WO2023070053A1 - Inhibiteurs de kinases raf - Google Patents

Inhibiteurs de kinases raf Download PDF

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WO2023070053A1
WO2023070053A1 PCT/US2022/078461 US2022078461W WO2023070053A1 WO 2023070053 A1 WO2023070053 A1 WO 2023070053A1 US 2022078461 W US2022078461 W US 2022078461W WO 2023070053 A1 WO2023070053 A1 WO 2023070053A1
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optionally substituted
pharmaceutically acceptable
compound
solvate
acceptable salt
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PCT/US2022/078461
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Toufike Kanouni
Eric A. Murphy
Jason Cox
Robert Kania
Stephen W. Kaldor
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Kinnate Biopharma Inc.
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Publication of WO2023070053A1 publication Critical patent/WO2023070053A1/fr

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    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
  • MAPK mitogen activated protein kinase
  • RAF kinase activity occurs frequently in tumors. Accordingly, therapies that target RAF kinase activity are desired for use in the treatment of cancer and other disorders characterized by aberrant MAPKZERK pathway signaling.
  • RAF receptor tyrosine kinase effector Raf
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): wherein,
  • X is independently N or C-H
  • Y is independently N or C-H
  • R is selected from H, -C(R 1 )(R 2 )(R 3 ), optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
  • R 1 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl
  • R 2 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl
  • R 3 is selected from H, -OH, -OR 4 , -NH2, -NHR 4 , -N(R 4 )2, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each R 4 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R 2 and R 4 join to form a ring; and Z is an optionally substituted aryl or optionally substituted heteroaryl.
  • One embodiment provides a pharmaceutical composition
  • 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.
  • Amino refers to the -NH2 radical.
  • Cyano refers to the -CN radical.
  • Niro refers to the -NO2 radical.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., Ci- C8 alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl).
  • 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).
  • 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).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl ( n-propyl), 1 -methylethyl (/.w-propyl), 1 -butyl ( n-butyl), 1 -methylpropyl ( ec-butyl), 2-m ethylpropyl (/.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (n -pentyl).
  • 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, trimethyl silanyl, -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)
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-l-enyl i.e., allyl
  • but-l-enyl pent-l-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, trimethyl silanyl, -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)tR a
  • 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, ⁇ -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., 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., Ci alkylene).
  • 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).
  • 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)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),
  • 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., C2-C5 alkenylene).
  • 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).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)tR a
  • 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., C2-C8 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., 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).
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)tR
  • 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, ie., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Huckel 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 -0R 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.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • 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.
  • 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.
  • 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, norbomyl (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 c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula -R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula -O- R c -carbocyclyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • Examples of carboxylic acid bioisosteres include, but are not limited to,
  • 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, l-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 quatemized. 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[l,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-thio
  • 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 -0R a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -0C(0)-N(
  • 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 A-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 Hiickel 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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
  • 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 -0R a , -R b -0C(0)-R a , -R b -0C(0)-0R a
  • 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 A-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 heteroaryl alkyl 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 heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 1 7 0, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 C1, 37 C1, 79 Br, 81 Br, 125 I are all contemplated.
  • isotopic substitution with 18 F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or
  • the compounds disclosed herein have some or all of the atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • CD3I iodomethane-ds
  • LiAlD4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the 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, phenyl acetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • 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, isopropyl amine, 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, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et
  • 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.
  • 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 MAPKZERK 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 MAPKZERK 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 1 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.
  • 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.
  • 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.
  • H-Ras, N-Ras, and K-Ras stimulate all 3 RAF isoforms and are the only Ras proteins that activate B-RAF.
  • A-RAF is also activated by R-Ras3, while C-RAF responds weakly to R-Ras3, Rit, and TC21as well.
  • 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 was first to be identified and is a ubiquitously expressed isoform. In humans, C-RAF is encoded by the RAFI 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.
  • 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.
  • 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.
  • 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.
  • hnRNP H splice factor heterogenous nuclear ribonucleoprotein H
  • 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.
  • 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.
  • CNS drug candidates have lower success rates and longer development times than those in the other therapeutic areas.
  • BBB blood-brain barrier
  • Pgp P-glycoprotein
