from the group consisting of: - (CH 2 ) p1 -SO 2 - (CH 2 CH 2 O) p2 - (CH 2 ) p3 -, - (CH 2 ) p1 -SO 2 -NH- (CH 2 CH 2 O) p2 - (CH 2 ) p3 -, - (CH 2 ) p1 -NH-SO 2 - (CH 2 CH 2 O) p2 - (CH 2 ) p3 -, - (CH 2 ) p1 -SO 2 - (CH 2 ) p2 -, - (CH 2 ) p1 -SO 2 -NH- (CH 2 ) p2 -, - (CH 2 ) p1 -NH-SO 2 - (CH 2 ) p2 -, - (CH 2 ) p1 -NH-SO 2 - (CH 2 ) p2 -, - (
  • L is a bivalent linker selected from the group consisting of: - (CH 2 ) 0-3 - (C 3 -C 12 cycloalkyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 - (3-12 membered heterocyclyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 - (C 6 -C 12 aryl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 - (5-13 membered heteroaryl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 -SO 2 - (CH 2 ) 0-3 - (C 3 -C 12 cycloalkyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 -SO 2 - (CH 2 ) 0-3 - (C 3 -C 12 cycloalkyl)
  • L is a bivalent linker selected from the group consisting of: - (CH 2 ) 0-3 - (C 3 -C 12 cycloalkyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 - (3-12 membered heterocyclyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 -SO 2 - (CH 2 ) 0-3 - (C 3 -C 12 cycloalkyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 -SO 2 - (CH 2 ) 0-3 - (3-12 membered heterocyclyl) - (CH 2 ) 0-4 -, - (CH 2 ) 0-3 -SO 2 NH- (CH 2 ) 0-3 - (C 3 -C 12 cycloalkyl)
  • L is a bivalent linker selected from the group consisting of: - (CH 2 ) 1-9 -, -SO 2 (CH 2 ) 1-8 -, - (CH 2 ) 1-2 SO 2 NH (CH 2 ) 2-9 -, - (CH 2 ) 1-2 SO 2 NH (CH 2 ) 1-3 - (OCH 2 CH 2 ) 1-7 -, - (CH 2 ) 0-1 SO 2 (CH 2 ) 1-3 (OCH 2 CH 2 ) 1-7 -, -SO 2 (CH 2 ) 0-3 (alkenylene) (CH 2 ) 0-3 -, -SO 2 - (CH 2 ) 0- 3 (alkynylene) (CH 2 ) 0-3 -, -SO 2 (CH 2 ) 0-3 (3-8 membered carbocyclyl) (CH 2 ) 0-3 -, -SO 2 (CH 2 ) (CH 2 ) 0-3 (3-8 membered carbocyclyl
  • L is a bivalent linker selected from the group consisting of: -SO 2 -C 1 -C 10 alkylene, -SO 2 -C 2 -C 10 heteroalkylene, -SO 2 -C 1 -C 10 alkylene-C 1 -C 10 alkylene, -SO 2 -C 1 -C 10 alkylene-C 2 -C 10 heteroalkylene, -SO 2 -C 2 -C 10 heteroalkylene-C 1 -C 10 alkylene, and -SO 2 -C 2 -C 10 heteroalkylene-C 2 -C 10 heteroalkylene.
  • the compounds of Formulae (I) - (XI-2) described herein have any combination of one, two, three, four, five, or more than five of the following preferred features, which may be independently selected, provided the selected features are applicable and are not incompatible with each other: q is the integer 1 and r is the integer 1; R 1 is OR 1a ; R 1a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 7 cycloalkyl; R 1a is C 1 -C 6 alkyl; R 1a is C 1 -C 6 haloalkyl; R 1a is C 3 -C 7 cycloalkyl; R 1a is Et, i Pr, c Bu, or CH 2 CF 3 ; R 1a is i Pr; R 1a is Et; R 1 is OEt, O i Pr, O c Bu, or OCH 2 CF 3 ; R 1 is O i Pr; R 1 is OE
  • a heterobifunctional compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above.
  • E12 The compound of any one of embodiments E1-E5, having the structure of Formula (V-1) , (V-A-1) or (V-B-1) : or a pharmaceutically acceptable salt thereof.
  • E17 The compound of any one of embodiments E1-E5, E7 or E9-E12, having the structure of Formula (VII-1) , (VII-A-1) or (VII-B-1) : or a pharmaceutically acceptable salt thereof.
  • E35 The compound of any one of embodiments E29-E33, having the structure of Formula (III-2) , (III-A-2) or (III-B-2) : or a pharmaceutically acceptable salt thereof.
  • E36 The compound of any one of embodiments E29-E32 or 3E4, having the structure of Formula (IV-2) , (IV-A-2) or (IV-B-2) : or a pharmaceutically acceptable salt thereof.
  • E42 The compound of any one of embodiments E36-E38 or E40, having the structure of Formula (IX-2) , (IX-A-2) or (IX-B-2) : or a pharmaceutically acceptable salt thereof.
  • E45 The compound of any one of embodiments E1-E42, or a pharmaceutically acceptable salt thereof, wherein R 1 is independently H, D, C 1 -C 6 alkyl, OR 1a , SR 1a , NR 1b R 1c , 4-7 membered heterocyclyl, or phenyl, wherein each said C 1 -C 6 alkyl is optionally substituted by one or more R 1A , and each said 4-7 membered heterocyclyl or phenyl is optionally substituted by one or more R 1R .
  • each R 1a , R 1b and R 1c is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 7 cycloalkyl.
  • E48 The compound of any one of embodiments E45-E47, or a pharmaceutically acceptable salt thereof, wherein R 1 is OR 1a and R 1a is Et, i Pr, c Bu, or CH 2 CF 3 .
  • each R 4 is independently selected from halo, CN, C 1 -C 6 alkyl, OR 4a , NR 4b R 4c or C 3 -C 7 cycloalkyl, wherein each said C 1 -C 6 alkyl is optionally substituted by one or more R 4A , and each said C 3 -C 7 cycloalkyl is optionally substituted by one or more R 4R ; each R 4a , R 4b and R 4c is independently selected from H or C 1 -C 6 alkyl, wherein each said C 1- C 6 alkyl is optionally substituted by one or more R 4A ; R 4A is halo; and p is an integer selected from 0, 1 or 2.
  • E53 The compound of any one of embodiments E1-E5, E7, E9-E12, E17-E20, E23, E24-E32, E34, E36-E38, E40, E42, or E44-E52, or a pharmaceutically acceptable salt thereof, wherein R 2 is H or halo.
  • E58 The compound of any one of embodiments E55-E57, wherein L is a bivalent linker of Formula (L) , (L-2) , (L-3) , (L-4) , or (L-5) , comprising one or more R L r moieties selected from the group consisting of formula (L-a) , formula (L-b) , formula (L-c) , formula (L-d) and formula (L-e) , each as described above.
  • L is a bivalent linker of Formula (L) , (L-2) , (L-3) , (L-4) , or (L-5) , comprising one or more R L r moieties selected from the group consisting of formula (L-a) , formula (L-b) , formula (L-c) , formula (L-d) and formula (L-e) , each as described above.
  • E60 The compound of any one of embodiments E1-E56, or a pharmaceutically acceptable salt thereof, wherein L is a bivalent linker selected from the group consisting of: -C (O) -C 1 -C 10 alkylene, -C (O) -C 2 -C 10 heteroalkylene, -C (O) -C 1 -C 10 alkylene-C 1 -C 10 alkylene, -C (O) -C 1 - C 10 alkylene-C 2 -C 10 heteroalkylene, -C (O) -C 2 -C 10 heteroalkylene-C 1 -C 10 alkylene, and -C (O) -C 2 -C 10 heteroalkylene-C 2 -C 10 heteroalkylene.
