WO2023193789A1 - Composés de dégradation de wee1 - Google Patents

Composés de dégradation de wee1 Download PDF

Info

Publication number
WO2023193789A1
WO2023193789A1 PCT/CN2023/086879 CN2023086879W WO2023193789A1 WO 2023193789 A1 WO2023193789 A1 WO 2023193789A1 CN 2023086879 W CN2023086879 W CN 2023086879W WO 2023193789 A1 WO2023193789 A1 WO 2023193789A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methyl
amino
pyrazolo
pyrimidin
Prior art date
Application number
PCT/CN2023/086879
Other languages
English (en)
Inventor
Jianxiong DIAO
Mingchen CHEN
Weiting Lai
Long He
Weiqiang XING
Hang Chen
Fan Liu
Original Assignee
Beijing Neox Biotech Limited
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 Beijing Neox Biotech Limited filed Critical Beijing Neox Biotech Limited
Priority to CN202380009470.1A priority Critical patent/CN116829570A/zh
Publication of WO2023193789A1 publication Critical patent/WO2023193789A1/fr

Links

Classifications

    • 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

Definitions

  • WEE1 is a kinase belonging to the Ser/Thr family of protein kinases and is a key regulator of cell cycle progression. Pharmacological intervention in the cell cycle is strategy for the treatment of cancer and other proliferative disease.
  • the present disclosure provides compounds, compositions and methods for the reduction or elimination of WEE1 activity via the targeting of WEE1 protein in a cell through ubiquitination and proteasomal degradation.
  • One embodiment provides a compound, or pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I) :
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, optionally substituted straight or branched C 1-6 alkyl, optionally substituted C 1-3 alkoxy, halogen, amino, hydroxyl, and cyano; or
  • R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 together with the intervening atoms to which they are attached form an optionally substituted 5-6 membered cycloalkyl or optionally substituted heterocycloalkyl ring;
  • L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
  • Ak 1 is selected from - (CR 5 R 6 ) k -;
  • Ak 2 is selected from - (CR 5 R 6 ) m -;
  • Ak 3 is selected from - (CR 5 R 6 ) n -;
  • each of k, m, and n is selected from 0 to 10
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl;
  • Z 1 and Z 2 are each independently selected from bond, -O-, -NR 7 -, -S-, heterocyclene, and cycloalkylene;
  • R 7 is hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced;
  • L is a polyethylene glycol containing moiety
  • U is a VHL ligand.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, and at least one pharmaceutically acceptable excipient.
  • One embodiment provides a compound of Formula (I) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof for use in a method of treatment of a human or animal.
  • One embodiment provides a compound of Formula (I) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides the use of a compound of Formula (I) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) , or pharmaceutically acceptable salt solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.
  • Amino refers to the —NH 2 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 and hydrogen atoms, containing no unsaturation, having 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) .
  • 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) . In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl) .
  • an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl) . In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl) . In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl) .
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl) , 1-methylethyl (iso-propyl) , 1-butyl (n-butyl) , 1-methylpropyl (sec-butyl) , 2-methylpropyl (iso-butyl) , 1, 1-dimethylethyl (tert-butyl) , and 1-pentyl (n-pentyl) .
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where t
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • pent-1-enyl penta-1, 4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene) . In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene) . In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene) . In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene) . In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene) .
  • an alkylene comprises one carbon atom (e.g., C 1 alkylene) . In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene) . In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene) . In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene) .
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where t
  • Alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene) .
  • an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene) .
  • an alkenylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkenylene) . In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkenylene) . In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene) . In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkenylene) . In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene) .
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene) .
  • an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene) .
  • an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene) . In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene) . In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene) . In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkynylene) . In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkynylene) .
