WO2022066580A1 - Raf degrading compounds - Google Patents

Raf degrading compounds Download PDF

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Publication number
WO2022066580A1
WO2022066580A1 PCT/US2021/051115 US2021051115W WO2022066580A1 WO 2022066580 A1 WO2022066580 A1 WO 2022066580A1 US 2021051115 W US2021051115 W US 2021051115W WO 2022066580 A1 WO2022066580 A1 WO 2022066580A1
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optionally substituted
alkyl
pharmaceutically acceptable
solvate
compound
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PCT/US2021/051115
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French (fr)
Inventor
Toufike Kanouni
Eric Murphy
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Kinnate Biopharma Inc.
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Publication of WO2022066580A1 publication Critical patent/WO2022066580A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • RAF kinase functions in the Ras-Raf-MEK-ERK mitogen activated protein kinase (MAPK) pathway (also known as MAPK/ERK pathway) by phosphorylating and activating MEK.
  • MAPK mitogen activated protein kinase
  • the present disclosure provides compounds, compositions and methods for the reduction or elimination of RAF signaling via the targeting of RAF protein in a cell through ubiquitination and proteasomal degradation.
  • BRIEF SUMMARY OF THE INVENTION [0003] Provided herein are compounds which target RAF kinase proteins for ubiquitination and proteasomal degradation. Also provided herein are methods for using said compounds for the treatment of diseases.
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): wherein, L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH 3 ; R 1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R 1 groups join to form a fused ring; R 2 is H, D or F; R is halogen, optionally substituted C1 C3 alkyl, CD3, or optionally substituted C1-C3 alkoxy; R 6 is H, D, Cl or F; Z is selected from: (a) -NR a R b , wherein R a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 al
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II): wherein, L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R 1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R 1 groups join to form a fused ring; R 2 is H, D or F; R 4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R 6 is H, D, Cl or F; Z is selected from: (a) -NR a R b , wherein R a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • 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 or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • 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 (II), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
  • an agent includes a plurality of such agents
  • the cell includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.
  • ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • the term "about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
  • Oxa refers to the -O- radical.
  • Thioxo refers to the S 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., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl).
  • 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., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 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., C3-C5 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), 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)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)
  • 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.
  • 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
  • but-1-enyl i.e., 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 R a (where t is 1 or 2), -
  • 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)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2)
  • 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., C1-C8 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., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene).
  • 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., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 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)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S
  • 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., C2-C8 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., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 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)tR a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O
  • 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., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C2-C4 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., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 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)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2)
  • 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)-N(R
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • “Aralkenyl” 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.
  • alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • "Aralkynyl” 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.
  • 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 or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms. In other embodiments, 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.
  • 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)- N(R
  • Carbocyclylalkyl refers to a radical of the formula R 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. 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.
  • carboxylic acid bioisosteres include, but are not limited to, O O N N N O S N N
  • 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 or tetracyclic 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
  • 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)- N(
  • 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 (benzothienyl (benzothion
  • 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 -OC(O)-R a , -R b -OC(O)-R
  • 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.
  • tautomeric equilibrium includes: [0053]
  • the compounds disclosed herein, in some embodiments, 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).
  • 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.
  • 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.
  • Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions such as iodomethane-d3 (CD3I) are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
  • LiAlD 4 t um a uminum deuteride
  • 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.
  • 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 RAF 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
  • 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.
  • 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.
  • “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.
  • 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.
  • the RAF kinases are a family of serine/thronine protein kinases constitute core components of the RAS–RAF–MEK–ERK mitogen activated protein kinase (MAPK) signalling cascade (also known as the MAPK/ERK pathway), a pathway that mediates signals from cell surface receptors to the nucleus to regulate cell growth, differentiation and survival.
  • MAPK mitogen activated protein kinase
  • the RAF proteins are related to retroviral oncogenes and are structurally conserved from metazoans to mammals, as is the MAPK/ERK pathway. Their dysregulation leads to uncontrolled cellular proliferation, survival and dedifferentiation. Consequently, RAF kinases are altered or inappropriately activated in a majority of cancers.
  • the MAPK/ERK signalling pathway is a network of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
  • the signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division.
  • the pathway includes many proteins, which communicate by adding phosphate groups to a neighboring protein, which acts as a molecular "on” or “off” switch, and overall the pathway can be divided into 3 steps: (i) Ras activation, (ii) a kinase signal transduction cascade, and (iii) regulation of translation and transcription.
  • an extracellular mitogen or a signaling molecule binds to the membrane receptor.
  • Ras a small GTPase
  • RAF kinase phosphorylates and activates MEK (MEK1 and MEK2).
  • MEK then phosphorylates and activates a MAPK (also known as ERK).
  • MAPK activation regulates activities of several transcription factors and also alters the translation of mRNA to proteins. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle.
  • C-RAF also known as RAF-1, or c-RAF-1
  • B- RAF B- RAF
  • A-RAF A-RAF.
  • All RAF kinases share a common modular structure consisting of 3 conserved regions (CR1, CR2, and CR3) with distinct functions.
  • CR1 contains (i) a Ras-binding domain (RBD), which is necessary for the interaction with Ras and with membrane phospholipids required for membrane recruitment, and (ii) a cysteine-rich domain (CRD), which is a secondary Ras-binding site and also necessary for the interaction of CR1 with the kinase domain for RAF autoinhibition.
  • RBD Ras-binding domain
  • CCD cysteine-rich domain
  • CR2 contains important inhibitory phosphorylation sites participating in the negative regulation of Ras binding and RAF activation.
  • CR3 features the kinase domain, including the activation segment, whose phosphorylation is crucial for kinase activation.
  • the RAF structure can be split into a regulatory N-terminal region, containing the RBD, which is critical for activation as well as inhibitory phosphorylation sites, and a catalytic C-terminal region, which includes phosphorylation sites necessary for the kinase activation.
  • the regulatory domain restrains the activity of the kinase domain, and its removal results in constitutive oncogenic activation.
  • the activity of the isolated C- RAF kinase domain is subjected to further regulation and can be stimulated by phorbol esters, v- Src, and phosphorylation.
  • the common and key step in the activation of all 3 RAF kinase isoforms is membrane recruitment by a Ras family protein.
  • the RAF kinases are located in the cytosol in their inactive state when bound to 14-3-3 proteins. In the presence of active Ras, they translocate to the plasma membrane.
  • Membrane translocation triggers further activation events, such as the binding of PP2A to dephosphorylate the inhibitory pS259 site in RAF-1 (and presumably the corresponding sites in A-RAF and B-RAF) and the co-localization with the kinases responsible for the multiple activating phosphorylations.
  • the sequences forming the binding interface are well conserved in the RAF as well as Ras family indicating that several members of the Ras family have the ability to bind RAF kinases.
  • H-Ras, N-Ras, and K-Ras stimulate all 3 RAF isoforms and are the only Ras proteins that activate B-RAF.
  • C-RAF is also activated by R-Ras3, while C-RAF responds weakly to R-Ras3, Rit, and TC21as well. But, all RAF kinases share MEK1/2 kinases as substrates. MEK1/2 in turn activate ERK1/2, and this pathway regulates many cellular functions such as cell proliferation, differentiation, migration, or apoptosis.