  • L is a bivalent linker selected from the group consisting of: -C (O) -C 1 -C 10 alkylene, -C (O) -C 2 -C 10 heteroalkylene, -
  • E63 The compound of any one of embodiments E1 to E62, or a pharmaceutically acceptable salt thereof, wherein CBM is a moiety selected from the group consisting of: (i) Formulae (A) , (B) , (C) and (D) ; (ii) Formulae (E) , (F) , (G) , (H) , (I′) , (J) , (K) , (ZA) , (ZB) , (ZC) , (M) , (N) , (O) and (P) ; (iii) Formulae (Q) , (R) , (S) , (T) , (ZD) , (ZE) , (U) , (V) , (W) , (X) and (Y) ; or (iv) Formulae (AA) , (AB) and (AC) ; each as further described above, including embodiments thereof.
  • CBM is a moiety selected from the group consisting of
  • a pharmaceutical composition comprising a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Also provided herein are therapeutic methods and uses comprising administering a compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt, alone or in combination with one or more other therapeutic agents or palliative agents.
  • a method for the treatment of a disease or disorder associated with abnormal cell growth, such as cancer, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering an additional therapeutic agent (e.g., an anticancer therapeutic agent) to the subject.
  • a heterobifunctional compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder associated with abnormal cell growth, such as cancer, in a subject is provided.
  • a heterobifunctional compound of any of Formulae (I) -(XI-2) , or a pharmaceutically acceptable salt thereof as a medicament, e.g., a medicament for the treatment of a disease or disorder associated with abnormal cell growth, such as cancer.
  • a heterobifunctional compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, e.g., a medicament for the treatment of a disease or disorder associated with abnormal cell growth, such as cancer.
  • the a disease or disorder associated with abnormal cell growth is cancer.
  • Enumerated embodiments E65 to E101 relate to methods of treatment, compounds for use, uses, and combinations comprising a heterobifunctional compound of Formula (I) - (XI-2) , or a sub-formula thereof.
  • E66 A method for the treatment of a disease or disorder associated with abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment E65.
  • a method for the treatment of cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment E65.
  • a method for the treatment of cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment E65, in combination with a therapeutically effective amount of at least one additional therapeutic agent.
  • E70 The method of embodiment E69, wherein the additional therapeutic agent is an anticancer agent selected from a chemotherapy, targeted therapy, immunotherapy, radiotherapy, or photodynamic therapy (PDT) , or any combination thereof.
  • the additional therapeutic agent is an anticancer agent selected from a chemotherapy, targeted therapy, immunotherapy, radiotherapy, or photodynamic therapy (PDT) , or any combination thereof.
  • E72 Use of a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof: a. in therapy; b. in the treatment of a disease or disorder associated with abnormal cell growth; c. in the treatment of cancer; d. as a medicament; e. in the manufacture of a medicament; or f. in the manufacture of a medicament for the treatment of cancer.
  • a combination comprising a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  • E75 The combination of embodiment E73 or E74, wherein the additional therapeutic agent is an anticancer agent selected from chemotherapy, targeted therapy, immunotherapy, radiotherapy, or photodynamic therapy (PDT) , or any combination thereof.
  • the additional therapeutic agent is an anticancer agent selected from chemotherapy, targeted therapy, immunotherapy, radiotherapy, or photodynamic therapy (PDT) , or any combination thereof.
  • a pharmaceutical composition comprising the fixed combination of embodiment E77, and at least one pharmaceutically acceptable excipient.
  • E81 The method, compound, use, or combination of any one of embodiments E67 to E72, or E74 to E80, wherein the cancer is selected from: breast cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, bladder cancer, biliary tract cancer, prostate cancer, lung cancer, bone cancer, central nervous system (CNS) cancer, oral cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, melanoma, and hematopoietic or lymphoid cancer.
  • the cancer is selected from: breast cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, bladder cancer, biliary tract cancer, prostate cancer, lung cancer, bone cancer, central nervous system (CNS) cancer, oral cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, melanoma, and
  • E84 The method, compound, use, or combination of embodiment E83, wherein the cancer is CCNE1 amplified ovarian cancer, gastric cancer, esophageal cancer (including GEJ adenocarcinoma) , uterine carcinosarcoma, fallopian tube cancer, peritoneal cancer, endometrial cancer, TNBC, SCLC, or NSCLC.
  • the cancer is CCNE1 amplified ovarian cancer, gastric cancer, esophageal cancer (including GEJ adenocarcinoma) , uterine carcinosarcoma, fallopian tube cancer, peritoneal cancer, endometrial cancer, TNBC, SCLC, or NSCLC.
  • the breast cancer is post-CDK 4/6 inhibitor treated hormone receptor positive (HR+) breast cancer.
  • E96 A method of degrading CDK2 in a cell, system, or subject, comprising administering to the cell, system, or subject an effective amount of a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof.
  • a method of identifying a compound capable of degrading CDK2, comprising the steps of: (1) providing a test system for monitoring degradation of CDK2; and (2) determining whether a test compound degrades CDK2 in the test system.
  • test system comprises a cancer cell.
  • test compound is a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof.
  • a method of degrading a protein selected from CDK2 or CCNE comprising contacting the protein with a heterobifunctional compound of any one of embodiments E1 to E64, or a pharmaceutically acceptable salt thereof, wherein the contacting comprises contacting a cell comprising the protein with the heterobifunctional compound and results in degradation of the target protein.
  • provided herein is a method to (a) degrade, (b) inhibit, or (c) modulate CDK2 or CCNE (e.g., CCNE1 and/or CCNE2) in a cell, system, or subject, said method comprising administering an effective amount of a heterobifunctional compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof.
  • CCNE e.g., CCNE1 and/or CCNE2
  • the desired selectivity for a target protein over one or more off-target proteins may be determined using standard assays, such as enzyme activity assays, binding assays, cell based assays, or kinetic assays.
  • a compound having an IC 50 for a target protein of 10 nM and an IC 50 of an off-target protein of 100 nM demonstrates ten-fold selectivity for the target protein over the off-target protein.
  • the compounds described herein selectively degrade CDK2 over one or more other CDKs, and in particular selectively degrade CDK2 over CDK1.
  • the compounds described herein selectively degrade CDK2 over CDK4 and/or CDK6.
  • the compounds described herein selectively degrade CDK2 over CDK1, CDK4 and CDK6. In other embodiments, the compounds described herein degrade CDK2 and CDK4. In other embodiments, the compounds described herein degrade CDK2 and CDK4 selectively over CDK1. In some embodiments, compounds demonstrating selectivity degrade the target protein with at least ten-fold, preferably at least twenty-fold, and more preferably at least thirty-fold selectivity for CDK2 over one or more off target proteins. Such selective compounds may have an improved therapeutic window by avoiding off-target mediated toxicity, e.g., toxicity to normal cells.
  • the disease or disorder is cancer.
  • Cancer includes solid tumors or cancers of the blood, bone marrow, or lymphatic system (sometimes referred to as “liquid tumors” ) .
  • Solid tumors refer to abnormal masses of cells that grow in an organ system and generally do not contain cysts or liquid areas. Solid tumors may be noncancerous (benign) or cancerous (malignant) and may include a single mass or multiple masses. Cancerous solid tumors are typically named for the type of cells that form them, and include, but are not limited to, sarcomas and carcinomas. “Liquid tumors” may circulate throughout the body via the bloodstream.
  • Cancers of the blood include, but are not limited to, leukemia, lymphoma, or myeloma. Cancer may include a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, or a second primary cancer in a person with a prior history of cancer of a different type.
  • the cancer is selected from gastrointestinal cancer, gynecologic cancer, biliary tract cancer, hepatobiliary tract cancer, breast cancer, thyroid cancer, adrenal gland cancer, genitourinary tract cancer, central nervous system cancer, skin cancer, lung cancer, head and neck cancer, hematologic or lymphoid cancer, or sarcoma.