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC (O) -R a , -N (R a ) 2 , -C (O) R a , -C (O) OR a , -C (O) N (R a ) 2 , -N (R a ) C (O) OR a , -OC (O) -N (R a ) 2 , -N (R a ) C (O) R a , -N (R a ) S (O) t R a (where t is 1 or 2) , -S (O) t OR a (where t is 1 or 2) , -S (O) t OR a (where
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, 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.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl” ) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O)
  • Alkyl 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.
  • alkenyl refers to a radical of the formula –R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • 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.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged, or spirocyclic ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms.
  • the carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds) .
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as “cycloalkenyl.
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptanyl) , norbornenyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like.
  • Spirocyclic carbocyclyl or cycloalkyl radicals include, for example, spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, spiro [2.5] octane, spiro [2.6] nonane, spiro [3.3] heptane, spiro [3.4] octane, spiro [3.5] nonane, spiro [3.6] decane, spiro [4.4] nonane, spiro [4.5] decane, spiro [4.6] undecane, spiro [5.5] undecane, spiro [5.6] dodecane, spiro [6.6] tridecane, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O) -OR a , -R b -OC
  • Cycloalkylene refers to a divalent carbocyclyl or cycloalkyl linking the rest of the molecule to a radical group.
  • Carbocyclylalkyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-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 is optionally substituted as defined above.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, and the like.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3-to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, tetracyclic, or spirocyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring (s) .
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorph
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O)
  • Heterocyclene refers to a divalent heterocyclyl linking the rest of the molecule to a radical group.
  • N-heterocyclyl or “N-attached 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-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached 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-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-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.
  • Heterocyclylalkyl refers to a radical of the formula –R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3-to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, 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.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom (s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring (s) .
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzo
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -
  • N-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 nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-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-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R) -or (S) -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans. ) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, 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.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C-or 14 C-enriched carbon are within the scope of the present disclosure.
  • 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, such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • isotopes such as for example, deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) .
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated.
  • isotopic substitution with 18 F is contemplated. All isotopic variations
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6 (10) ] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21) , 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2) , 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • CD 3 I iodomethane-d 3
  • LiAlD 4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the heteroaromatic WEE1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “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.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts, " Journal of Pharmaceutical Science, 66: 1-19 (1997) ) .
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “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. See Berge et al
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • Prodrug refers to a compound that undergoes biotransformation before exhibiting its pharmacological effects. Prodrugs can thus be viewed as drugs containing specialized protective groups used in a transient manner to alter pharmacological properties in the parent molecule.
  • treatment or “treating, ” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • WEE1 is a kinase belonging to the Ser/Thr family of protein kinases and is a key regulator of cell cycle progression.
  • the WEE1 kinase is encoded by the WEE1 gene.
  • WEE1 is an important regulator of the G2/M cell cycle checkpoint.
  • WEE1 mediates cell-cycle arrest by regulating the phosphorylation of cyclin-dependent kinase 1 (Cdk1) .
  • Cdk1 cyclin-dependent kinase 1
  • WEE1 inhibits Cdk1 by phosphorylating it on two different sites, Tyr15 and Thr14. Phosphorylated Cdk1 has reduced kinase activity and therefore prevents entry into mitosis.