  • C-RAF [0073] C RAF was first to be identified and is a ubiquitously expressed isoform. In humans, C-RAF is encoded by the RAF1 gene. C-RAF also has a known splice variant preferentially expressed in the muscle and brain. C-RAF plays a critical role in mediating the cellular effects of growth factor signals.
  • C-RAF exists in a closed conformation in which the N-terminal regulatory region folds over and occludes the catalytic region. This conformation is stabilized by a 14-3-3 dimer binding to an N-terminal site, phospho-S259 (pS259), and a C-terminal site, pS621. Dephosphorylation of pS259 at the cell membrane by specific phosphatases (PP2A, PP1) releases 14-3-3 from its N-terminal binding site in C-RAF, thereby allowing conformational changes to occur that unmask the RBD and CRD domains in the CR1 region to enable Ras binding and membrane recruitment.
  • PP2A specific phosphatases
  • B-RAF is encoded in humans by the BRAF gene, also known as proto- oncogene B-RAF and v-RAF murine sarcoma viral oncogene homolog B. Alternative splicing gives rise to multiple B-RAF isoforms which are differentially expressed in various tissues. Whereas activation of A-RAF and C-RAF requires both phosphorylation and dephosphorylation of certain residues, as well as binding to other proteins, B-RAF becomes activated immediately upon translocation to the plasma membrane. B-RAF exhibits higher basal kinase activity than A- RAF and C-RAF.
  • B-RAF requires Ras and 14-3-3 binding for its activation, and is inhibited or activated by PKA depending on the levels of 14-3-3 expression, which need to be high for permitting activation.
  • B-RAF activity is also regulated by splicing.
  • B-RAF isoforms containing exon 8b are more phosphorylated on the inhibitory S365 site, leading to an increased interaction with 14-3-3 and strengthening the inhibitory interaction between N-terminal regulatory domain and kinase domain, altogether resulting in lower kinase activity.
  • A-RAF [0075] Serine/threonine-protein kinase A-RAF or A-RAF is an enzyme encoded by the ARAF gene in humans.
  • A-RAF A-RAF - DA-RAF1 and D- RAF2. They lack the kinase domain and act as dominant inhibitory mutants of Ras and ARF GTPases.
  • DA-RAF1 is a positive regulator of myogenic differentiation by mediating the inhibition of the ERK pathway required for differentiation.
  • A-RAF is different from the other RAF kinases.
  • A-RAF is the only steroid hormone-regulated Raf isoform.
  • the A-RAFprotein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region), which contributes to its low basal activity.
  • A- RAF is also only weakly activated by oncogenic H-Ras and Src and also displays low kinase activity towards MEK (the lowest kinase activity towards MEK proteins in the Raf kinase family).
  • MEK the lowest kinase activity towards MEK proteins in the Raf kinase family.
  • A-RAF also inhibits MST2, a tumor suppressor and pro apoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A RAF prevents apoptosis from occurring. However, this inhibition is only occurs when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-RAF protein.
  • hnRNP H splice factor heterogenous nuclear ribonucleoprotein H
  • A-RAF also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway.
  • PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells.
  • A-RAF upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form.
  • B-RAF Aberrant activation of the MAPK/ERK pathway is frequently found in various cancers and is a target for cancer therapeutics.
  • B-RAF has emerged as one of the most attractive molecular targets for cancer therapeutics because somatic mutations of B- RAF have frequently been found in human tumors.
  • B-RAF-V600E a missense mutation in the kinase domain generated by the substitution of glutamic acid with valine at position 600 is the most common B-RAF mutation.
  • C-RAF is mutated in ⁇ 1% of the various tumor types tested and the rate of mutations in A-RAF is even lower.
  • B-RAF and C-RAF form both homo- and heterodimers as part of their activation mechanism and A-RAF stabilizes the B-RAF:C-RAF complexes to sustain signaling efficiency.
  • C-RAF not B-RAF, that transmits signals from oncogenic RAS to MEK. Therefore, in different contexts, each of the RAF isoforms act as a potential therapeutic target.
  • Selective Protein Degradation [0077] The levels of proteins within a cell are determined by by both the rate of protein synthesis and the rate of protein degradation.
  • ubiquitin-proteasone pathway two pathways exist for selective protein degradation, the ubiquitin-proteasone 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, or lysosomal proteolysis.
  • Recruitment motifs include E3 ligase recognition agents, proteasome recognition agents, lysosomal recognition peptides, or hydrophobic tagging agents. Conjugation of recruitment motifs with high affinity ligands for RAF kinase will provide compounds capable of selectively directing pathways for protein degradation to the RAF kinase protein itself.
  • heteroaromatic RAF degradation compound having the general formula provided below: , wherein the RAF kinase affinity motif is a molecular construct having high affinity for the RAF 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 RAF kinase affinity motif and the recruitment motif, and the recruitment motif is a molecular construct having the ability to selectively target and recruit protein degradation.
  • Recruitment motifs include E3 ligase recognition agents, proteasome recognition agents, lysosomal recognition peptides, or hydrophobic tagging agents.
  • the recruitment motif is derived from pomalidomide, 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 derived from pomalidomide.
  • the recruitment motif is selected from a molecular construct illustrated below:
  • the recruitment motif is selected from a molecular construct illustrated below: O O O O O O O O NH NH NH with the p oint of bonding to the linking motif as indicated, and R is an optionally substituted C1- C6 alkyl group.
  • the recruitment motif is selected from a molecular construct related to VHL ligand as illustrated below: HO HO with the point of b onding to the linking motif as indicated.
  • the recruitment motif is selected from a molecular construct related to IAP ligand as illustrated below: with the point of bo nding to the linking motif as indicated.
  • the recruitment motif is selected from a molecular construct known to induce protein mis-folding such as HyT13 or HyT36. Use of hydrophobic tags for the degradation of proteins is discussed in Tae et al. (Chembiochem (2012), 13(4), 538- 541). [ 0084] In some embodiments, the recruitment motif is selected from a molecular construct known to recruit the proteasome, such as Boc 3 Arginine. In some embodiments, the recruitment motif is selected from a molecular construct known to induce lysosomal degradation, such as the peptide KFERQ or the peptide H2N-KFERQKILDQRFFE-CO2H.
  • 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 20 atoms.
  • the linking motif comprises between 4 and 25 atoms.
  • the linking motif comprises between 4 and 30 atoms.
  • the linking motif comprises between 6 and 18 atoms.
  • the linking motif comprises between 5 and 10 atoms.
  • the linking motif is selected from a molecular fragment illustrated below: with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. [0086] In some embodiments, the linking motif is selected from a molecular fragment illustrated below: with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk.
  • the linking motif is selected from a molecular fragment illustrated below: wh erein R is an optionally substituted alkyl or an optionally substituted -CO-alkyl, with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk.
  • the linking motif is a polyethylene glycol selected from –(O-CH2-CH2)n-O- or –(O-CH2-CH2)n-N(R 23 )-*, wherein n is selected from 1 to 20, and R 23 is optionally substituted alkyl, or optionally substituted -CO-alkyl; and the point of bonding to the recruitment motif indicated by the asterisk.
  • the linking motif is selected from: with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk, and wherein n is 0, 1, 2, or 3, and R 22 is an optionally substituted alkyl.