  • the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, fallopian tube cancer, peritoneal cancer, bladder cancer, biliary tract cancer, prostate cancer, lung cancer (e.g., SCLC or NSCLC) , bone cancer, central nervous system (CNS) cancer, oral cancer, esophageal cancer (including, e.g., GEJ adenocarcinoma) , head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, melanoma, and hematopoietic or lymphoid cancer.
  • the cancer is gastrointestinal (GI) cancer.
  • the cancer is colorectal cancer, gastric cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma (HCC) ) , esophageal cancer (e.g., squamous cell carcinoma (SCC) or gastroesophageal junction (GEJ) adenocarcinoma) , small intestinal cancer, or anal cancer.
  • GI gastrointestinal
  • the cancer is colorectal cancer, gastric cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma (HCC) ) , esophageal cancer (e.g., squamous cell carcinoma (SCC) or gastroesophageal junction (GEJ) adenocarcinoma) , small intestinal cancer, or anal cancer.
  • HCC hepatocellular carcinoma
  • GEJ gastroesophageal junction
  • the cancer is gynecologic cancer.
  • the cancer is endometrial cancer, ovarian cancer, cervical cancer, uterine cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, or vulvar cancer.
  • the cancer is biliary tract cancer.
  • the cancer is gallbladder cancer, ampullary cancer, or bile duct cancer (e.g., extra-hepatic cholangiocarcinoma or intra-hepatic cholangiocarcinoma) .
  • the cancer is hepatobiliary tract cancer.
  • the cancer is liver cancer or gallbladder cancer.
  • the cancer is breast cancer.
  • the cancer is triple negative breast cancer (TNBC) .
  • the cancer is thyroid cancer.
  • the cancer is thyroid epithelial cancer.
  • the cancer is adrenal gland cancer.
  • the cancer is adrenocortical cancer or neuroblastoma.
  • the cancer is genitourinary tract cancer.
  • the cancer is kidney cancer (e.g., RCC) , bladder cancer (e.g., urothelial bladder cancer (BC) ) , upper tract urothelial carcinoma (UTUC) , prostate cancer, urethral cancer, testicular cancer, or penile cancer.
  • kidney cancer e.g., RCC
  • bladder cancer e.g., urothelial bladder cancer (BC)
  • UTUC upper tract urothelial carcinoma
  • prostate cancer urethral cancer
  • testicular cancer urethral cancer
  • penile cancer e.g., urethral cancer, testicular cancer, or penile cancer.
  • the cancer is central nervous system (CNS) cancer.
  • the cancer is brain cancer or spinal cord cancer (e.g., glioma, glioblastoma, glioblastoma multiforme (GBM) , or meningioma) .
  • the cancer is skin cancer.
  • the cancer is melanoma, squamous cell carcinoma, or basal cell carcinoma (BCC) .
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer (NSCLC) , small cell lung cancer (SCLC) , squamous cell carcinoma or adenocarcinoma (e.g., lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LUAD) ) .
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • squamous cell carcinoma or adenocarcinoma e.g., lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LUAD)
  • the cancer is head and neck cancer.
  • the cancer is squamous cell carcinoma of the head and neck (SCCHN) , oral cavity cancer, laryngeal cancer, or throat cancer.
  • the cancer is hematologic or lymphoid cancer.
  • the cancer is leukemia (e.g., ALL, AML or CLL) , lymphoma (e.g., B-cell lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma (MCL) ) , or multiple myeloma.
  • the cancer is sarcoma.
  • the cancer is bone cancer (e.g., osteosarcoma or Ewing sarcoma) , or soft-tissue sarcoma (e.g., pediatric rhabdoid sarcoma or CIC-rearranged sarcoma) .
  • the cancer is breast cancer.
  • the breast cancer is hormone receptor positive (HR+) .
  • the breast cancer is hormone receptor negative (HR-) .
  • the breast cancer is human epidermal growth factor 2 (HER2) -positive.
  • the breast cancer is human epidermal growth factor 2 (HER2) -negative.
  • the breast cancer is hormone receptor positive (HR+) , human epidermal growth factor 2 (HER2) -negative breast cancer.
  • the breast cancer is triple negative breast cancer (TNBC) .
  • the breast cancer is inflammatory breast cancer.
  • the breast cancer is advanced or metastatic breast cancer.
  • the cancer is ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, fallopian tube cancer, or peritoneal cancer.
  • the cancer is ovarian cancer.
  • the ovarian cancer is high-grade serous ovarian cancer (HGSOC) .
  • the cancer is endometrial cancer.
  • the cancer is cervical cancer.
  • the cancer is uterine cancer.
  • the uterine cancer is uterine carcinosarcoma.
  • the cancer is fallopian tube cancer.
  • the cancer is peritoneal cancer.
  • the cancer is bladder cancer. In some embodiments of any of the methods and uses herein, the cancer is biliary tract cancer. In some embodiments of any of the methods and uses herein, the cancer is prostate cancer.
  • the cancer is lung cancer.
  • the lung cancer is NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma.
  • the lung cancer is NSCLC.
  • the lung cancer is lung adenocarcinoma (LUAD) .
  • the lung cancer is lung squamous cell carcinoma (LUSC) .
  • the cancer is bone cancer.
  • the bone cancer is primary bone cancer.
  • the bone cancer is bone metastasis.
  • the bone cancer is sarcoma.
  • the sarcoma is osteosarcoma or Ewing sarcoma.
  • the methods and uses herein may reduce or ameliorate bone cancer pain (BCP) .
  • the cancer is soft tissue sarcoma. In some such embodiments, the cancer is pediatric rhabdoid sarcoma or CIC-rearranged sarcoma.
  • the cancer is a nervous system cancer.
  • the cancer is central nervous system (CNS) cancer.
  • the cancer is brain cancer or spinal cord cancer (e.g., glioma, glioblastoma, glioblastoma multiforme (GBM) , or meningioma) .
  • the glioma is astrocytoma, oligodendroglioma, or glioblastoma.
  • the cancer is a sympathetic nervous system cancer. In some such embodiments, the nervous system cancer is neuroblastoma.
  • the cancer is oral cancer, esophageal cancer, or head and neck cancer.
  • the cancer is oral cancer.
  • the cancer is esophageal cancer.
  • the esophageal cancer is GEJ adenocarcinoma.
  • the cancer is head and neck cancer.
  • the head and neck cancer is HNSSC.
  • the HNSSC is HPV-negative HNSCC.
  • the HNSSC is HPV-positive HNSCC.
  • the cancer is melanoma.
  • the cancer is hematologic or lymphoid cancer.
  • the hematologic or lymphoid cancer is lymphoma, myeloma, or leukemia.
  • the cancer is leukemia (e.g., ALL, AML or CLL) .
  • the cancer is lymphoma (e.g., B-cell lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma (MCL) ) .
  • the cancer is multiple myeloma.
  • the cancer is characterized by primary or acquired resistance to treatment with one or more standard of care agents for a particular cancer.
  • the cancer is advanced or metastatic cancer.
  • the cancer is relapsed or refractory cancer.
  • the cancer is characterized by overexpression or amplification of CDK2 or CCNE.
  • the cancer is CDK2 amplified cancer.
  • the cancer is CCNE amplified cancer.
  • the cancer is CCNE1 amplified cancer.
  • the cancer is CCNE2 amplified cancer.
  • a compound or composition as described herein may be administered as a single agent or in combination with one or more additional therapeutic agents, e.g., an additional therapeutic agent that is a standard of care agent for the disease or disorder being treated, such as an anti-cancer therapeutic agent appropriate for a particular cancer.
  • additional therapeutic agents e.g., an additional therapeutic agent that is a standard of care agent for the disease or disorder being treated, such as an anti-cancer therapeutic agent appropriate for a particular cancer.
  • a method of inhibiting or degrading CDK2 in a cell, system, or subject comprising administering to the cell, system, or subject an effective amount of a compound or salt of any of the formulae herein.