  • WEE1 As a cell progress through the cell cycle, WEE1 is inactivated and degraded, and the cell is allowed to enter mitosis.
  • Cancer cells are often deficient in p53 signaling, display genomic instability, and rely on the WEE1 and G2/M cell cycle checkpoint to avoid mitotic catastrophe due to DNA damage. Inhibition or degradation of WEE1 sensitizes cancers to DNA-damaging therapies. Additional information may be found in a) LL Parker, and H Piwnica-Worms.
  • the levels of proteins within a cell are determined by both the rate of protein synthesis and the rate of protein degradation.
  • two pathways exist for selective protein degradation the ubiquitin-proteasome pathway and the lysosomal proteolysis pathway.
  • selective protein degradation is mediated by the presence of a recruitment motif which promotes binding of degradation proteins, such as proteasomal degradation proteins, or proteins associated with ubiquitin-proteasome pathway.
  • Recruitment motifs include E3 ligase recognition agents and proteasome recognition agents. Conjugation of recruitment motifs with high affinity ligands for WEE1 kinase provides compounds capable of selectively directing pathways for protein degradation to the WEE1 kinase protein itself. Such an outcome will reduce levels of WEE1 kinase activity.
  • heteroaromatic WEE1 degradation compound having the general formula provided below:
  • the WEE1 kinase affinity motif is a molecular construct having high affinity for the WEE1 kinase protein independent of the linking motif and/or the recruitment motif
  • the linking motif is a molecular construct providing a covalent bond to both the WEE1 kinase affinity motif and the recruitment motif
  • the recruitment motif is a molecular construct having the ability to selectively target and recruit protein degradation.
  • Recruitment motifs include E3 ligase recognition agents and proteasome recognition agents.
  • the recruitment motif is derived from, VHL ligand, nutlin, bestatin, HIF-1 ⁇ –VHL binding peptide, hydroxy proline-HIF-1 ⁇ -VHL binding peptide, SCFb-TRCP targeting peptide or an inhibitor of apoptosis protein ligand.
  • the recruitment motif is selected from a molecular construct related to VHL ligand as illustrated below:
  • the recruitment motif is selected from a molecular construct related to VHL ligand as illustrated below:
  • the recruitment motif is In some embodiments, the recruitment motif is In some embodiments, the recruitment motif is
  • VHL ligand VHL binder
  • VHL E3 ubiquitin ligase binder VHL E3 ubiquitin ligase binder
  • the linking motif is a molecular construct providing a covalent bond to both the WEE1 kinase affinity motif and the recruitment motif.
  • the linking motif comprises a cyclic moiety.
  • the linking motif comprises an acyclic moiety.
  • the linking motif comprises an unsaturated moiety.
  • the linking motif comprises between 4 and 50 non-hydrogen atoms in a linear sequence.
  • the linking motif comprises between 4 and 20 non-hydrogen atoms in a linear sequence.
  • the linking motif comprises between 4 and 25 non-hydrogen atoms in a linear sequence.
  • the linking motif comprises between 4 and 30 non-hydrogen atoms in a linear sequence.
  • the linking motif comprises between 6 and 18 atoms. In some embodiments, the linking motif comprises between 5 and 10 non-hydrogen atoms in a linear sequence. In some embodiments, the linking motif comprises 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 non-hydrogen atoms in a linear sequence.
  • the linking motif is represented by the following formula:
  • Ak 1 is selected from - (CR 5 R 6 ) k -;
  • Ak 2 is selected from - (CR 5 R 6 ) m -;
  • Ak 3 is selected from - (CR 5 R 6 ) n -;
  • each of k, m, and n is selected from 0 to 10;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl;
  • Z 1 and Z 2 are each independently selected from bond, -O-, -NR 7 -, -S-, heterocyclene, and cycloalkylene;
  • R 7 is hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced;
  • the linking motif is a polyethylene glycol containing moiety.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is selected from 1 to 10, and m is selected from 1 to 10; and the point of bonding to the VHL ligand indicated by the asterisk.
  • said n is selected from 1 to 5 (e.g. 1, 2, 3, 4 or 5)
  • said m is selected from 1 to 5 (e.g. 1, 2, 3, 4 or 5) .
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from - (CR 5 R 6 ) n -NR 7 – (CR 5 R 6 ) m -*, wherein n is selected from 0 to 10, m is selected from 0 to 10, R 7 is hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced; and the point of bonding to the VHL ligand indicated by the asterisk. In some embodiments, n is selected from 1 to 10, m is selected from 1 to 10.
  • said n is selected from 1 to 5 (e.g. 1, 2, 3, 4 or 5)
  • said m is selected from 1 to 5 (e.g. 1, 2, 3, 4 or 5)
  • said n is selected from 1 to 7
  • said m is selected from 0-3.
  • R 7 is hydrogen or methyl.
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*wherein k is selected from 1 to 10, n is selected from 1 to 10, and m is selected from 1 to 10; and the point of bonding to the VHL ligand indicated by the asterisk.
  • said k is selected from 1 to 5
  • said n is selected from 1 to 5 (e.g. 1, 2, 3, 4 or 5)
  • said m is selected from 1 to 5 (e.g. 1, 2, 3, 4 or 5) .
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • X, X1, and X2 at each instance are independently CH or N and wherein the point of bonding to the VHL ligand is indicated by the asterisk.