  • the linking motif is selected from: N O N N N N N N N N N N N O O O with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. [0091] In some embodiments, the linking motif is selected from: with t he point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk.
  • RAF Kinase Affinity Motif [0092]
  • L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation;
  • X is N, C-H, C-D, C-F, or C-CH3;
  • R 1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R 1 groups join to form a fused ring;
  • R 2 is H, D or F;
  • R is halogen, optionally substituted C1 C3 alkyl, CD3, or optionally substituted C1-C3 alkoxy;
  • R 6 is H, D, Cl or F;
  • Z is selected from: (a) -NR a R b , wherein R a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0094] One embodiment provides a compound, or p harmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0095] One embodiment provides a compound, or p harmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0096] One embodiment provides a compound, or p harmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0097] One embodiment provides a compound, or p harmaceutically acceptable salt or solvate thereof, having the structure of Formula (II): wherein, L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R 1 is C1-C3 optionally substituted alkyl,
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [0099]
  • One embodiment provides a compound, or ph armaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [00100]
  • One embodiment provides a compound, or ph armaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [00101]
  • One embodiment provides a compound, or ph armaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [00102]
  • the heteroaromatic RAF degradation compound as described herein has a structure provided in Table 1. Table 1 Synthetic - - - [00103]
  • the heteroaromatic RAF degradation compound as described herein has a structure provided below. O O NH
  • the heteroaromatic RAF degradation compound described herein is administered as a pure chemical.
  • the heteroaromatic RAF 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 RAF degradation compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the heteroaromatic RAF degradation compound as described by Formula (I) or (II), 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 RAF degradation compound as described by Formula (I) or (II), or 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 RAF 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.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • Methods of Treatment [00117] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00118] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00119] One embodiment provides a use of a compound of Formula (I), 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), 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), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a compound of Formula (II), 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 (II), 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 (II), 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 (II), 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 (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (II), 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.
  • the pharmaceutical composition is administered by injection.
  • Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I.
  • heteroaromatic RAF kinase inhibitory compounds disclosed herein are synthesized according to the following examples.
  • the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: o C degrees Celsius ⁇ H chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) 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
  • Example 2 (3S)N(6 (2(4(2(2,6dioxopiperidin3yl)1,3 dioxoisoindolin-5-yl)piperazin l)ethoxy)-2-methyl-5'-morpholino-[3,3'-bipyridin]-5-yl)- 3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide [ ] e aove roue prov e or mg o ( )- -( -(-(-(-(-(-(, - dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)-2-methyl-5'-morpholino- [3,3'-bipyridin]-5-yl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a yellow solid.
  • WM3629 or A375 cells were seeded at 8000 or 15000 cells/well in 24 ⁇ l growth media (80% MDAB153 + 20% L-15 + 2% FBS + 1.68mM calcium chloride or DMEM + 10% FBS, respectively) into 384-well plates and allowed to adhere overnight at 37 ⁇ C 5%CO2. The following day compounds were serially diluted from a 10 mM DMSO stock into a 10-point, 3-fold dose curve in DMSO.
  • IC 50 was calculated using a four parameter fit model using Dotmatics Knowledge Solutions Studies curve fitting (Dotmatics, Bishops Stortford, UK, CM23). Representative data for exemplary compounds is presented in Table 2. Table 2 Synthetic Chemistry Note: IC50 data are designated within the following ranges: A: ⁇ 0.010 ⁇ M C: > 0.10 ⁇ M to ⁇ 1.0 ⁇ M B: > 0.010 ⁇ M to ⁇ 0.10 ⁇ M D: > 1.0 ⁇ M to ⁇ 10 ⁇ M III.
  • Oral capsule [00134] The active ingredient is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof.
  • a capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • Example 2 Solution for injection
  • the active ingredient is a compound of Table (I) or (II), or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg- eq/mL.
  • the examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Abstract

Provided herein are compounds which target RAF kinase proteins for ubiquitination and proteasomal degradation. Also provided herein are methods for using said compounds for the treatment of diseases.

Description

x xxx xEGRADING COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims benefit of U.S. Patent Application No.63/082,409 filed on September 23, 2020 which is incorporated by reference in its entirety. BACKGROUND [0002] RAF kinase functions in the Ras-Raf-MEK-ERK mitogen activated protein kinase (MAPK) pathway (also known as MAPK/ERK pathway) by phosphorylating and activating MEK. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle. Deregulation of MAPK activity occurs frequently in tumors. The present disclosure provides compounds, compositions and methods for the reduction or elimination of RAF signaling via the targeting of RAF protein in a cell through ubiquitination and proteasomal degradation. BRIEF SUMMARY OF THE INVENTION [0003] Provided herein are compounds which target RAF kinase proteins for ubiquitination and proteasomal degradation. Also provided herein are methods for using said compounds for the treatment of diseases. [0004] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): wherein,
Figure imgf000002_0001
L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R1 groups join to form a fused ring; R2 is H, D or F; R is halogen, optionally substituted C1 C3 alkyl, CD3, or optionally substituted C1-C3 alkoxy; R6 is H, D, Cl or F; Z is selected from: (a) -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R11 is in
Figure imgf000003_0001
p y m amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(
Figure imgf000003_0002
O), SO2, NH or N(optionally substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2
Figure imgf000004_0001
p ov ded bot a d a e not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3
Figure imgf000004_0002
; , , ( ), , or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH-CH2-, -NH- CHR11-, -NH-C(R11)2-, -CH2-NH-, -CHR11-NH-, -C(R11)2-NH-, -N(R11)-CH2-, -N(R11)-CHR11-, -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-, -O-CH2-, or -CH2-O-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2;
Figure imgf000004_0003
m1 is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n a
Figure imgf000005_0002
e ot bot 0; p s 0, , , 3, or 4; and each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R13 or R1
Figure imgf000005_0003
is independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2
Figure imgf000005_0001
; q , ; , S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1 C6 alkoxy, optionally substituted C2 C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo. [0005] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II): wherein,
Figure imgf000006_0001
L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R1 groups join to form a fused ring; R2 is H, D or F; R4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R6 is H, D, Cl or F; Z is selected from: (a) -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R11 is i
Figure imgf000007_0001
ndependently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O
Figure imgf000007_0002
), SO2, NH or N(optionally substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2 pr
Figure imgf000007_0003
ovided both m1 and n1 are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3
Figure imgf000008_0001
; , , ( ), , or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH-CH2-, -NH- CHR11-, -NH-C(R11)2-, -CH2-NH-, -CHR11-NH-, -C(R11)2-NH-, -N(R11)-CH2-, -N(R11)-CHR11-, -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-, -O-CH2-, or -CH2-O-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m
Figure imgf000008_0002
1 is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are n
Figure imgf000008_0003
ot both 0; p is 0, 1, 2, 3, or 4; and each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R13 or R14
Figure imgf000009_0001
s epe e y se ected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; a
Figure imgf000009_0002