  • a method of inhibiting or degrading CDK2 in a sample by contacting the sample with a compound or salt of any of the formulae herein, or pharmaceutical composition comprising such compound or salt, thereby inhibiting CDK2.
  • the sample is a biological sample.
  • the biological sample comprises a tissue, a cell, or a biological fluid.
  • the biological sample is a cell.
  • the cell is a eukaryotic cell.
  • the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a cancer cell collected from a subject, e.g., via biopsy. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, CDK2 is inhibited. In some embodiments, CDK2 is degraded.
  • a method of identifying a compound capable of inhibiting or degrading CDK2 comprising the steps of: (1) providing a test system for monitoring inhibition or degradation of CDK2; and (2) determining whether a test compound inhibits or degraders CDK2 in the test system.
  • the test system comprises a cancer cell.
  • the test compound is a compound or salt of any of the formulae described herein.
  • provided herein is a method to degrade one or more proteins selected from CDK2 or CCNE (i.e., CCNE1 and/or CCNE2) .
  • a method to modulate one or more proteins selected from CDK2 or CCNE i.e., CCNE1 and/or CCNE2 , for example by reducing the activity of the protein, or by reducing the expression level of the protein or reducing the expression level of its corresponding gene.
  • provided herein is a method to inhibit one or more proteins selected from CDK2 or CCNE (i.e., CCNE1 and/or CCNE2) .
  • provided herein is a method to (a) degrade, (b) inhibit, or (c) modulate one or more proteins selected from CDK2 or CCNE, comprising administering to a subject in need thereof an effective amount of a heterobifunctional compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof.
  • the compounds, compositions, methods and uses described herein selectively degrade CDK2. In some embodiments, the compounds, compositions, methods and uses described herein selectively degrade CCNE. In some embodiments of the compounds, compositions, methods and uses described herein selectively degrade CDK2 and CCNE. In some embodiments of each of the foregoing, selectively is determined relative to degradation of CDK1.
  • the amount of the protein (s) is decreased in the subject after administration of a compound described herein relative to a baseline measurement.
  • the amount of the protein (s) may be measured in a test sample (e.g., a tissue sample or fluid sample) obtained from a subject following administration, and the amount may be determined relative to a baseline measurement for the protein (s) in a first sample obtained from the subject prior to administration of said compound.
  • the amount of the protein (s) may also be measured relative to an average baseline measurement in a test population.
  • Some embodiments include measuring a decrease in the amount of one or more protein (s) following the administration.
  • the method further comprises comparing the amount of the protein (s) in a first sample obtained from a subject prior to administration of a compound described herein, and the amount of the protein (s) in a test sample (i.e., a second or later sample) obtained from the subject (at a relevant timepoint) after administration of said compound.
  • a test sample i.e., a second or later sample
  • the amount of the protein (s) in the test sample is expected to be decreased relative to a baseline measurement from the first sample.
  • the extent of the decrease may be greater than: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%at relevant timepoints.
  • Each such sample may be a tissue sample or a fluid sample.
  • the measurement of the amount of a protein in a first (baseline) sample and/or a test (treatment) sample may be obtained directly in the subject.
  • the measurement may include a concentration.
  • the measurement may be normalized, for example to a sample weight, to a sample volume, to a total sample protein measurement, or to a housekeeping protein measurement. Measurement of the protein in the test sample obtained at defined timepoint (s) after administration of the compound described herein, during administration of the compound described herein to a subject.
  • Measurements of test and baseline levels of POIs may include any method known in the art. For example, such measurements may be obtained using an assay such as an immunoassay, a bioluminescence assay, a colorimetric assay, a lateral flow assay, a fluorescence assay, a proteomics assay, or a cell-based assay.
  • An immunoassay may include an immunoblot such as a Western blot or a dot blot, an enzyme-linked immunosorbent assay, or immunostaining.
  • a bioluminescence assay may include a HiBiT assay, a NanoBRET assay, or similar.
  • a proteomics assay may include mass spectrometry. Such measurements may be obtained using flow cytometry. Such measurements may also be obtained using chromatography, for example high performance liquid chromatography.
  • the disease or disorder is cancer.
  • Cancer includes solid tumors or cancers of the blood, bone marrow, or lymphatic system (sometimes referred to as “liquid tumors” ) .
  • Solid tumors refer to abnormal masses of cells that grow in an organ system and generally do not contain cysts or liquid areas. Solid tumors may be noncancerous (benign) or cancerous (malignant) and may include a single mass or multiple masses. Cancerous solid tumors are typically named for the type of cells that form them, and include, but are not limited to, sarcomas and carcinomas. “Liquid tumors” may circulate throughout the body via the bloodstream. Cancers of the blood include, but are not limited to, leukemia, lymphoma, or myeloma.
  • Cancer may include a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, or a second primary cancer in a person with a prior history of cancer of a different type.
  • the cancer is selected from breast cancer (e.g., TNBC) , ovarian cancer (e.g., HGSOC) , endometrial cancer, cervical cancer, uterine cancer, bladder cancer, biliary tract cancer, prostate cancer, lung cancer (e.g., NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma) , bone cancer, central nervous system (CNS) cancer (e.g., glioblastoma) , oral cancer, esophageal cancer, head and neck cancer (e.g., HNSSC) , colorectal cancer, kidney cancer (e.g., RCC) , liver cancer (e.g., HCC) , pancreatic cancer, gastric cancer, thyroid cancer, melanoma, and hematopoietic or lymphoid cancer (e.g., B-cell lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma (MCL
  • a compound or composition as described herein may be administered as a single agent or in combination with one or more additional therapeutic agents, e.g., an additional therapeutic agent that is a standard of care agent for the disease or disorder being treated, such as an anti-cancer therapeutic agent appropriate for a particular cancer.
  • additional therapeutic agents e.g., an additional therapeutic agent that is a standard of care agent for the disease or disorder being treated, such as an anti-cancer therapeutic agent appropriate for a particular cancer.
  • the compound or composition is administered in combination with a standard of care agent for the particular cancer.
  • the compound or composition is administered in combination with a chemotherapeutic agent (e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, and the like) .
  • a chemotherapeutic agent e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, and the like.
  • the cancer is characterized by primary or acquired resistance to treatment with one or more standard of care agents for a particular cancer. In some embodiments, the cancer is advanced or metastatic cancer.
  • the methods and uses herein relate to treatment of (1) tumors or tumor cells having increased expression of CDK2 or CCNE; (2) tumors or tumor cells that proliferate by aberrant CDK2 or CCNE activation; (3) tumors or tumor cells characterized by amplification or overexpression of CCNE1 and/or CCNE2; (4) tumors or tumor cells characterized by amplification or overexpression of CDK2; or (5) tumors or tumor cells that are resistant to, or have progressed on, treatment with an endocrine therapeutic agent and/or a CDK4/6 inhibitor.
  • the heterobifunctional compound of any of the formulae herein is administered as first line therapy. In other embodiments, the heterobifunctional compound of any of the formulae herein is administered as second (or later) line therapy. In some embodiments, the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, one or more standard of care agent (s) for the disease or disorder, such as an anti-cancer therapeutic agent appropriate for a particular cancer. In some embodiments, the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, one or more chemotherapy agents. In some embodiments, the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, one or more targeted anti-cancer therapeutic agents.
  • standard of care agent s
  • the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, one or more chemotherapy agents.
  • the cancer is breast cancer
  • the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, an endocrine therapeutic agent and/or a CDK4/6 inhibitor.
  • the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, an endocrine therapeutic agent (e.g., an aromatase inhibitor, a SERM or a SERD) .
  • the heterobifunctional compound is administered as second (or later) line therapy following treatment with, or progression on, a CDK4/6 inhibitor.
  • the sample is a biological sample.
  • the biological sample comprises a tissue, a cell, or a biological fluid.
  • the biological sample is a cell.
  • the cell is a eukaryotic cell.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • the cell is a cancer cell.