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif the -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • the linking motif -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is selected from a molecular fragment illustrated below:
  • each R 7 is independently hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced , wherein the point of bonding to the VHL ligand is indicated by the asterisk.
  • R 7 is hydrogen or methyl.
  • k is1, 2, 3, 4, 5, 6, or 7, and m is 0, 1, 2, 3, 4, or 5.
  • k is1, 2, 3, 4, 5, 6, or 7, and m is 0.
  • k is1, 2, 3, 4, or 5 and m is 1, 2, 3, 4, or 5.
  • the linking motif the linking motif is a polyethylene glycol selected from– (O-CH 2 -CH 2 ) n -O-and – (O-CH 2 -CH 2 ) n -N (R 23 ) -*, wherein n is selected from 1 to 20, and R 23 is optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced; and wherein the point of bonding to the VHL ligand is indicated by the asterisk.
  • n is 1, 2, 3, 4, or 5
  • Adavosertib (MK-1775, AZD1775) is a potent and selective Wee1 inhibitor with IC 50 of 5.2 nM in a cell-free assay as described in Hirai et al., “Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents” Mol. Can. Therap. 2009. DOI: 10.1158/1535-7163. MCT-09-0463 which is incorporated herein by reference.
  • ZN-c3 also is a potent and selective Wee1 inhibitor with IC 50 of 3.8 nM in a cell-free assay as described in Huang et al., “Discovery of ZN-c3, a Highly Potent and Selective Wee1 inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer” J. Med. Chem. 2021. DOI: 10.1021/acs. jmedchem. 1c01121which is incorporated herein by reference.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, optionally substituted straight or branched C 1-6 alkyl, optionally substituted C 1-3 alkoxy, halogen, amino, hydroxyl, and cyano; or
  • R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 together with the intervening atoms to which they are attached form an optionally substituted 5-6 membered cycloalkyl or optionally substituted heterocyclyl ring;
  • L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
  • Ak 1 is selected from - (CR 5 R 6 ) k -;
  • Ak 2 is selected from - (CR 5 R 6 ) m -;
  • Ak 3 is selected from - (CR 5 R 6 ) n -;
  • each of k, m, and n is selected from 0 to 10
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl;
  • Z 1 and Z 2 are each independently selected from bond, -O-, -NR 7 -, -S-, heterocyclene, and cycloalkylene;
  • R 7 is hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced;
  • L is a polyethylene glycol containing moiety
  • U is a VHL ligand.
  • provided herein is a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, optionally substituted straight or branched C 1-6 alkyl, optionally substituted C 1-3 alkoxy, halogen, amino, hydroxyl, and cyano, wherein the alkyl is optionally substituted with hydroxy.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, optionally substituted straight or branched C 1-6 alkyl, optionally substituted C 1-3 alkoxy, and halogen, wherein the alkyl is optionally substituted with hydroxyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen and optionally substituted straight or branched C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy.
  • R 1 is optionally substituted branched C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy.
  • R 1 is optionally substituted branched C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy and R 2 , R 3 , and R 4 are each hydrogen.
  • R 1 is
  • R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 together with the intervening atoms to which they are attached form an optionally substituted 5-6 membered cycloalkyl or optionally substituted heterocyclyl ring, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from C 1-6 alkyl and hydroxyl.
  • R 1 and R 2 taken together with the intervening atoms to which they are attached form an optionally substituted 5-6 membered cycloalkyl or optionally substituted heterocyclyl ring, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from C 1-6 alkyl and hydroxyl, and R 3 and R 4 are hydrogen.
  • R 1 and R 2 taken together with the intervening atoms to which they are attached form an optionally substituted 5-6 membered cycloalkyl.
  • R 1 and R 2 taken together with the intervening atoms to which they are attached form an optionally substituted 5-6 membered cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and hydroxyl.
  • R 1 and R 2 taken together with the intervening atoms to which they are attached form a substituted 5-6 membered cycloalkyl, wherein the cycloalkyl is substituted with C 1-6 alkyl and hydroxyl.
  • R 1 and R 2 taken together with the intervening atoms to which they are attached form
  • L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
  • Ak 1 is selected from - (CR 5 R 6 ) k -;
  • Ak 2 is selected from - (CR 5 R 6 ) m -;
  • Ak 3 is selected from - (CR 5 R 6 ) n -;
  • each of k, m, and n is selected from 0 to 10
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl;
  • Z 1 and Z 2 are each independently selected from bond, -O-, -NR 7 -, -S-, heterocyclene, and cycloalkylene;
  • R 7 is hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced;
  • L is a polyethylene glycol containing moiety
  • U is a VHL ligand.
  • provided herein is a compound of Formula (I-a) , or a pharmaceutically acceptable salt or solvate thereof.
  • L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*;
  • Ak 1 is selected from - (CR 5 R 6 ) k -;
  • Ak 2 is selected from - (CR 5 R 6 ) m -;
  • Ak 3 is selected from - (CR 5 R 6 ) n -;
  • each of k, m, and n is selected from 0 to 10