q s , o ; s , S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo. [0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0007] 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 or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. [0008] One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0009] 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 (II), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. INCORPORATION BY REFERENCE [0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION [0011] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions [0012] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. [0013] "Amino" refers to the –NH2 radical. [0014] "Cyano" refers to the -CN radical. [0015] "Nitro" refers to the -NO2 radical. [0016] "Oxa" refers to the -O- radical. [0017] "Oxo" refers to the =O radical. [0018] Thioxo refers to the S radical. [0019] "Imino" refers to the =N-H radical. [0020] "Oximo" refers to the =N-OH radical. [0021] "Hydrazino" refers to the =N-NH2 radical. [0022] "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., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, 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), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0023] Alkoxy refers to a radical bonded through an oxygen atom of the formula O-alkyl, where alkyl is an alkyl chain as defined above. [0024] "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. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0025] "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. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, 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. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0026] "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. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0027] "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. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0028] "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. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0029] "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. Unless stated otherwise specifically in the specification, the term "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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb- O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), - Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0030] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc 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. [0031] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd 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. [0032] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re 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. [0033] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rc 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. [0034] Carbocyclyl refers to a stable non aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, 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." Examples of 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. Unless otherwise stated specifically in the specification, the term "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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0035] Carbocyclylalkyl refers to a radical of the formula R carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above. [0036] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above. [0037] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above. [0038] As used herein, “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, O O N N N O S N N [
Figure imgf000018_0001
0039] Halo or halogen refers to bromo, chloro, fluoro or iodo substituents. [0040] "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. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group. [0041] "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 or tetracyclic 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). Examples of such 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-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0042] "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. [0043] "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. [0044] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rc 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. [0045] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rc 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. [0046] "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. As used herein, 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. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of 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 (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb- S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0047] 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. [0048] "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. [0049] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc 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. [0050] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rc 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. [0051] 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. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. [0052] 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 presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000023_0001
[0053] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such 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. [0054] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [0055] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 125I are all contemplated. In some embodiments, isotopic substitution with 18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0056] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H 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. [0057] 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. [0058] 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. [0059] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below. OH CD3I O D [0060] Deuterium
Figure imgf000024_0001
-trans er reagents, suc as t um a uminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below. R LiAlD4 R NH2 LiAlD D D O CO 4 2H LiAlD4 D R' [00
Figure imgf000024_0002
6 ] euter um gas and pa ad um cata yst are emp oyed 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. H D 2 H D [0062]
Figure imgf000025_0001
In one embodiment, 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 1H 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. [0063] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heteroaromatic RAF 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. [0064] "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. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and 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. [0065] "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., supra. [0066] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, 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. The term “subject” or “patient” encompasses mammals. Examples of 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. In one aspect, the mammal is a human. [0067] As used herein, “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. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, 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. For prophylactic benefit, 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. The RAF Family of Kinases [0068] The RAF kinases are a family of serine/thronine protein kinases constitute core components of the RAS–RAF–MEK–ERK mitogen activated protein kinase (MAPK) signalling cascade (also known as the MAPK/ERK pathway), a pathway that mediates signals from cell surface receptors to the nucleus to regulate cell growth, differentiation and survival. The RAF proteins are related to retroviral oncogenes and are structurally conserved from metazoans to mammals, as is the MAPK/ERK pathway. Their dysregulation leads to uncontrolled cellular proliferation, survival and dedifferentiation. Consequently, RAF kinases are altered or inappropriately activated in a majority of cancers. [0069] The MAPK/ERK signalling pathway is a network of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, which communicate by adding phosphate groups to a neighboring protein, which acts as a molecular "on" or "off" switch, and overall the pathway can be divided into 3 steps: (i) Ras activation, (ii) a kinase signal transduction cascade, and (iii) regulation of translation and transcription. Briefly, an extracellular mitogen or a signaling molecule binds to the membrane receptor. This allows Ras (a small GTPase) to swap its GDP for a GTP and become active. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinase phosphorylates and activates MEK (MEK1 and MEK2). MEK then phosphorylates and activates a MAPK (also known as ERK). MAPK activation regulates activities of several transcription factors and also alters the translation of mRNA to proteins. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle. [0070] There are three known mammalian RAF isoforms: C-RAF (also known as RAF-1, or c-RAF-1), B- RAF, and A-RAF. All RAF kinases share a common modular structure consisting of 3 conserved regions (CR1, CR2, and CR3) with distinct functions. CR1 contains (i) a Ras-binding domain (RBD), which is necessary for the interaction with Ras and with membrane phospholipids required for membrane recruitment, and (ii) a cysteine-rich domain (CRD), which is a secondary Ras-binding site and also necessary for the interaction of CR1 with the kinase domain for RAF autoinhibition. CR2 contains important inhibitory phosphorylation sites participating in the negative regulation of Ras binding and RAF activation. CR3 features the kinase domain, including the activation segment, whose phosphorylation is crucial for kinase activation. [0071] Functionally, the RAF structure can be split into a regulatory N-terminal region, containing the RBD, which is critical for activation as well as inhibitory phosphorylation sites, and a catalytic C-terminal region, which includes phosphorylation sites necessary for the kinase activation. The regulatory domain restrains the activity of the kinase domain, and its removal results in constitutive oncogenic activation. However, the activity of the isolated C- RAF kinase domain is subjected to further regulation and can be stimulated by phorbol esters, v- Src, and phosphorylation. [0072] The common and key step in the activation of all 3 RAF kinase isoforms is membrane recruitment by a Ras family protein. The RAF kinases are located in the cytosol in their inactive state when bound to 14-3-3 proteins. In the presence of active Ras, they translocate to the plasma membrane. Membrane translocation