  • the cell is a cancer cell collected from a subject, e.g., via biopsy.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the target protein or POI upon being contacted with the compound or composition, is ubiquitinated to form a ubiquitinated protein.
  • the ubiquitinated protein upon administration or contact, is degraded.
  • the degradation of the target protein or POI is selective for the target protein or POI.
  • the target protein or POI comprises proteasomal degradation.
  • the target protein or POI is degraded by the proteasome.
  • any of the methods and uses herein include a step of measuring the amount of cyclin E or CDK2 in the cell.
  • the interaction between cyclin E and CDK2 comprises binding or dimerization.
  • the CCNE is CCNE1 or CCNE2.
  • the CCNE is CCNE1.
  • the CCNE is CCNE2.
  • a method of identifying a compound capable of degrading one or more proteins selected from CDK2 or CCNE comprising the steps of: (1) providing a test system for monitoring degradation of the protein; and (2) determining whether a given test compound leads to degradation of the protein in said test system.
  • the test system comprises a cell.
  • the test system comprises a cancer cell.
  • the cell is in a subject.
  • the cancer cell is in a subject.
  • the test compound is a compound or salt of any of formulae (I) - (XI-2) provided herein.
  • abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition) .
  • Abnormal cell growth may be benign (not cancerous) , or malignant (cancerous) .
  • additional anticancer therapeutic agents refers to one or more therapeutic agent, other than a compound described herein, that can be used in the treatment of cancer.
  • additional anticancer therapeutic agents may include one or more: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormone or endocrine therapy agents (such as aromatase inhibitors, SERMs or SERDs) , growth factor inhibitors, radiation therapy, signal transduction inhibitors (such as tyrosine or serine/threonine kinase inhibitors) , cell cycle inhibitors (such as CDK inhibitors) , biological response modifiers (such as immunotherapy agents or immune checkpoint inhibitors) , enzyme inhibitors, antisense oligonucleotides or derivatives, cytotoxic agents, and the like.
  • ameliorate or “ameliorating” mean a lessening or improvement of one or more symptoms of a disease or disorder upon treatment with a compound of composition as described herein, as compared to not administering the compound of composition.
  • cancer or “cancerous” refer to any malignant and/or invasive growth or tumor caused by abnormal cell growth, typically including the rapid, uncontrolled or invasive growth of aberrant cells.
  • an effective amount refers to the amount of a compound or pharmaceutical composition as described herein, alone or in combination with one or more other agents, that is sufficient to achieve a desired or beneficial biological result, e.g., the amount sufficient to affect the biochemical, histological, or behavioral symptoms of a disease or disorder, its complications, or pathological phenotypes.
  • the therapeutically effective amount is the amount of a compound or composition that, when administered to a subject, achieves a therapeutic effect relevant for the disease or disorder.
  • the therapeutically effective amount is the amount that: (1) treats or prevents the disease or disorder; (2) ameliorates or eliminates one or more symptoms of the disease or disorder; or (3) prevents or delays the onset, progression, or recurrence of one or more symptoms of the disease or disorder.
  • the effective amount is the amount of a compound, salt, or composition that, when administered to a cell, a tissue, a system, or a non-cellular biological material or medium, is effective to at least partially inhibit or degrade a POI, inhibit or reduce the activity of a POI, or reduce the expression level of a POI or its corresponding gene.
  • prevent refers to the prophylactic treatment of a disease or disorder, or to delaying the onset, progression or recurrence of the disease or disorder.
  • the terms "subject” or “patient” refer to a human or non-human animal subject. Examples of subjects include humans and other mammals, such as dogs, cats, cattle, mice, rats, monkeys, or other non-human primates. In some preferred embodiments, the subject is a human. Subjects may include, e.g., human or veterinary patients, or human or veterinary subjects participating in clinical trials.
  • treat or “treating” as used herein means to administer a compound, salt, or composition, as described herein, to a subject having a disease or disorder, such as cancer, to achieve at least one positive therapeutic effect. Such therapeutic effects may include reversing, relieving, alleviating, or slowing the progression of, or any damage associated with any symptoms of the disease or disorder.
  • treatment refers to the act of treating as “treating” as defined above.
  • a therapeutic (or "anti-cancer” ) effect may include a decrease in the number of cancer cells; a decrease in tumor size or volume; a decrease in the rate of cancer cell infiltration into peripheral organs; a decrease in the rate or number of metastases; a decrease in rate of tumor growth.
  • the method or use results in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.
  • Additional beneficial effects in treating cancer may include: decreasing or ameliorating at least one symptom of the cancer; increasing the quality of life of the subject having cancer; decreasing the dose, or enhancing the effectiveness, of another agent used to treat the cancer; inducing remission of the cancer; delaying the progression or recurrence of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and/or prolonging survival of the subject having cancer.
  • Positive therapeutic effects in cancer can be measured in several ways, including by measuring a reduction in tumor growth or tumor volume.
  • treatment results in reduction in tumor growth and/or tumor volume by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, relative to untreated subjects.
  • the effect may also be determined in animal model systems predictive of efficacy in human tumors.
  • the effect may be evaluated by measuring responses using in vitro, ex vivo, or in vivo assays known to the skilled practitioner.
  • the tumor growth inhibition T/C ratio may be used to quantify treatment effects in tumor xenograft experiments. (J. Wu, Statistical Inference for Tumor Growth Inhibition T/C Ratio, J. Biopharm. Stat. 2010, 20: 954-964. )
  • efficacy can be determined by analyzing data obtained from well-designed clinical trials using appropriate biostatistical methods known in the art (e.g., T-test, ANOVA, Chi-squared test, Fisher’s exact test, Kaplan-Meier curves, log-rank test, Cox proportional hazards model, linear or logistic regression, Mann-Whitney U test, sign test, Wilcoxon signed-rank test, or Kruskal-Wallis test) .
  • Biostatistical methods may be applied to unadjusted or adjusted findings, and analyze continuous, binary, or time-to-event outcomes.
  • the effect of treatment may be defined by reference to partial response (PR) , complete response (CR) , overall response (OR) , progression free survival (PFS) , disease free survival (DFS) and overall survival (OS) .
  • PR partial response
  • CR complete response
  • OR overall response
  • PFS progression free survival
  • DFS disease free survival
  • OS overall survival
  • Evaluation of PR, CR, PFS, DFS, OR or OS may be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.
  • a pharmaceutical composition comprising a compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises two or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises a compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  • the additional therapeutic agent is an additional anti-cancer agent.
  • the compound or salt of any of Formulae (I) - (XI-2) is co-formulated with an additional therapeutic agent, such as an additional anti-cancer agent (i.e., a fixed dose combination) .
  • the compound or salt of any of Formulae (I) - (XI-2) is packaged with an additional therapeutic agent, such as an additional anti-cancer agent.
  • the pharmaceutical composition further comprises at least one additional therapeutic agent. In some embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent (e.g., a fixed dose combination) . In some embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer agent.
  • combination refers to either a fixed dose combination or a combined administration where a compound or salt as described herein and one or more additional therapeutic agents may be administered independently, at the same time, or separately within time intervals, especially where the time intervals allow the combination partners to show a cooperative effect, e.g., a synergistic effect.
  • the term "combination therapy” refers to the administration of a compound as described herein together with an at least one additional therapeutic agent (e.g., an additional anti-cancer agent) .
  • the two agents may be administered sequentially or simultaneously, in any order.
  • the compound described herein is administered prior to the additional therapeutic agent.
  • the compound described herein is administered after the additional therapeutic agent.
  • the compound described herein and the additional therapeutic agent are administered simultaneously .
  • the two or more agents can be administered with independent frequencies, dosing regimens and/or routes of administration.
  • the compound of any of Formulae (I) - (XI-2) , or a pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition.
  • the medicament if for use in the treatment of a disease or disorder associated with abnormal cell growth, such as cancer.
  • pharmaceutically acceptable means the compound, salt, or pharmaceutical composition is suitable for administration to a subject.