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl;
  • Z 1 and Z 2 are each independently selected from bond, -O-, -NR 7 -, -S-, heterocyclene, and cycloalkylene;
  • R 7 is hydrogen, optionally substituted alkyl, or optionally substituted alkyl wherein 1 or more -CH 2 -units are replaced with O provided that two adjacent -CH 2 -units are not both replaced;
  • L is a polyethylene glycol containing moiety
  • U is a VHL ligand.
  • provided herein is a compound of Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1, 2, 3, 4, 5, or 6 and m is 1, 2, 3, 4, or 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1, and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2, and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4, and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is - (CR 5 R 6 ) n -NR 7 – (CR 5 R 6 ) m -*, wherein n is 1, 2, 3, 4, 5 or 6, and m is 1, 2, 3, 4, or 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, 2, 3, or 4, n is 1, 2, or 3, and m is 1 or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O– – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is and each R 7 is independently hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is and each R 7 is independently hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-7, m is 0-5, and R 7 is hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-6, m is 0-3, and R 7 is hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-6, m is 0, and R 7 is hydrogen or methyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is, wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1 or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1 and X2 are each independently CH or N and wherein each k is independently 0, 1, or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1, X2, X3, and X4 are each independently CH or N and wherein each k is independently 0, 1 or 2, each m is independently 0, 1, or 2, and each n is independently 0, 1, or 2.
  • R 5 and R 6 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, and C 1-3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, halogen, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R 5 and R 6 are both hydrogen.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1 and X2 are each independently CH or N and wherein each k is independently 0, 1, or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is .
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is .
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is,
  • L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1, 2, 3, 4, 5, or 6 and m is 1, 2, 3, 4, or 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1, and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2, and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4, and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is - (CR 5 R 6 ) n -NR 7 – (CR 5 R 6 ) m -*, wherein n is 1, 2, 3, 4, 5 or 6, and m is 1, 2, 3, 4, or 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, 2, 3, or 4, n is 1, 2, or 3, and m is 1 or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is and each R 7 is independently hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is and each R 7 is independently hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-7, m is 0-5, and R 7 is hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-6, m is 0-3, and R 7 is hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-6, m is 0, and R 7 is hydrogen or methyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is , wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1 or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1 and X2 are each independently CH or N and wherein each k is independently 0, 1, or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1, X2, X3, and X4 are each independently CH or N and wherein each k is independently 0, 1 or 2, each m is independently 0, 1, or 2, and each n is independently 0, 1, or 2.
  • R 5 and R 6 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, and C 1-3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, halogen, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R 5 and R 6 are both hydrogen.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1 and X2 are each independently CH or N and wherein each k is independently 0, 1, or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*
  • provided herein is a compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, having the structure of Formula (I-b)
  • L is -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1, 2, 3, 4, 5, or 6 and m is 1, 2, 3, 4, or 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 1, and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 2, and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 3 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4, and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 4 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 5 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 3.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 4.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein n is 6 and m is 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is - (CR 5 R 6 ) n -NR 7 – (CR 5 R 6 ) m -*, wherein n is 1, 2, 3, 4, 5 or 6, and m is 1, 2, 3, 4, or 5.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, 2, 3, or 4, n is 1, 2, or 3, and m is 1 or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 1, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 2, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 3, and m is 1.