triggers further activation events, such as the binding of PP2A to dephosphorylate the inhibitory pS259 site in RAF-1 (and presumably the corresponding sites in A-RAF and B-RAF) and the co-localization with the kinases responsible for the multiple activating phosphorylations. The sequences forming the binding interface are well conserved in the RAF as well as Ras family indicating that several members of the Ras family have the ability to bind RAF kinases. H-Ras, N-Ras, and K-Ras stimulate all 3 RAF isoforms and are the only Ras proteins that activate B-RAF. In contrast, A-RAF is also activated by R-Ras3, while C-RAF responds weakly to R-Ras3, Rit, and TC21as well. But, all RAF kinases share MEK1/2 kinases as substrates. MEK1/2 in turn activate ERK1/2, and this pathway regulates many cellular functions such as cell proliferation, differentiation, migration, or apoptosis. C-RAF [0073] C RAF was first to be identified and is a ubiquitously expressed isoform. In humans, C-RAF is encoded by the RAF1 gene. C-RAF also has a known splice variant preferentially expressed in the muscle and brain. C-RAF plays a critical role in mediating the cellular effects of growth factor signals. In the inactive state, C-RAF exists in a closed conformation in which the N-terminal regulatory region folds over and occludes the catalytic region. This conformation is stabilized by a 14-3-3 dimer binding to an N-terminal site, phospho-S259 (pS259), and a C-terminal site, pS621. Dephosphorylation of pS259 at the cell membrane by specific phosphatases (PP2A, PP1) releases 14-3-3 from its N-terminal binding site in C-RAF, thereby allowing conformational changes to occur that unmask the RBD and CRD domains in the CR1 region to enable Ras binding and membrane recruitment. B-RAF [0074] B-RAF is encoded in humans by the BRAF gene, also known as proto- oncogene B-RAF and v-RAF murine sarcoma viral oncogene homolog B. Alternative splicing gives rise to multiple B-RAF isoforms which are differentially expressed in various tissues. Whereas activation of A-RAF and C-RAF requires both phosphorylation and dephosphorylation of certain residues, as well as binding to other proteins, B-RAF becomes activated immediately upon translocation to the plasma membrane. B-RAF exhibits higher basal kinase activity than A- RAF and C-RAF. B-RAF requires Ras and 14-3-3 binding for its activation, and is inhibited or activated by PKA depending on the levels of 14-3-3 expression, which need to be high for permitting activation. B-RAF activity is also regulated by splicing. B-RAF isoforms containing exon 8b are more phosphorylated on the inhibitory S365 site, leading to an increased interaction with 14-3-3 and strengthening the inhibitory interaction between N-terminal regulatory domain and kinase domain, altogether resulting in lower kinase activity. A-RAF [0075] Serine/threonine-protein kinase A-RAF or A-RAF is an enzyme encoded by the ARAF gene in humans. There are 2 known splice isoforms of A-RAF - DA-RAF1 and D- RAF2. They lack the kinase domain and act as dominant inhibitory mutants of Ras and ARF GTPases. DA-RAF1 is a positive regulator of myogenic differentiation by mediating the inhibition of the ERK pathway required for differentiation. There are several ways A-RAF is different from the other RAF kinases. A-RAF is the only steroid hormone-regulated Raf isoform. In addition, the A-RAFprotein has amino acid substitutions in a negatively charged region upstream of the kinase domain (N-region), which contributes to its low basal activity. A- RAF is also only weakly activated by oncogenic H-Ras and Src and also displays low kinase activity towards MEK (the lowest kinase activity towards MEK proteins in the Raf kinase family). In addition to phosphorylating MEK, A-RAF also inhibits MST2, a tumor suppressor and pro apoptotic kinase not found in the MAPK pathway. By inhibiting MST2, A RAF prevents apoptosis from occurring. However, this inhibition is only occurs when the splice factor heterogenous nuclear ribonucleoprotein H (hnRNP H) maintains the expression of a full-length A-RAF protein. Tumorous cells often overexpress hnRNP H which leads to full-length expression of A-Raf which then inhibits apoptosis, allowing cancerous cells that should be destroyed to stay alive. A-RAF also binds to pyruvate kinase M2 (PKM2), again outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase that is responsible for the Warburg effect in cancer cells. A-RAF upregulates the activity of PKM2 by promoting a conformational change in PKM2. This causes PKM2 to transition from its low-activity dimeric form to a highly active tetrameric form. This causes more glucose carbons to be converted to pyruvate and lactate, producing energy for the cell, linking A-Raf to energy metabolism regulation and cell transformation, both of which are very important in tumorigenesis. [0076] Aberrant activation of the MAPK/ERK pathway is frequently found in various cancers and is a target for cancer therapeutics. In particular, B-RAF has emerged as one of the most attractive molecular targets for cancer therapeutics because somatic mutations of B- RAF have frequently been found in human tumors. Approximately 20% of all cancer samples tested to date harbor mutations in B-RAF. B-RAF-V600E, a missense mutation in the kinase domain generated by the substitution of glutamic acid with valine at position 600 is the most common B-RAF mutation. C-RAF is mutated in ~ 1% of the various tumor types tested and the rate of mutations in A-RAF is even lower. B-RAF and C-RAF form both homo- and heterodimers as part of their activation mechanism and A-RAF stabilizes the B-RAF:C-RAF complexes to sustain signaling efficiency. Also, it is C-RAF, not B-RAF, that transmits signals from oncogenic RAS to MEK. Therefore, in different contexts, each of the RAF isoforms act as a potential therapeutic target. Selective Protein Degradation [0077] The levels of proteins within a cell are determined by by both the rate of protein synthesis and the rate of protein degradation. In eukaryotic cells two pathways exist for selective protein degradation, the ubiquitin-proteasone pathway and the lysosomal proteolysis pathway. In general, 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, or lysosomal proteolysis. Recruitment motifs include E3 ligase recognition agents, proteasome recognition agents, lysosomal recognition peptides, or hydrophobic tagging agents. Conjugation of recruitment motifs with high affinity ligands for RAF kinase will provide compounds capable of selectively directing pathways for protein degradation to the RAF kinase protein itself. Such an outcome will reduce levels of RAF kinase activity and RAF signaling. Heteroaromatic RAF Degradation Compounds [0078] In one aspect, provided herein is a heteroaromatic RAF degradation compound having the general formula provided below: ,
Figure imgf000031_0001
wherein the RAF kinase affinity motif is a molecular construct having high affinity for the RAF 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 RAF kinase affinity motif and the recruitment motif, and the recruitment motif is a molecular construct having the ability to selectively target and recruit protein degradation. Recruitment motif [0079] Recruitment motifs include E3 ligase recognition agents, proteasome recognition agents, lysosomal recognition peptides, or hydrophobic tagging agents. In some embodiments the recruitment motif is derived from pomalidomide, 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. In some embodiments the recruitment motif is derived from pomalidomide. In some embodiments, the recruitment motif is selected from a molecular construct illustrated below:
with the
Figure imgf000032_0001
point of bonding to the linking motif as indicated. [0080] In some embodiments, the recruitment motif is selected from a molecular construct illustrated below: O O O O O O O O NH NH NH with the p
Figure imgf000032_0002
oint of bonding to the linking motif as indicated, and R is an optionally substituted C1- C6 alkyl group. [0081] In some embodiments, the recruitment motif is selected from a molecular construct related to VHL ligand as illustrated below: HO HO with the point of b
Figure imgf000032_0003
onding to the linking motif as indicated. [0082] In some embodiments, the recruitment motif is selected from a molecular construct related to IAP ligand as illustrated below: with the point of bo
Figure imgf000033_0001
nding to the linking motif as indicated. [0083] In some embodiments, the recruitment motif is selected from a molecular construct known to induce protein mis-folding such as HyT13 or HyT36. Use of hydrophobic tags for the degradation of proteins is discussed in Tae et al. (Chembiochem (2012), 13(4), 538- 541). [
Figure imgf000033_0002
0084] In some embodiments, the recruitment motif is selected from a molecular construct known to recruit the proteasome, such as Boc3Arginine. In some embodiments, the recruitment motif is selected from a molecular construct known to induce lysosomal degradation, such as the peptide KFERQ or the peptide H2N-KFERQKILDQRFFE-CO2H. Linking Motif [0085] The linking motief is a molecular construct providing a covalent bond to both the RAF kinase affinity motif and the recruitment motif. In some embodiments, the linking motif comprises a cyclic moiety. In some embodiments, the linking motif comprises an acyclic moiety. In some embodiments, the linking motif comprises an unsaturated moiety. In some embodiments, the linking motif comprises between 4 and 20 atoms. In some embodiments, the linking motif comprises between 4 and 25 atoms. In some embodiments, the linking motif comprises between 4 and 30 atoms. In some embodiments, the linking motif comprises between 6 and 18 atoms. In some embodiments, the linking motif comprises between 5 and 10 atoms. In some embodiments, the linking motif is selected from a molecular fragment illustrated below:
Figure imgf000033_0003
with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. [0086] In some embodiments, the linking motif is selected from a molecular fragment illustrated below:
Figure imgf000034_0001
with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. [0087] In some embodiments, the linking motif is selected from a molecular fragment illustrated below: wh
Figure imgf000034_0002
erein R is an optionally substituted alkyl or an optionally substituted -CO-alkyl, with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. [0088] In some embodiments, the linking motif is a polyethylene glycol selected from –(O-CH2-CH2)n-O- or –(O-CH2-CH2)n-N(R23)-*, wherein n is selected from 1 to 20, and R23 is optionally substituted alkyl, or optionally substituted -CO-alkyl; and the point of bonding to the recruitment motif indicated by the asterisk. [0089] In some embodiments, the linking motif is selected from:
Figure imgf000034_0003
with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk, and wherein n is 0, 1, 2, or 3, and R22 is an optionally substituted alkyl. [0090] In some embodiments, the linking motif is selected from: N O N N
Figure imgf000034_0004
N O N N N O N N O O with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. [0091] In some embodiments, the linking motif is selected from: with t
Figure imgf000035_0001
he point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk. RAF Kinase Affinity Motif [0092] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): wherein,
Figure imgf000035_0002
L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R1 groups join to form a fused ring; R2 is H, D or F; R is halogen, optionally substituted C1 C3 alkyl, CD3, or optionally substituted C1-C3 alkoxy; R6 is H, D, Cl or F; Z is selected from: (a) -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R11 is inde
Figure imgf000036_0001
pen en y se ec e rom amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O)
Figure imgf000036_0002
, , o op o a y substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2 pro
Figure imgf000037_0001
v e o a are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3;
Figure imgf000037_0002
s , , ( ), 2, or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH-CH2-, -NH- CHR11-, -NH-C(R11)2-, -CH2-NH-, -CHR11-NH-, -C(R11)2-NH-, -N(R11)-CH2-, -N(R11)-CHR11-, -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-, -O-CH2-, or -CH2-O-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; is 0, 1, or 2; m1
Figure imgf000037_0003
s , , or ; p s , , or ; s , , ( ), 2, or (op ona y su s u ed C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, OH, halogen, optionally substituted C1 C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not
Figure imgf000038_0001
o ; p s , , , , or 4; and each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R13 or R14
Figure imgf000038_0002
s n epen en y se ected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; a
Figure imgf000038_0003
q s , o ; s , S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1 C6 alkoxy, optionally substituted C2 C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo. [0093] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0094] One embodiment provides a compound, or p
Figure imgf000039_0001
harmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0095] One embodiment provides a compound, or p
Figure imgf000039_0002
harmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0096] One embodiment provides a compound, or p
Figure imgf000039_0003
harmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) wherein [0097] One embodiment provides a compound, or p
Figure imgf000039_0004
harmaceutically acceptable salt or solvate thereof, having the structure of Formula (II): wherein,
Figure imgf000039_0005
L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R1 groups join to form a fused ring; R2 is H, D or F; R4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R6 is H, D, Cl or F; Z is selected from: (a) -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R11 is inde
Figure imgf000040_0001
pen en y se ec e rom amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O)
Figure imgf000040_0002
, 2, or (op ona y substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3 C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2 pro
Figure imgf000041_0001
v e o m an n are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3;
Figure imgf000041_0002
s , , , 2, or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH-CH2-, -NH- CHR11-, -NH-C(R11)2-, -CH2-NH-, -CHR11-NH-, -C(R11)2-NH-, -N(R11)-CH2-, -N(R11)-CHR11-, -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-, -O-CH2-, or -CH2-O-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; is 0, 1, or 2; m1
Figure imgf000042_0001
s , , o ; p s , , o ; s , , , , o op o a y su s u ed C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not
Figure imgf000042_0002
o ; p s , , , , or 4; and each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; (h) wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R13 or R14 is independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; a
Figure imgf000043_0001
q s , o ; s , S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo. [0098] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [0099] One embodiment provides a compound, or ph
Figure imgf000043_0002
armaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [00100] One embodiment provides a compound, or ph
Figure imgf000043_0003
armaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein [00101] One embodiment provides a compound, or ph
Figure imgf000043_0004
armaceutically acceptable salt or solvate thereof, having the structure of Formula (II) wherein
Figure imgf000043_0005
[00102] In some embodiments, the heteroaromatic RAF degradation compound as described herein has a structure provided in Table 1. Table 1 Synthetic - - -
Figure imgf000044_0001
[00103] In some embodiments, the heteroaromatic RAF degradation compound as described herein has a structure provided below. O O NH
Figure imgf000044_0002
Figure imgf000045_0001
Preparation of Compounds [00104] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [00105] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471- 19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (19422000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. [00106] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions [00107] In certain embodiments, the heteroaromatic RAF degradation compound described herein is administered as a pure chemical. In other embodiments, the heteroaromatic RAF 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00108] Provided herein is a pharmaceutical composition comprising at least one heteroaromatic RAF degradation compound as described herein, 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. [00109] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof. [00110] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. [00111] In certain embodiments, the heteroaromatic RAF degradation compound as described by Formula (I) or (II), 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. [00112] 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. In some embodiments, suitable nontoxic solid carriers are used which 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00113] In some embodiments, the heteroaromatic RAF degradation compound as described by Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like. [00114] The dose of the composition comprising at least one heteroaromatic RAF 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. [00115] Pharmaceutical 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. In general, 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. [00116] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment [00117] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00118] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00119] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. [00120] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, 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), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. [00121] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00122] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00123] One embodiment provides a use of a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. [00124] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, 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 (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. [00125] 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. [00126] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis [00127] In some embodiments, the heteroaromatic RAF kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: oC degrees Celsius δH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) 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 μ 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) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) T temperature TFA trifluoroacetic acid THF tetrahydrofuran [00128] Example 1: (3S)-N-(3-(6-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperaz
Figure imgf000051_0001
ethoxy)-5-morpholinopyridin-3-yl)-4-methylphenyl)-3- (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
Figure imgf000051_0002
[ ] e aove roue prov e or . mg o ( )- -(-(-(-(-( -(,- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)-5-morpholinopyridin-3- yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a yellow solid. MS ESI calculated for C42H47F3N8O7 [M + H]+, 833.36, found 833.4. [00130] Example 2: (3S)N(6 (2(4(2(2,6dioxopiperidin3yl)1,3 dioxoisoindolin-5-yl)piperazin
Figure imgf000052_0001
l)ethoxy)-2-methyl-5'-morpholino-[3,3'-bipyridin]-5-yl)- 3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide
Figure imgf000052_0002