  • Plasma protein binding which reduces the free drug concentration available for BBB penetration, and metabolism and renal excretion, which reduces the total blood concentration, also affect brain penetration.
  • passive diffusion is the major driving force moving most molecules into the brain; however, the other mechanisms discussed above can reduce brain penetration, depending on the structure and properties of the compound.
  • Bioanalytical methods and screening strategies provide the rationale for design and evaluation of compounds with desirable BBB distribution properties.
  • a superior representation of brain distribution is based on the ratio of unbound compound in the brain extracellular fluid to the unbound blood concentration, represented as Kp,uu. (Liu and Chen, Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs (2015), p. 42-65, Wiley & Sons).
  • Kp,uu is a steady-state distribution term denoting the unbound concentration gradient across the BBB. If Kp,uu is lower than 1, then drug passage across the BBB is restricted by some factor. If Kp,uu is larger than 1, then drug passage across the BBB is assisted by some factor. AKp,uu value of about 1 indicates passive diffusion across the BBB is predominate, or that active pathways (e.g. influx and efflux) are balanced. (Summerfield et al. vide supra)
  • 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. 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.
  • Sorafenib was the first RAF inhibitor to enter clinical trials. Sorafenib is a broad specificity drug that inhibits additional kinases, including vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3), platelet-derived growth factor receptor family (PDGFR-b and KIT) and FLT3. Clinical trials showed no correlation between the clinical responses with B-RAF mutation status, indicating it is a poor inhibitor of B-RAF. This led to the development of a new generation of B-RAF inhibitors, including, but not limited to vemurafenib, SB-590885, and dabrafenib (GSK2118436).
  • VEGFR-2 and VEGFR-3 vascular endothelial growth factor receptor family
  • PDGFR-b and KIT platelet-derived growth factor receptor family
  • FLT3 FLT3
  • Clinical trials showed no correlation between the clinical responses with B-RAF mutation status, indicating it is a poor inhibitor of B-RAF. This led to the development of a
  • B- Raf alternative splicing and amplification of B-RAF-V600E have also been implicated in ⁇ 30 and 20% of patients, respectively.
  • RAF kinase inhibitors cause paradoxical activation of the MAPK pathway, which, in some instances, leads to the development of secondary RAS mutation-driven malignancies.
  • RAF kinase inhibitors that overcome the existing pitfalls and challenges posed by the current inhibitors.
  • RAF inhibitory compound In one aspect, provided herein is a RAF inhibitory compound.
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I): wherein,
  • X is independently N or C-H;
  • Y is independently N or C-H;
  • R is selected from H, -C(R 1 )(R 2 )(R 3 ), optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
  • R 1 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
  • R 2 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
  • R 3 is selected from H, -OH, -OR 4 , -NH2, -NHR 4 , -N(R 4 )2, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each R 4 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R 2 and R 4 join to form a ring; and Z is an optionally substituted aryl or optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X is N, and Y is C-H. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X is N, and Y is N. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H, and Y is N. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H, and Y is C-H.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R is H.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R is -C(R 1 )(R 2 )(R 3 ).
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted C3-C7 cycloalkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted Cl- C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted C3-C7 cycloalkyl. [0087] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OH. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -NH2.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -NHR 4 . Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -N(R 4 )2. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OR 4 . Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is optionally substituted heterocyclyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 3 is optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 4 is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 4 is optionally substituted C1-C6 acyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 4 join to form a ring.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted cycloalkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkyl is an optionally substituted C3-C6 cycloalkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkyl is an optionally substituted cyclopropyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted heterocyclyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted O-containing heterocyclyl, an optionally substituted N-containing heterocyclyl, or an optionally substituted S- containing heterocyclyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted O-containing heterocyclyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted O-containing heterocyclyl is an optionally substituted oxetane, an optionally substituted tetrahydrofuran, or an optionally substituted tetrahydropyran.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted N- containing heterocyclyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted N- containing heterocyclyl is an optionally substituted azetidine, an optionally substituted pyrrolidine, or an optionally substituted piperidine.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted S-containing heterocyclyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted aryl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is optionally substituted with at least one group selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C6 cycloalkoxy.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted six-membered heteroaryl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted six-membered heteroaryl is an optionally substituted pyridyl, optionally substituted pyridazine, or optionally substituted pyrimidine.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is optionally substituted with at least one group selected from halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C6 cycloalkoxy.
  • the RAF kinase inhibitory compound as described herein has a structure provided in Table 1.
  • Table 1 Table 1
  • 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.
  • the RAF kinase inhibitory compound described herein is administered as a pure chemical.
  • the RAF kinase inhibitory 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 RAF kinase inhibitory 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.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the RAF kinase inhibitory compound as described by Formula (I), 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 RAF kinase inhibitory compound as described by Formula (I), 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 RAF kinase inhibitory 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.
  • 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.
  • 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.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
  • 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.
  • 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.
  • 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.