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 1, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 2, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 1, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 2, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 3, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is – (CR 5 R 6 ) k -O–– (CR 5 R 6 ) n -O– (CR 5 R 6 ) m -*, wherein k is 4, n is 3, and m is 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is and each R 7 is independently hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is and each R 7 is independently hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-7, m is 0-5, and R 7 is hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-6, m is 0-3, and R 7 is hydrogen or C 1-3 alkyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein k is 1-6, m is 0, and R 7 is hydrogen or methyl.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is, wherein X, X1, and X2 are each independently CH or N and wherein each k is independently 0, 1 or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1 and X2 are each independently CH or N and wherein each k is independently 0, 1, or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1, X2, X3, and X4 are each independently CH or N and wherein each k is independently 0, 1 or 2, each m is independently 0, 1, or 2, and each n is independently 0, 1, or 2.
  • R 5 and R 6 are independently selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, and C 1-3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, halogen, C 1-3 alkyl, and C 3 cycloalkyl. In some embodiments, R 5 and R 6 are independently selected from hydrogen, fluoro, and methyl. In some embodiments, R 5 and R 6 are both hydrogen.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is wherein X1 and X2 are each independently CH or N and wherein each k is independently 0, 1, or 2, and each m is independently 0, 1, or 2.
  • -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -* is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*is, In some embodiments, -Ak 1 -Z 1 -Ak 2 -Z 2 -Ak 3 -*
  • the compounds as described herein have a structure provided in Table 1, Table 2, or Table 3. In some embodiments, the compounds as described herein have a structure provided in Table 1.
  • compounds as described herein has a structure provided in Table 2.
  • compounds as described herein has a structure provided in Table 3.
  • the heteroaromatic WEE1 degradation compound described e.g., a compound of Formula (I) , Formula (I-a) , or Formula (I-b) ) herein is administered as a pure chemical.
  • the heteroaromatic WEE1 degradation compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
  • a pharmaceutical composition comprising at least one heteroaromatic WEE1 degradation compound as described herein (e.g., a compound of Formula (I) , Formula (I-a) , or Formula (I-b) ) , or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier (s) or excipient (s) ) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the heteroaromatic WEE1 degradation compound as described by Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005) ) .
  • the heteroaromatic WEE1 degradation compound as described by Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the dose of the composition comprising at least one heteroaromatic WEE1 degradation compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented) .
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition (s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • One embodiment provides a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) , Formula (I-a) , or Formula (I-b) , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.
  • the compounds disclosed herein are synthesized according to the following examples.
  • the following abbreviations unless otherwise indicated, shall be understood to have the following meanings: °C degrees Celsius ⁇ H chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH 2 Cl 2 ) DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl g gram (s) h hour (s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry ⁇ micro m multiplet (spectral) ; meter (s) ; milli M molar M + parent molecular ion Me methyl MHz megahertz min minute (s) mol mole (s) ; molecular (as in mol wt
  • Step 1 methyl 4- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ butanoate
  • Step 2 4- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ butanoic acid
  • Step 1 tert-butyl 6- [4- [4- ( [1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl] amino) phenyl] piperazin-1-yl] hexanoate
  • Step 2 6- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ hexanoic acid
  • Step 2 7- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ heptanoic acid
  • Step 1 ethyl 4- (2-allyl-2- (tert-butoxycarbonyl) hydrazineyl) -2- (methylthio) pyrimidine-5-carboxylate
  • Step 8 ethyl 8- [4- [4- ( [1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl] amino) phenyl] piperazin-1-yl] octanoate
  • Step 9 8- [4- [4- ( [1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl] amino) phenyl] piperazin-1-yl] octanoic acid
  • Step 1 ethyl 9- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) nonanoate
  • Step 2 9- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) nonanoic acid
  • Step 1 tert-butyl 10- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) decanoate
  • Step 2 10- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) decanoic acid
  • Step 1 methyl 11- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) undecanoate
  • Step 4 methyl 4- (2- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) ethoxy) butanoate