[ ] e aove roue prov e or mg o ( )- -( -(-(-(-(, - dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)-2-methyl-5'-morpholino- [3,3'-bipyridin]-5-yl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a yellow solid. MS ESI calculated for C41H46F3N9O7 [M + H]+, 834.35, found 834.4. II. Biological Evaluation Example 1: Cellular RAF Activity Determination: [00132] To evaluate the effects of RAF inhibition in the WM3629 and A375 cells, the MAPK pathway signaling was assessed via phosphorylation of ERK at Thr202/Tyr204 using a commercial HTRF (homogenous time resolved technology) assay kit (CisBio, Cat # 64AERPET). This technology uses two labeled antibodies that bind the target specifically, yet independently, one with a donor fluorophore and the other with an acceptor. Phosphorylation of the target promotes an immune complex formation, generating a FRET (fluorescence resonance energy transfer) signal proportional to the amount of phosphorylated ERK present in the sample. [00133] WM3629 or A375 cells were seeded at 8000 or 15000 cells/well in 24 ^l growth media (80% MDAB153 + 20% L-15 + 2% FBS + 1.68mM calcium chloride or DMEM + 10% FBS, respectively) into 384-well plates and allowed to adhere overnight at 37 ^C 5%CO2. The following day compounds were serially diluted from a 10 mM DMSO stock into a 10-point, 3-fold dose curve in DMSO. Compounds were transferred to cell plate for a final concentration of 10 μM to 0.51 nM in 0.1% DMSO. Cells were incubated for 6 hours at 37 ^C 5%CO2. Cell lysate was transferred to a plate containing 2.5 μl of anti-ERK1/2-Europium/Terbium Cryptate and 2.5 μl of anti-Phospho-ERK1/2-d2 antibody solutions and incubated overnight at room temperature prior to reading at 665 nm (acceptor) and 620 nm (donor) on an Envision plate reader (PerkinElmer). HTRF ratios (665nm/620nm*1000) and % activity relative to DMSO control calculated. IC50 was calculated using a four parameter fit model using Dotmatics Knowledge Solutions Studies curve fitting (Dotmatics, Bishops Stortford, UK, CM23). Representative data for exemplary compounds is presented in Table 2. Table 2 Synthetic Chemistry
Figure imgf000053_0001
Note: IC50 data are designated within the following ranges: A: ≤ 0.010 µM C: > 0.10 µM to ≤ 1.0 µM B: > 0.010 µM to ≤ 0.10 µM D: > 1.0 µM to ≤ 10 µM III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral capsule [00134] The active ingredient is a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration. Example 2: Solution for injection [00135] The active ingredient is a compound of Table (I) or (II), or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg- eq/mL. [00136] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS We claim: 1. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): wherein,
Figure imgf000055_0001
L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R1 groups join to form a fused ring; R2 is H, D or F; R4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R6 is H, D, Cl or F; Z is selected from: (a) -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and
Figure imgf000055_0002
each R is independently selected from amino, alkylamino, dialkylamino, OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O)
Figure imgf000056_0003
, 2, o op o a y substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2 pro
Figure imgf000056_0001
v e o m an n are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3;
Figure imgf000056_0002
s , , ( ), 2, or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH-CH2-, -NH- CHR , NHC(R )2, CH2NH, CHR NH, C(R )2NH, N(R )CH2, N(R )CHR , -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-, -O-CH2-, or -CH2-O-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; is 0, 1, or 2; m1
Figure imgf000057_0001
s , , o ; p s , , o ; s , , , 2, o op oa y sus ued C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not
Figure imgf000057_0002
o ; p s , , , , or 4; and each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R13 or R14
Figure imgf000058_0001
s n epen en y se ected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; a
Figure imgf000058_0002
n q s , or ; s , S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo. 2. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II): wherein,
Figure imgf000058_0003
L is a linking motif having between 4 and 30 atoms; U is a recruitment motif having the ability to selectively target and recruit protein degradation; X is N, C-H, C-D, C-F, or C-CH3; R1 is C1-C3 optionally substituted alkyl, and q is 0, 1, or 2; or optionally, if q is 2, then two R1 groups join to form a fused ring; R2 is H, D or F; R4 is halogen, optionally substituted C1-C3 alkyl, -CD3, or optionally substituted C1-C3 alkoxy; R6 is H, D, Cl or F; Z is selected from: (a) -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R11 is inde
Figure imgf000059_0001
pen en y se ec e rom amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -S-alkyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo; wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O)
Figure imgf000059_0002
, 2, or (op ona y substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3 C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2 pro
Figure imgf000060_0001
v e o m an n are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3;
Figure imgf000060_0002
s , , , 2, or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH-CH2-, -NH- CHR11-, -NH-C(R11)2-, -CH2-NH-, -CHR11-NH-, -C(R11)2-NH-, -N(R11)-CH2-, -N(R11)-CHR11-, -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-, -O-CH2-, or -CH2-O-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; is 0, 1, or 2; m1
Figure imgf000061_0001
s , , o ; p s , , o ; s , , , , o op o a y su s u ed C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl; wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n are not
Figure imgf000061_0002
o ; p s , , , , or 4; and each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; (h) wherein m is 1, 2, or 3; n is 1,
2, or 3; p is 0, 1, or 2; and each R13 or R14 is independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; a
Figure imgf000062_0001
q s , o ; s , S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo.
3. The compound of claim 1 or 2, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen or deuterium.
4. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen or deuterium.
5. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is F.
6. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R6 is F.
7. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein X is N.
8. The compound of any one of claims 1-7, or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D.
9. The compound of any one of claims 1-8, or pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.
10. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted C1 alkyl.
11. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
12. The compound of any one of claims 1-10, or pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
13. The compound of any one of claims 1-10 or 12, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is CH3, q is 1, and R1 is positioned to provide a 3- methylmorpholino.
14. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen.
15. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C3 alkyl.
16. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is methyl.
17. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein Z is -NRaRb, wherein Ra is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and Rb is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3- C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl.
18. The compound of claim 17, or pharmaceutically acceptable salt or solvate thereof, wherein Ra is H.
19. The compound of claim 17, or pharmaceutically acceptable salt or solvate thereof, wherein Ra is optionally substituted alkyl.
20. The compound of any one of claims 17-19, or pharmaceutically acceptable salt or solvate thereof, wherein Rb is optionally substituted alkyl.
21. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and
Figure imgf000064_0001
each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R11 groups together form an oxo.
22. The compound of claim 21, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1.
23. The compound of claim 21, or pharmaceutically acceptable salt or solvate thereof, wherein m is 2.
24. The compound of claim 21, or pharmaceutically acceptable salt or solvate thereof, wherein m is 3.
25. The compound of any one of claims 21-24, or pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
26. The compound of any one of claims 21-24, or pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
27. The compound of any one of claims 21-24, or pharmaceutically acceptable salt or solvate thereof, wherein p is 2.
28. The compound of any one of claims 21-24, or pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
29. The compound of any one of claims 21-28, or pharmaceutically acceptable salt or solvate thereof, wherein R11 is optionally substituted C1-C6 alkyl, or optionally substituted C3- C6 cycloalkyl.
30. The compound of claim 29, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.
31. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4;
Figure imgf000065_0001
W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl); and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo.
32. The compound of claim 31, or pharmaceutically acceptable salt or solvate thereof, wherein W is O.
33. The compound of claim 31, or pharmaceutically acceptable salt or solvate thereof, wherein W is S.
34. The compound of any one of claims 31-33, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1.
35. The compound of any one of claims 31-33, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 2.
36. The compound of any one of claims 31-33, or pharmaceutically acceptable salt or solvate thereof, wherein R11 is optionally substituted C1-C6 alkyl, or optionally substituted C3- C6 cycloalkyl.
37. The compound of claim 36, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.
38. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein Z is wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0,
Figure imgf000066_0001
1, or 2; n1 is 0, 1, or 2 provided both m1 and n1 are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted - SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo.
39. The compound of claim 38, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1.
40. The compound of any one of claims 38-39, or pharmaceutically acceptable salt or solvate thereof, wherein m is 0, and n is 2.