  • the compound of Formula (I) partitions across the BBB with a. Kp,uu of greater than 1. In some embodiments described herein, the compound of Formula (I) exhibits a. Kp,uu greater than 0.3. In some embodiments described herein, the compound of Formula (I) exhibits a. Kp,uu greater than 0.4. In some embodiments described herein, the compound of Formula (I) exhibits a.Kp,uu greater than 0.6. In some embodiments described herein, the compound of Formula (I) exhibits a Kp,uu greater than 0.8. In some embodiments described herein, the compound of Formula (I) exhibits a.Kp,uu greater than 1.0.
  • the compound of Formula (I) exhibits a. Kp,im greater than 1.2. In some embodiments described herein, the compound of Formula (I) exhibits a. Kp,uu greater than 1.4. In some embodiments described herein, the compound of Formula (I) exhibits a Kp,uu greater than 1.6. In some embodiments described herein, the compound of Formula (I) exhibits a. Kp,uu greater than 1.8. In some embodiments described herein, the compound of Formula (I) exhibits a Kp,uu greater than 2.0. In some embodiments, the Kp,uu value is determined in a rat. In some embodiments, the Kp,uu value is determined in a mouse.
  • the Kp,uu value is determined in a rodent. In some embodiments, the Kp,uu value is determined in a dog. In some embodiments, the Kp,uu value is determined in a primate. In some embodiments, the Kp,uu value is determined in a human.
  • the 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: °C degrees Celsius ⁇ H chemical shift in parts per million downfield from tetramethylsilane
  • NMR nuclear magnetic resonance pH potential of hydrogen a measure of the acidity or basicity of an aqueous solution
  • the reaction mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (2 x 80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA/EtOH (4/3/1).
  • the reaction mixture was stirred for 10 min at room temperature under a argon atmosphere.
  • tris(trimethylsilyl)silane (1.15 g, 4.629 mmol) dropwise at room temperature.
  • the reaction was stirred and irradiated with a blue LED lamp (with cooling fan to keep the reaction temperature at room temperature) for 16 h.
  • the resulting mixture was quenched with water (100 mL).
  • the resulting mixture was extracted with EtOAc (3 x 70 mL).
  • the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 1 5-Fluoro-2-(prop-l-en-2-yl)pyridine-4-carboxylate
  • Example 1 N- ⁇ 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridin-3- yl]phenyl ⁇ -2-(trifluoromethyl)pyridine-4-carboxamide
  • the reaction mixture was degassed with nitrogen for 3 times and stirred for 2 h at 80 °C.
  • the resulting mixture was diluted with water (25 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers was washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (10 mM NH4HCO3), 25% to 70% gradient in 30 min; detector, UV 254 nm.
  • Example 7 N- ⁇ 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridin-3- yl]phenyl ⁇ -2-(trifluoromethyl)pyridine-4-carboxamide
  • Example 23 N- ⁇ 5-[6-ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylphenyl ⁇ -3-
  • the crude product was further purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH 3 CN in water (10 mM NH4HCO3), 35% to 95% gradient in 20 min; detector, UV 254 nm.
  • the fractions contained desired product were combined and cocnentrated to afford A- ⁇ 5-[6-ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro- 4-methylphenyl ⁇ -3-(trifluoromethyl)benzamide (79 mg, 51%) as an off-white solid.
  • Example 25 N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl)-2-
  • Example 25 N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide step 3
  • Example 26 N-(2-fluoro-5-(6-(3-hydroxy-3-methylbut-l-yn-l-yl)-5-morpholinopyridin-3-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide
  • Example 26 N-(2-fluoro-5-(6-(3-hydroxy-3-methylbut-l-yn-l-yl)-5-morpholinopyridin-3-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide
  • Example 27 2-cyclobutyl-N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl) isonicotinamide
  • Example 27A methyl 2-cyclobutylisonicotinate
  • Example 27B 2-cyclobutylisonicotinic acid
  • Example 27C 2-cyclobutyl-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl) phenyl)isonicotinamide
  • Example 27 2-cyclobutyl-N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4- methylphenyl)isonicotinamide
  • Example 28 2-fluoro-N-(2-fluoro-4-methyl-5-(5-morpholino-6-(prop-l-yn-l-yl)pyridin-3- yl)phenyl)-6-(l-methylcyclopropyl)isonicotinamide
  • Example 28 2-fluoro-N-(2-fluoro-4-methyl-5-(5-morpholino-6-(prop-l-yn-l-yl)pyridin-3- yl)phenyl)-6-(l-methylcyclopropyl)isonicotinamide
  • Example 78 A- ⁇ 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3- y 1 ] phenyl ⁇ -3 -methyl - 1 , 3 -b enzodi azol e-5 -carb oxami de
  • Step 1 4-(3,6-Dichloropyridazin-4-yl)morpholine step 1
  • Step 2 4-[6-Chl oro-3 -(prop- l-yn-l-yl)pyridazin-4-yl]morpholine step 2
  • Step 3 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3-yl]aniline
  • Step 4 N- ⁇ 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3-yl]phenyl ⁇ - 3 -methyl - 1 , 3 -b enzodi azol e-5 -carb oxami de step 4
  • Example 104 N- ⁇ 5-[6-Ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylphenyl ⁇ -4- fhioro-3-(2-fluoropropan-2-yl)benzamide
  • Step 1 4-(2-Bromo-5-chloropyridin-3-yl)morpholine
  • 2-bromo-5-chloropyridin-3-amine 5 g, 24.10 mmol
  • N,N- dimethylformamide 50.00 mL
  • sodium hydride (2.89 g, 72.30 mmol, 60%) in portions at 0 °C under argon atmosphere.
  • the reaction mixture was stirred for 30 min at room temperature under argon atmosphere.
  • To the above mixture was added l-bromo-2-(2- bromoethoxy)ethane (8.38 g, 36.13 mmol) dropwise at 0 °C.
  • the reaction mixture was stirred for additional 3 h at room temperature.
  • the resulting mxiture was quenched by the addition of sat. ammonium chloride (aq.) (400 mL) at 0 °C.
  • the resulting mixture was extracted with ethyl acetate (2 x 250 mL).
  • the combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/ EA (1/1).
  • Step 2 4- ⁇ 5-Chloro-2-[2-(trimethylsilyl)ethynyl]pyridin-3-yl ⁇ morpholine step 2
  • Step 3 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(trimethylsilyl)ethynyl]pyridin-3- yl]aniline
  • the reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 80 °C.
  • the resulting mixture was allowed to cool down to room temperature.
  • the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 80 mL).
  • the combined organic layers was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with petroleum ether/ ethyl acetate (5/1).
  • Step 4 5-[6-Ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylaniline
  • Step 5 N- ⁇ 5-[6-Ethynyl-5-(morpholin-4-yl)pyri din-3-yl]-2-fluoro-4-m ethylphenyl ⁇ -4-fluoro-3- (2-fluoropropan-2-yl)benzamide
  • the crude product was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 pm; Mobile Phase A: Water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 54% B to 62% B in 8 min, 62% B; Wave Length: 220 nm; RT1 : 5.35 min.
  • Small molecule inhibition of the BRAF and RAFI kinases was measured using ADP-Glo assay.
  • ADP is converted to ATP in the presence of test kinase and substrate, resulting in luciferase reaction and luminescent readout with light generated proportional to the relative kinase activity.
  • Compounds diluted in DMSO were used in 10-point, 3-fold dose curve for both assays. Final concentrations of 6 nM BRAF (CarnaBio, Cat. 09-122) or 3 nM RAFI (CamaBio, Cat. 09-125) and 30 nM MEK1 substrate (Millipore, Cat.
  • the active ingredient is a compound of Table 1, 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.
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.