  • Step 1 methyl 4- (3- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) propoxy) butanoate
  • Step 2 4- (3- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) propoxy) butanoic acid
  • Step 3 tert-butyl 2- ( (6- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) hexyl) oxy) acetate
  • Step 1 tert-butyl 2- (4- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) butoxy) acetate
  • Step 3 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) butoxy) acetamido) -3, 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (Compound 12)
  • Step 1 tert-butyl 2- ( (2- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) ethoxy) methoxy) acetate
  • reaction was purified by reverse column to afford [ (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) methoxy] acetic acid.
  • Step 1 tert-butyl 2- [ (5- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ pentyl) oxy] acetate
  • Step 2 [ (5- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ pentyl) oxy] acetic acid
  • Step 1 tert-butyl 5- (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) pentanoate
  • Step 2 5- (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) pentanoic acid
  • Step 1 tert-butyl 2- [2- (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) ethoxy] acetate
  • Step 2 methyl dodec-11-ynoate [2- (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) ethoxy] acetic acid
  • Step 1 tert-butyl 2- ( (3- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) propoxy) methoxy) acetate
  • Step 4 tert-butyl 3- ( (5- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) pentyl) oxy) propanoate
  • the resulting mixture was stirred at 50 °C overnight.
  • the reaction solution was quenched with water (20 mL) .
  • the resulting mixture was extracted with EtOAc (3 x 50 mL) .
  • the combined organic layers were washed with brine (4 x 100 mL) and then concentrated.
  • Step 3 4- (4- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ butoxy) butanoic acid
  • Step 3 tert-butyl 2- ( (3- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) propoxy) methoxy) acetate
  • Step 4 2- ( (3- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) propoxy) methoxy) acetic acid
  • Step 1 10, 10, 11, 11-tetramethyl-1-phenyl-2, 6, 9-trioxa-10-siladodecane
  • Step 7 [2- (3- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ propoxy) ethoxy] acetic acid
  • Step 4 methyl 6- (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) hexanoate
  • Step 5 6- (2- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ ethoxy) hexanoic acid
  • Step 1 tert-butyl 3- (2- (2- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) ethoxy) ethoxy) propanoate
  • Step 2 3- (2- (2- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) ethoxy) ethoxy) propanoic acid
  • the resulting mixture was stirred for 1 h at 60 °C in air atmosphere.
  • NaBH 3 CN 51.66 mg, 0.822 mmol, 1.6 equiv.
  • the resulting mixture was stirred for additional for 5 h at room temperature. Desired product could be detected by LCMS.
  • the reaction was quenched with sat. NaHCO 3 (aq. ) at room temperature.
  • the resulting mixture was extracted with EA (3 x 10 mL) . The combined organic layers were dried over anhydrous Na 2 SO 4 .
  • Step 6 4'- ⁇ 4- [4- ( ⁇ 1- [6- (2-Hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ - [1, 1'-bi (cyclohexane) ] -4-carboxylic acid
  • reaction mixture was further purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5 ⁇ m, n; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1%NH 3 .
  • Step 1 methyl 4- (1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) cyclohexane-1-carboxylate
  • Step 3 methyl 4- (4- (4- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) cyclohexane-1-carboxylate
  • Step 4 4- (4- (4- (4- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) cyclohexane-1-carboxylic acid
  • Step 1 tert-butyl 4- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) piperidine-1-carboxylate
  • the resulting mixture was stirred at 25 °C for 3 h.
  • the reaction was quenched with H 2 O (10 mL) .
  • the mixture was basified to pH ⁇ 9 with NaHCO 3 aqueous solution and extracted with EA (3 x 50 mL) , washed with brine (3 x 70 mL) , the organic layers were combined and concentrated under vacuum.
  • Step 4 6- ( (4- (4- ( [1, 4'-bipiperidin] -4-yl) piperazin-1-yl) phenyl) amino) -2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3, 4-d] pyrimidin-3-one
  • Step 6 4- (4- (4- ( (2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-6-yl) amino) phenyl) piperazin-1-yl) -N- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( (4- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) - [1, 4'-bipiperidine] -1'-carboxamide (Compound 29)
  • Step 1 ethyl 1- ⁇ 1, 4-dioxaspiro [4.5] decan-8-yl ⁇ piperidine-4-carboxylate
  • Step 4 1- (4- ⁇ 4- [4- ( ⁇ 1- [6- (2-hydroxypropan-2-yl) pyridin-2-yl] -3-oxo-2- (prop-2-en-1-yl) pyrazolo [3, 4-d] pyrimidin-6-yl ⁇ amino) phenyl] piperazin-1-yl ⁇ cyclohexyl) piperidine-4-carboxylic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés qui ciblent des protéines kinase WEE1 pour l'ubiquitination et la dégradation protéasomale. L'invention concerne également des procédés d'utilisation desdits composés pour le traitement de maladies.
PCT/CN2023/086879 2022-04-08 2023-04-07 Composés de dégradation de wee1 WO2023193789A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380009470.1A CN116829570A (zh) 2022-04-08 2023-04-07 Wee1降解化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022085833 2022-04-08
CNPCT/CN2022/085833 2022-04-08