  • pharmaceutically acceptable excipients refers to substances other than the active pharmaceutical ingredient ( “API” ) included in a pharmaceutical formulation or medicament, which are compatible with the other ingredients of the composition, are not deleterious to the subject, and do not abrogate the biological activity and properties of the API.
  • Excipients such as fillers or diluents, may bulk-up the formulation, allowing convenient and accurate dispensation of a drug substance when producing a dosage form. Excipients may also facilitate drug absorption, solubility, or other pharmacokinetic properties, or enhance stability of the drug product. In the manufacturing process, excipients may improve handling of the API (e.g., by facilitating powder flowability or non-stick properties) .
  • excipient also depends on factors such as the intended route of administration, the effect of the excipient on solubility and stability, the nature of the dosage form, and standard pharmaceutical practice. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
  • Such formulations may also be used as fillers in soft or hard capsules, typically including a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) , an emulsifying agent, and/or a suspending agent.
  • a carrier e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agent e.g., g., ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agent e.g., g., g., g., ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • the concentration of various excipients in a pharmaceutical formulation may be expressed as a ratio or percentage of the excipient to the drug product, by weight or volume.
  • concentrations are frequently described as the weight percent (wt%) of the total weight, or as the ratio of weight in weight (denoted as w/w) .
  • the concentration of a solid ingredient in a liquid vehicle may be expressed as the ratio of weight in volume (denoted as w/v) .
  • the concentration of a liquid ingredient in a solid vehicle may be expressed as the ratio of volume in weight (denoted as v/w) . If both ingredients are liquids, the ratio may be expressed as the ratio of volume in volume (denoted as v/v) .
  • the pharmaceutical composition maybe in a dosage form suitable for oral administration (e.g., a tablet or capsule) , for parenteral injection (e.g., a sterile solution, suspension, or emulsion) , for topical administration (e.g., an ointment or cream) , or for rectal administration (e.g., a suppository) .
  • dosage form suitable for oral administration include solid dosage forms, such as tablets, capsules (containing particulates, liquids, or powders) , lozenges (including liquid-filled) , chews, etc.
  • Liquid formulations for oral administration include suspensions, solutions, syrups, or elixirs.
  • Such formulations may also be used as fillers in soft or hard capsules, typically including a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) , an emulsifying agent, and/or a suspending agent.
  • a carrier e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agent emulsifying agent
  • a suspending agent e.g., emulsifying agent
  • Liquid formulations may also be prepared by the reconstitution of a solid formulation by addition of appropriate solvent or carrier.
  • concentration of various excipients in a pharmaceutical formulation may be expressed as a ratio or percentage of the excipient to the drug product, by weight or volume. For solid dosage forms, concentrations are frequently described as the weight percent (wt%) of the total weight, or as the ratio of weight in weight (denoted as w/w) .
  • the concentration of a solid ingredient in a liquid vehicle may be expressed as the ratio of weight in volume (denoted as w/v) .
  • the concentration of a liquid ingredient in a solid vehicle may be expressed as the ratio of volume in weight (denoted as v/w) . If both ingredients are liquids, the ratio may be expressed as the ratio of volume in volume (denoted as v/v) .
  • Frequently used excipients in solid dosage forms include diluents, binders, glidants, disintegrants, lubricants, or antioxidants. Such dosage forms may also include release modifiers (e.g., pH modifiers) , colorants, sweeteners, flavorants, preservatives, suspending agents, emulsifiers, or coating agents (e.g., film coating agents) .
  • release modifiers e.g., pH modifiers
  • colorants e.g., sweeteners, flavorants, preservatives, suspending agents, emulsifiers, or coating agents (e.g., film coating agents) .
  • the API may make up from 1 wt%to 80 wt%of the dosage form, more typically from 5 wt%to 60 wt%of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 wt%to 25 wt%, more typically from 5 wt%to 20 wt%of the dosage form.
  • Binders or binding agents may be used to impart cohesive qualities to a tablet formulation.
  • Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone (e.g., povidone k-30) , pregelatinized starch, carboxymethyl cellulose, sodium cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also optionally include surface active agents (e.g., wetting, dispersion, or emulsion agents) , such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide, magnesium silicate, calcium silicate and talc.
  • surface active agents e.g., wetting, dispersion, or emulsion agents
  • glidants such as silicon dioxide, magnesium silicate, calcium silicate and talc.
  • surface active agents are typically present in amounts from 0.2 wt%to 5 wt%of the tablet, and glidants are typically present in amounts from 0.2 wt%to 1 wt%of the tablet.
  • Tablets may also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt%to 10 wt%, more typically from 0.5 wt%to 3 wt%of the tablet.
  • antioxidants e.g., butyl hydroxyl toluene, butyl hydroxyl anisole, ascorbic acid, etc.
  • colorants e.g., butyl hydroxyl toluene, butyl hydroxyl anisole, ascorbic acid, etc.
  • flavoring agents e.g., benzyl alcohol, sodium benzoate, paraben esters, chlorocresol, etc.
  • taste-masking agents e.g., carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP) , ethyl cellulose, hydroxypropyl methylcellulose (HPMC) , hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymer, methyl cellulose, PEG, polyvinyl acetate, Shellac, titanium dioxide, wax, Carnauba wax, microcrystalline zein, etc.
  • coating agents e.g., carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP) , ethyl cellulose, hydroxypropyl methylcellulose (HPMC) , hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymer, methyl cellulose, PEG, polyvinyl acetate, Shellac, titanium dioxide, wax, Carnauba wax, microcrystalline zein, etc.
  • CAP carboxymethyl cellulose
  • CAP cellulose
  • Exemplary tablets contain up to about 80 wt%API, from about 10 wt%to about 90 wt%binder, from about 0 wt%to about 85 wt%diluent, from about 2 wt%to about 10 wt%disintegrant, and from about 0.25 wt%to about 10 wt%lubricant.
  • Exemplary tablets contain up to about 80 wt%API, from about 10 wt%to about 90 wt%binder, from about 0 wt%to about 85 wt%diluent, from about 2 wt%to about 10 wt%disintegrant, and from about 0.25 wt%to about 10 wt%lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting.
  • the final formulation may include one or more layers and may be coated (e.g., film coated) , uncoated, or encapsulated.
  • Solid compositions may also be employed in soft and hard filled gelatin capsules.
  • excipients include lactose or milk sugar and high molecular weight polyethylene glycols.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges may be formulated to contain a powder mix of the compound described herein, a suitable powder base such as lactose (e.g., anhydrous lactose or lactose monohydrate) or starch and a performance modifier such as I-leucine, mannitol, or magnesium stearate.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the API may be combined with various sweetening or flavoring agents, colorants, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • excipients in oral liquid dosage formulations include solvents (e.g., water, alcohol, acetic acid, etc. ) , co-solvents (e.g., ethanol, sorbitol, glycerin, propylene glycol, etc.
  • buffers e.g., phosphate, acetate or citric acid phosphate buffers
  • antimicrobial preservatives e.g., benzyl alcohol, sodium benzoate, paraben esters, etc.
  • antioxidants e.g., ascorbic acid, sodium bisulphate, thiourea, BHT, tocopherols, etc.
  • wetting agents e.g., sodium lauryl sulphate, Tween 80, Spans, lecithins, etc.
  • emulsifying agents e.g., sodium lauryl sulphate, PEG esters, sorbitan esters, etc.
  • sweeteners e.g., sucrose, sorbitol, saccharin, aspartame, sucralose, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be buffered, if desired.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffering agents (preferably to a pH of from 3 to 9) .
  • parenteral formulations may be formulated as a sterile non-aqueous solution or as a dried form to be reconstituted and used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques known to those skilled in the art.
  • solubility of compounds or salts as used in the preparation of parenteral solutions may be increased by appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • kits comprising two or more pharmaceutical compositions suitable for coadministration of the compositions.