41. The compound of any one of claims 38-39, or pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0, and n1 is 2.
42. The compound of any one of claims 38-39, or pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1, and n1 is 1.
43. The compound of any one of claims 38-42, or pharmaceutically acceptable salt or solvate thereof, wherein W is O.
44. The compound of any one of claims 38-42, or pharmaceutically acceptable salt or solvate thereof, wherein W is CH2.
45. The compound of any one of claims 38-42, or pharmaceutically acceptable salt or solvate thereof, wherein W is CHR11.
46. The compound of any one of claims 38-42, or pharmaceutically acceptable salt or solvate thereof, wherein W is C(R11)2.
47. The compound of any one of claims 46-46, or pharmaceutically acceptable salt or solvate thereof, wherein R11 is halogen and q is 1.
48. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3;
Figure imgf000067_0001
W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, -CH2-CH2-, -CH2-CHR11-, -CH2-C(R11)2-, -CHR11-CH2-, -C(R11)2-CH2-, -NH- CH2-, -NH-CHR11-, -NH-C(R11)2-, -CH2-NH-, -CHR11-NH-, -C(R11)2-NH-, -N(R11)-CH2-, - N(R11)-CHR11-, -N(R11)-C(R11)2-, -CH2-N(R11)-, -CHR11-N(R11)-, -C(R11)2-N(R11)-; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl.
49. The compound of claim 48, or pharmaceutically acceptable salt or solvate thereof, wherein m is 0, n is 1, and m1 is 1; and W is -O-CH2-, or -CH2-O-.
50. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein Z is wherein m is 0,
Figure imgf000068_0001
1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R11 groups together form an oxo; and R12 and R13 are each independently selected from H, or optionally substituted C1-C6 alkyl.
51. The compound of claim 50, or pharmaceutically acceptable salt or solvate thereof, wherein W is O.
52. The compound of any one of claims 50-51, or pharmaceutically acceptable salt or solvate thereof, wherein W is CH2, or CHR11.
53. The compound of any one of claims 50-52, or pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0.
54. The compound of any one of claims 50-52, or pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1.
55. The compound of any one of claims 50-54, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1.
56. The compound of any one of claims 50-54, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 0.
57. The compound of any one of claims 5054, or pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 1.
58. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3 provided both m and n ar
Figure imgf000069_0001
e not both 0; p is 0, 1, 2, 3, or 4; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
59. The compound of claim 58, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 1.
60. The compound of claim 58, or pharmaceutically acceptable salt or solvate thereof, wherein m is 1, and n is 2.
61. The compound of any one of claims 58-60, or pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
62. The compound of any one of claims 58-60, or pharmaceutically acceptable salt or solvate thereof, wherein p is 2.
63. The compound of any one of claims 58-62, or pharmaceutically acceptable salt or solvate thereof, wherein at least one R11 is attached to an alkene carbon.
64. The compound of any one of claims 58-62, or pharmaceutically acceptable salt or solvate thereof, wherein at least one R11 is not attached to an alkene carbon.
65. The compound of any one of claims 58-62, or pharmaceutically acceptable salt or solvate thereof, wherein R11 is optionally substituted C1-C6 alkyl, or optionally substituted C3- C6 cycloalkyl.
66. The compound of any one of claims 58-62, or pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
67. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and each R13 or R14
Figure imgf000070_0001
is independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
68. The compound of claim 67, or pharmaceutically acceptable salt or solvate thereof, wherein m is 2, and n is 1.
69. The compound of claim 67 or 68, or pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
70. The compound of claim 67 or 68, or pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
71. The compound of any one of claims 67-70, or pharmaceutically acceptable salt or solvate thereof, wherein one of R13 or R14 is not hydrogen.
72. The compound of any one of claims 67-70, or pharmaceutically acceptable salt or solvate thereof, wherein one of R13 or R14 is optionally substituted C1-C6 alkyl.
73. The compound of claim 67-72, or pharmaceutically acceptable salt or solvate thereof, wherein R13 is optionally substituted C1-C6 alkyl.
74. The compound of claim 6772, or pharmaceutically acceptable salt or solvate thereof, wherein R14 is optionally substituted C1-C6 alkyl.
75. The compound of any one of claims 1-16, or pharmaceutically acceptable salt or solvate thereof, wherein wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2;
Figure imgf000071_0001
and q is 0, 1 or 2; W is O, S, S(O), SO2, NH or N(optionally substituted C1-C6 alkyl), CH2, CHR11, or C(R11)2; and each R11 is independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted -SO2alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R11 groups together form an oxo.
76. The compound of claim 75, or pharmaceutically acceptable salt or solvate thereof, wherein W is O.
77. The compound of claim 75 or 76, or pharmaceutically acceptable salt or solvate thereof, wherein m is 2, and n is 1.
78. The compound of any one of claims 75-77, or pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 or 2.
79. The compound of any one of claims 75-78, or pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1, and q is 0 or 1.
80. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein L is between 4 and 20 atoms.
81. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein L is between 6 and 18 atoms.
82. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein L is between 5 and 10 atoms.
83. The compound of any one of claims 1-82, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from a molecular fragment illustrated below:
Figure imgf000072_0001
with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk.
84. The compound of any one of claims 1-82, or pharmaceutically acceptable salt or solvate thereof, wherein L is is selected from a molecular fragment illustrated below: R21 O wherein
Figure imgf000072_0002
R is an optionally substituted alkyl or an optionally substituted -CO-alkyl, with the point of bonding to the RAF kinase affinity motif indicated by the wavy line and the point of bonding to the recruitment motif indicated by the asterisk.
85. The compound of any one of claims 1-84, or pharmaceutically acceptable salt or solvate thereof, wherein U is selected from:
with t
Figure imgf000073_0001
he point of bonding to the linking motif as indicated.
86. The compound of any one of claims 1-84, or pharmaceutically acceptable salt or solvate thereof, wherein U is selected from: O O O O O O O O NH NH w
Figure imgf000073_0002
ith the point of bonding to the linking motif as indicated, and R is an optionally substituted C1- C6 alkyl group.
87. A compound, or pharmaceutically acceptable salt or solvate thereof, selected from a compound described in Table 1.
88. A pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1 or 3-87.
89. A pharmaceutical composition comprising a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 2-87.
90. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims claims 1- 87, and a pharmaceutically acceptable carrier.
91. A compound of any one of claims 1-87 or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
92. A compound of any one of claims 1-87, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
93. Use of a compound of any one of claims 1-87, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
94. A method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I) as described in any one of claims 1 or 3-87, or pharmaceutically acceptable salt or solvate thereof.
95. 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) as described in any one of claims 1 or 3-87, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
96. A method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (II) as described in any one of claims 2-87, or pharmaceutically acceptable salt or solvate thereof.
97. A method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II) as described in any one of claims 287, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
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Citations (4)

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US20180037567A1 (en) * 2010-02-11 2018-02-08 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
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WO2010019930A1 (en) * 2008-08-15 2010-02-18 Locus Pharmaceuticals, Inc. Urea derivatives as inhibitors of map kinases
US20180037567A1 (en) * 2010-02-11 2018-02-08 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
WO2016038581A1 (en) * 2014-09-12 2016-03-17 Novartis Ag Compounds and compositions as raf kinase inhibitors
WO2018102067A2 (en) * 2016-11-01 2018-06-07 Arvinas, Inc. Tau-protein targeting protacs and associated methods of use

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