Publications (1)

Publication Number Publication Date
WO2023193789A1 true WO2023193789A1 (fr) 2023-10-12

Family

ID=88244111

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/086879 WO2023193789A1 (fr) 2022-04-08 2023-04-07 Composés de dégradation de wee1

Country Status (1)

Country Link
WO (1) WO2023193789A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020069105A1 (fr) * 2018-09-27 2020-04-02 Dana-Farber Cancer Institute, Inc. Agents de dégradation de la kinase wee1
CN111902413A (zh) * 2018-03-09 2020-11-06 里科瑞尔姆Ip控股有限责任公司 取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮
CN112142748A (zh) * 2019-06-28 2020-12-29 上海医药集团股份有限公司 一种吡唑酮并嘧啶类化合物、其制备方法及应用
CN113387930A (zh) * 2020-03-11 2021-09-14 苏州开拓药业股份有限公司 一种双官能化合物及其制备方法和用途
CN113402520A (zh) * 2020-03-16 2021-09-17 中国科学院上海药物研究所 Wee1蛋白降解剂
WO2021236695A1 (fr) * 2020-05-18 2021-11-25 Montelino Therapeutics, Inc. Composés bi-fonctionnels et procédés d'ubiquitination ciblée du récepteur des androgènes
WO2022251224A1 (fr) * 2021-05-28 2022-12-01 Recurium Ip Holdings, Llc Inhibiteurs de wee1 et méthodes de traitement du cancer

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111902413A (zh) * 2018-03-09 2020-11-06 里科瑞尔姆Ip控股有限责任公司 取代的1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮
WO2020069105A1 (fr) * 2018-09-27 2020-04-02 Dana-Farber Cancer Institute, Inc. Agents de dégradation de la kinase wee1
CN112142748A (zh) * 2019-06-28 2020-12-29 上海医药集团股份有限公司 一种吡唑酮并嘧啶类化合物、其制备方法及应用
CN113387930A (zh) * 2020-03-11 2021-09-14 苏州开拓药业股份有限公司 一种双官能化合物及其制备方法和用途
CN113402520A (zh) * 2020-03-16 2021-09-17 中国科学院上海药物研究所 Wee1蛋白降解剂
WO2021236695A1 (fr) * 2020-05-18 2021-11-25 Montelino Therapeutics, Inc. Composés bi-fonctionnels et procédés d'ubiquitination ciblée du récepteur des androgènes
WO2022251224A1 (fr) * 2021-05-28 2022-12-01 Recurium Ip Holdings, Llc Inhibiteurs de wee1 et méthodes de traitement du cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AUBLETTE MARINE C., HARRISON TOM A., THORPE ELIZABETH J., GADD MORGAN S.: "Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 64, 1 May 2022 (2022-05-01), Amsterdam NL , pages 128636, XP093080410, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2022.128636 *

Similar Documents

Publication Publication Date Title
US11267812B2 (en) KRAS G12C inhibitors
US11407740B2 (en) Antibacterial compounds
ES2926255T3 (es) Métodos de fabricación de niraparib
WO2019014308A1 (fr) Amides hétérocycliques à 5 chaînons et bicycliques utilisés en tant qu'inhibiteurs de rock
CN112142735A (zh) 一类稠和氰基吡啶类化合物、制备方法和用途
JP2009530372A (ja) ピリドピリミジン誘導体およびｐｄｅ４阻害剤としてのその使用
EP2396325B1 (fr) Dérivés d'azaindoles comme inhibiteurs des protéines kinases abl et src
CA2636605A1 (fr) Nouvelles arylthienopyrimidinones substituees par azacyclyle, leur procede de synthese et leur emploi en tant que medicaments
EP3455226A1 (fr) Composés spirocycliques et procédés de préparation et d'utilisation de ceux-ci
EP3768272A1 (fr) Inhibiteurs de jak
CN113365996A (zh) 咪唑吡啶衍生化合物以及其应用
WO2024108765A1 (fr) Dérivé spiro utilisé en tant qu'inhibiteur de kif18a
CN112939982A (zh) 一种炔类杂环btk抑制剂及其制备方法和用途
WO2023193789A1 (fr) Composés de dégradation de wee1
WO2021099842A1 (fr) Dérivés de pentafluorobenzènesulfonamide et leurs utilisations
WO2021113368A1 (fr) Antagonistes de sstr5
WO2024027706A1 (fr) Composés de dégradation de bcl-xl
WO2024107565A1 (fr) Modulateurs de akt1
WO2024037527A1 (fr) Composés de dégradation de btk
WO2022194087A1 (fr) Protéines et liants protéiques modifiés
WO2022234339A2 (fr) Agonistes du récepteur 5-ht2a et/ou 5-ht2c
CN116829570A (zh) Wee1降解化合物
WO2024064026A1 (fr) Modulateurs d'akt1
WO2024102621A1 (fr) Modulateurs de akt1
RU2772274C2 (ru) Селективные ингибиторы hdac6, способ их получения и их применение

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: 23784352

Country of ref document: EP

Kind code of ref document: A1