  • the kit includes two or more separate pharmaceutical compositions, at least one of which contains a compound or salt of any of the formulae disclosed herein, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules, and the like. Kits are particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • kits typically include written directions for use and may be provided with a memory aid. Dosage Forms and Dosing Regimens:
  • the compounds described herein may be administered by any method which delivers the compound systemically and/or locally to the intended site of action.
  • exemplary methods of administration include oral, parenteral (e.g., intravenous, intramuscular, subcutaneous, intraperitoneal, intravascular, or intramedullary injection or infusion) , intraduodenal, rectal, buccal, intranasal, topical, transdermal, etc.
  • the dose and dosing regimen for a compound or composition as described herein, including the frequency of administration, the total dose, the dose administered per administration, the time interval between administrations, and the duration or treatment, may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit a response in the subject.
  • An effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, typically about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the range above may be sufficient, while in other cases still larger doses may be used without causing harmful side effects, with larger doses typically divided into several smaller doses for administration throughout the day.
  • a “dosing regimen” or “dosing schedule” refers to the dose and timing of administration of the compounds or compositions described herein comprising one or more treatment cycles, wherein each cycle can include administration of one or more agents described herein at different times or in different amounts, alone or in combination with another therapeutic agent. Dosing regimens may be adjusted to provide the desired prophylactic or therapeutic response. An effective dose can be administered in one or more administrations. The total dose may be administered as a single dose or divided into several doses and administered over time. In some embodiments, a compound or composition is administered once per day (QD) , twice per day (BID) , or three times per day (TID) .
  • QD per day
  • BID twice per day
  • TID three times per day
  • the compound or composition is administered on a continuous dosing regimen comprising daily administration, during one or more treatment cycles. In some embodiments, the compound or composition is administered on an intermittent dosing regimen comprising administration on one or more consecutive days followed by one or more consecutive days of rest on which the compound is not administered, during one or more treatment cycles. In certain embodiments, the compound or composition is administered orally. The dose may be reduced or increased proportionally as appropriate for the circumstances.
  • Unit dosage forms refer to physically discrete units suited as unitary dosages for the subjects to be treated. Each unit dosage form contains a predetermined quantity of the API, wherein the dose is calculated to produce the desired therapeutic effect.
  • the unit dosage form may be a tablet or capsule.
  • compositions described herein may be administered in an immediate release dosage or a modified release dosage.
  • An immediate-release (IR) dosage includes an oral dosage form that is formulated to release the API immediately after administration.
  • An extended-release (ER) dosage includes an oral dosage form that is formulated to release the API over a prolonged period after administration.
  • ER dosages include sustained-release (SR) or controlled-release (CR) dosage forms.
  • SR means the API is released over a sustained period, but not at a constant rate.
  • CR means the API is released over a sustained period at a nearly constant rate.
  • Methods of defining an appropriate dose include determining the Maximum Tolerated Dose (MTD) , Maximum Feasible Dose (MFD) , limiting dose (1000 mg/kg) , exposure saturation, or the dose providing a 50-fold margin of exposure.
  • MTD is the highest dose that does not cause unacceptable side effects or overt toxicity in a specific period of time, and can be determined by acute toxicity studies, short duration dose escalation studies and dose ranging studies.
  • An appropriate dosage may also be determined by a measurable parameter, such as a reduction in tumor growth, e.g., by at least about 20%, at least about 40%, at least about 60%, or at least about 80%relative to untreated subjects.
  • the effect may be evaluated in an animal model system predictive of efficacy in human tumors. Alternatively, the effect may be evaluated by measuring responses in vitro, ex vivo, or in vivo assays or models known to the skilled practitioner.
  • the dose and dosing regimen may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition and use. For example, doses may be adjusted based on the pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Characterization of Exemplary Heterobifunctional Compounds
  • heterobifunctional compounds were designed and synthesized by incorporating three moieties: CRBN ligands, linkers, and CDK binders.
  • Specific exemplary heterobifunctional compounds were characterized in T47D breast cancer cells. Cells were treated with heterobifunctional compounds disclosed herein at indicated concentrations for 24 hours. Cells were collected, lysed and subject to immunoblotting using an antibody specific to CDK2, CDK1, CCNE1, CDK4, CCND1 or phosphorylated Rb proteins. ⁇ -actin was used as the loading control. DMSO treatment was used as the negative control.
  • CDK2, CCNE1, CDK4 or CCND1 protein levels in T47D cells were significantly decreased, while CDK1 proteins were not affected.
  • Heterobifunctional compounds also significantly inhibited downstream Rb phosphorylation in a concentration-dependent manner.
  • HiBiT detection system quantitatively measures total amounts of HiBiT-tagged proteins using a luminescent based method.
  • T47D or HEK293T cells stably or endogenously expressing HiBiT tagged target proteins were treated with heterobifunctional compounds at indicated concentrations, then lysed with Nano-Glo HiBiT Lytic detection reagents.
  • Tables 5A-B following a 24-hour treatment of various heterobifunctional compounds, endogenously expressed CDK2 and ectopically expressed CCNE1 protein levels in HEK293T cells were significantly decreased, while endogenous CDK1 proteins were not dramatically affected.
  • Table 6 following a 6-hour treatment of various heterobifunctional compounds, ectopically expressed CDK2 or CCNE1 protein levels in HEK293T cells were significantly decreased, while overexpressed CDK1 proteins were not dramatically affected.
  • Heterobifunctional compounds exemplified by CPD-19, CPD-26, CPD-40, and CPD-41, were found to be particularly effective in reducing CDK2 and cyclin E1 protein levels in a concentration-dependent manner in KURAMOCHI cells (FIG. 1A-1B) .
  • CDK2-cyclin E pathway plays an important role in controlling the G1/Stransition and targeting CDK2 pathway has been demonstrated to compromise cancer cell proliferation and survival.
  • LCMS spectra for all compounds were acquired using a Waters LC-MS AcQuity H UPLC class system.
  • the Waters LC-MS AcQuity H UPLC class system comprising a pump (Quaternary Solvent Manager) with degasser, an autosampler (FTN) , a column oven (40 °C, unless otherwise indicated) , a photo-diode array PDA detector.
  • the purification of intermediates or final products were performed on Agilent Prep 1260 series with UV detector set to 254 nm or 220 nm. Samples were injected onto a Phenomenex Luna C18 column (5 ⁇ m, 30 x 75 mm, ) at room temperature. The flow rate was 40 mL/min. A linear gradient was used with either 10%or 50%MeOH in H 2 O containing 0.1 %TFA as solvent A and 100%of MeOH as solvent B.
  • TBS tert-butyl (dimethyl) silyl
  • TFCH means N, N, N′, N′-tetramethylchloroformamidinium hexafluorophosphate
  • TEA means triethyl amine
  • TFA means trifluoroacetic acid
  • THF means tetrahydrofuran
  • TLC means thin layer chromatography
  • TsCl means p-toluenesulfonyl chloride
  • rt means room temperature
  • h means hours
  • min means minutes.
  • Step 8 Synthesis of 5-isopropoxy-N- ( (3R, 4S) -3-methylpiperidin-4-yl) -6- (1H-pyrazol-4-yl) - [1, 2, 4] triazolo [1, 5-a] pyrazin-2-amine
  • Example 7-1 Tert-butyl (3R, 4S) -4- ( (8-cyclobutoxy-7- (1H-pyrazol-4-yl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-2-yl) amino) -3-methylpiperidine-1-carboxylate (WH-7)
  • Example 7-2 Tert-butyl 2- ( (8-cyclobutoxy-7- (1H-pyrazol-4-yl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-2-yl) amino) -7-azaspiro [3.5] nonane-7-carboxylate (WH-8)
  • H-005 was synthesized following the procedure for preparing H-004 (37 mg, yield: 31%over 2 steps) as a pale-yellow oil.