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Abstract

L'invention concerne des inhibiteurs de récepteur tyrosine kinase-effecteur, RAF, des compositions pharmaceutiques comprenant lesdits composés, et des méthodes d'utilisation desdits composés pour le traitement de maladies.
PCT/US2022/078461 2021-10-21 2022-10-20 Inhibiteurs de kinases raf WO2023070053A1 (fr)

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US11814384B2 (en) 2022-02-03 2023-11-14 Kinnate Biopharma Inc. Inhibtors of Raf kinases

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US20180346457A1 (en) * 2017-04-28 2018-12-06 Quartz Therapeutics, Inc. Raf-degrading conjugate compounds
WO2020198058A1 (fr) * 2019-03-22 2020-10-01 Kinnate Biopharma Inc. Inhibiteurs de kinases raf
US20210300904A1 (en) * 2019-10-24 2021-09-30 Kinnate Biopharma Inc. Inhibitors of raf kinases

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Publication number Priority date Publication date Assignee Title
US20180346457A1 (en) * 2017-04-28 2018-12-06 Quartz Therapeutics, Inc. Raf-degrading conjugate compounds
WO2020198058A1 (fr) * 2019-03-22 2020-10-01 Kinnate Biopharma Inc. Inhibiteurs de kinases raf
US20210300904A1 (en) * 2019-10-24 2021-09-30 Kinnate Biopharma Inc. Inhibitors of raf kinases

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US11814384B2 (en) 2022-02-03 2023-11-14 Kinnate Biopharma Inc. Inhibtors of Raf kinases

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