  • H-006 was synthesized following the procedure for step 1 of preparing H-004 (formic acid salt, 45.1 mg, yield: 13%) as a white solid.
  • MS (ESI) m/z 417.2 [M+H] + .
  • H-010 was synthesized following the procedure for preparing H-009 (25 mg, yield: 17%over 4 steps) .
  • MS (ESI) m/z 360.4 [M+H] + .
  • H-011 was synthesized following the procedure for preparing H-009 (31 mg, yield: 25%over 4 steps) .
  • MS (ESI) m/z 388.5 [M+H] + .
  • H-014 was synthesized following the procedure for preparing H-013 (287.1 mg, yield: 31%over 2 steps) as a yellow solid.
  • MS (ESI) m/z 433.1 [M+H] + .
  • H-015 was synthesized following the procedure for preparing H-013 (350 mg, yield: 50%over 2 steps) as a red solid.
  • H-016 was synthesized following the procedure for preparing H-013 (365 mg, yield: 34%over 2 steps) as a green solid.
  • H-021 was synthesized following the procedure of step 2 for preparing H-020 (140 mg, yield: 60%) .
  • MS (ESI) m/z 428.5 [M+H] + .
  • Example 33 4- (4- (3, 3-Dimethoxypropyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (H-024)
  • Example 50 1- (5- (4- (3-Hydroxypropyl) piperidine-1-carbonyl) -2-methoxyphenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (H-041)
  • Example 51 1- (5- (4- (4-Hydroxybutyl) piperidine-1-carbonyl) -2-methoxyphenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (H-042)
  • Example 52 1- (5- (4- (2-Hydroxyethoxy) piperidine-1-carbonyl) -2-methoxyphenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (H-043)
  • Step 1 Synthesis of dimethyl 4-bromo-5- [4- (3-tert-butoxy-3-oxo-propyl) -1-piperidyl] ben zene-1, 2-dicarboxylate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés hétérobifonctionnels de l'une quelconque des formules (I) à (XI-2), ainsi que des sels pharmaceutiquement acceptables, des compositions pharmaceutiques et des utilisations associées, qui peuvent être utiles pour la dégradation ciblée de protéines d'intérêt.
PCT/CN2024/132651 2023-11-16 2024-11-18 Composés et méthodes de traitement de cancers Pending WO2025103502A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CNPCT/CN2023/132078 2023-11-16
CN2023132078 2023-11-16
CNPCT/CN2024/100679 2024-06-21
CN2024100679 2024-06-21

Publications (1)

Publication Number Publication Date
WO2025103502A1 true WO2025103502A1 (fr) 2025-05-22

Family

ID=95742041

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/132651 Pending WO2025103502A1 (fr) 2023-11-16 2024-11-18 Composés et méthodes de traitement de cancers

Country Status (1)

Country Link
WO (1) WO2025103502A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210107901A1 (en) * 2019-10-11 2021-04-15 Incyte Corporation Bicyclic amines as cdk2 inhibitors
CN113710661A (zh) * 2019-04-02 2021-11-26 上海睿跃生物科技有限公司 治疗癌症的化合物和方法
WO2022093742A1 (fr) * 2020-10-26 2022-05-05 Dana-Farber Cancer Institute, Inc. Composés pour la dégradation ciblée de protéines de kinases
WO2022236058A1 (fr) * 2021-05-07 2022-11-10 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et leurs utilisations
US20230002376A1 (en) * 2021-06-21 2023-01-05 Incyte Corporation Bicyclic pyrazolyl amines as cdk2 inhibitors
CN116323570A (zh) * 2020-09-30 2023-06-23 上海睿跃生物科技有限公司 治疗疾病的化合物和方法
WO2024039901A2 (fr) * 2022-08-19 2024-02-22 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et utilisations associées
WO2024182555A1 (fr) * 2023-02-28 2024-09-06 Differentiated Therapeutics, Inc. Agents de dégradation de kinase dépendant de la cycline et leurs procédés d'utilisation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113710661A (zh) * 2019-04-02 2021-11-26 上海睿跃生物科技有限公司 治疗癌症的化合物和方法
US20210107901A1 (en) * 2019-10-11 2021-04-15 Incyte Corporation Bicyclic amines as cdk2 inhibitors
CN116323570A (zh) * 2020-09-30 2023-06-23 上海睿跃生物科技有限公司 治疗疾病的化合物和方法
WO2022093742A1 (fr) * 2020-10-26 2022-05-05 Dana-Farber Cancer Institute, Inc. Composés pour la dégradation ciblée de protéines de kinases
WO2022236058A1 (fr) * 2021-05-07 2022-11-10 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et leurs utilisations
US20230002376A1 (en) * 2021-06-21 2023-01-05 Incyte Corporation Bicyclic pyrazolyl amines as cdk2 inhibitors
WO2024039901A2 (fr) * 2022-08-19 2024-02-22 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et utilisations associées
WO2024182555A1 (fr) * 2023-02-28 2024-09-06 Differentiated Therapeutics, Inc. Agents de dégradation de kinase dépendant de la cycline et leurs procédés d'utilisation

Similar Documents

Publication Publication Date Title
TWI794780B (zh) 用於治療疾病之磷酸肌醇3-激酶(pi3k)異位色烯酮抑制劑
ES2997941T3 (en) 1'-(imidazo[1,2-c]pyrimidin-5-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-5-amine derivatives and related compounds as shp2 inhibitors for the treatment of cancer
JP6554037B2 (ja) Ｐｉｍキナーゼ阻害剤として有用なチアゾールカルボキサミドおよびピリジンカルボキサミド化合物
KR100597505B1 (ko) 4-아미노-6-페닐-피롤로[2,3-ｄ]피리미딘 유도체
RU2617405C2 (ru) Пиридоновые и азапиридоновые соединения и способы применения
JP2025517395A (ja) アザ四環式オキサゼピン化合物及びその使用
BR112020026545A2 (pt) Compostos heterocíclicos e de heteroarila para o tratamento da doença de huntington
WO2021121397A1 (fr) Composé hétérocyclique alcynyle substitué
KR20220061958A (ko) Cd38의 억제제로서의 헤테로바이사이클릭 아미드
ES2770693T3 (es) Derivados de imidazopiridazina como inhibidores de caseína quinasa 1 delta/épsilon
AU2014249192A1 (en) BET bromodomain inhibitors and therapeutic methods using the same
CA3211110A1 (fr) Compose de 4-aminoquinazoline
JP2016528298A (ja) Ｐｉｍキナーゼ阻害剤として有用なフロピリジン及びチエノピリジンカルボキシアミド化合物
CN117736226A (zh) 泛-kras抑制剂及其在医药上的应用
ES2893154T3 (es) Derivados de tiazolopirimidina fusionados como inhibidores de MNKs
KR20250004897A (ko) 질환의 치료를 위한 포스포이노시티드 3-키나제 (pi3k)의 알로스테릭 크로메논 억제제
EP3694860A1 (fr) Composés de pyrrolotriazine et procédés d'inhibition de kinases tam
CN115996927A (zh) 作为ENT抑制剂用于治疗癌症的嘧啶并[5,4-d]嘧啶衍生物及其与腺苷受体拮抗剂的组合
US20200055847A1 (en) Modulators of hedgehog (hh) signalling pathway
CN111153891A (zh) 一种取代苯并咪唑类PI3Kα/mTOR双靶点抑制剂及其药物组合物和应用
WO2025103502A1 (fr) Composés et méthodes de traitement de cancers
WO2021113492A1 (fr) Composés cycliques et leurs procédés d'utilisation
CN113004282A (zh) 取代的炔基杂环化合物
US20240025922A1 (en) TETRAHYDROPYRIDO[3,4-d]PYRIMIDINES AS HPK1 INHIBITORS
WO2025252190A1 (fr) Agents de dégradation ciblée de l'hélicase recq du syndrome de werner

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24890854

Country of ref document: EP

Kind code of ref document: A1