WO2023070053A1 - Inhibitors of raf kinases - Google Patents

Inhibitors of raf kinases 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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French (fr)
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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/en

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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.

Abstract

Provided herein are inhibitors of receptor tyrosine kinase effector, RAF, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

Description

INHIBITORS OF RAF KINASES
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of U.S. Patent Application No. 63/270,497, filed on October 21, 2021; and U.S. Patent Application No. 63/401,485, filed on August 26, 2022, both of which are hereby incorporated by reference in their 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. 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.
BRIEF SUMMARY OF THE INVENTION
[0003] Provided herein are inhibitors of the receptor tyrosine kinase effector Raf (RAF), pharmaceutical compositions comprising said compounds, and 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):
Figure imgf000002_0001
wherein,
X is independently N or C-H;
Y is independently N or C-H;
R is selected from H, -C(R1)(R2)(R3), optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
R1 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; R2 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
R3 is selected from H, -OH, -OR4, -NH2, -NHR4, -N(R4)2, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each R4 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R2 and R4 join to form a ring; and Z is an optionally substituted aryl or optionally substituted heteroaryl.
[0005] 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.
[0006] 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.
INCORPORATION BY REFERENCE
[0007] 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
[0008] 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 [0009] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0010] " Amino" refers to the -NH2 radical.
[0011] "Cyano" refers to the -CN radical.
[0012] "Nitro" refers to the -NO2 radical.
[0013] " Oxa" refers to the -O- radical.
[0014] " Oxo" refers to the =O radical.
[0015] " Thioxo" refers to the =S radical.
[0016] " Imino" refers to the =N-H radical.
[0017] " Oximo" refers to the =N-OH radical.
[0018] "Hydrazino" refers to the =N-NH2 radical.
[0019] "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., Ci- 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 (/.w-propyl), 1 -butyl ( n-butyl), 1 -methylpropyl ( ec-butyl), 2-m ethylpropyl (/.w-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, trimethyl silanyl, -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).
[0020] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
[0021] "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. 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, trimethyl silanyl, -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 trifluorom ethyl).
[0022] "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 tri fluoromethyl).
[0023] "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. 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., Ci 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).
[0024] "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).
[0025] "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 trifluorom ethyl).
[0026] "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. 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-0Ra, -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.
[0027] "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.
[0028] "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.
[0029] "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.
[0030] "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.
[0031] "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, norbomyl (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.
[0032] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0033] "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.
[0034] "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.
[0035] 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,
Figure imgf000011_0001
[0036] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.
[0037] "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. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
[0038] "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). Examples of such 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-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-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb- N(Ra)C(0)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.
[0039] "/'/-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 A-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
[0040] " 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.
[0041] "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.
[0042] "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.
[0043] "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 Hiickel 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 quatemized. 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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,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[l,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-naphthyri dinonyl, 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-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb- C(O)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb- N(Ra)C(0)Ra, -Rb-N(Ra)S(0)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.
[0044] " 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.
[0045] " 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.
[0046] "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 heteroaryl alkyl radical is optionally substituted as defined above for a heteroaryl group.
[0047] "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 heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
[0048] 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. [0049] 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 imgf000016_0001
[0050] 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.
[0051] 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.
[0052] 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, 170, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35C1, 37C1, 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.
[0053] In certain embodiments, the compounds disclosed herein have some or all of the
Figure imgf000017_0001
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.
[0054] 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.
[0055] 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.
[0056] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-ds (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted 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.
Figure imgf000017_0003
[0057] Deuterium-transfer reagents, such as lithium aluminum deuteride (Li AID4), 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.
Figure imgf000017_0002
[0058] 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.
Figure imgf000018_0001
[0059] 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 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.
[0060] "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.
[0061] "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, phenyl acetates, 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.
[0062] "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 al., supra.
[0063] "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. [0064] 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
[0065] 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 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.
[0066] 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 "off1 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. [0067] 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.
[0068] 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.
[0069] 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
[0070] 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. 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
[0071] 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
[0072] 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 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.
BRAF-targeted therapy in CNS tumors and/or brain metastases
[0073] Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. In the case of melanoma, brain metastases are frequently the first site of diseaseprogression (Cohn-Cedermark, G. et al. Central nervous system metastases of cutaneous malignant melanoma — A population-based study. Acta Oncol. 1998, 37, 463-470). Metastatic CNS invasion is a multistep process. Primary tumor cells initially enter the circulation and then undergo hematogenous spread until they arrest within capillary beds of organs, where they proliferate and form the metastasis. (Redmer, T. Deciphering mechanisms of brain metastasis in melanoma — The gist of the matter. Mol. Cancer 2018, 17, 106; Tawbi, H. A.; et al. New era in the management of melanoma brain metastases. Am. Soc. Clin. Oncol. Educ. Book 2018, 38, 741-750). One shortcoming of current therapies is the inability of a small molecule RAF kinase inhibitor to cross the blood-brain barrier and provide a therapeutically effective amount of inhibitor at the location of the CNS tumor and/or brain metastatic tissue.
Determination of blood-brain barrier penetration by small molecules
[0074] In drug development, CNS drug candidates have lower success rates and longer development times than those in the other therapeutic areas. (Di, L. et al. Expert Opinion on Drug Discovery (2008) 3:6, 677-687. DOI: 10.1517/17460441.3.6.677) Low brain penetration of small molecules can be due to several factors, including, but not limited to, low blood-brain barrier (BBB) permeability, P-glycoprotein (Pgp) efflux, or high plasma protein binding.
[0075] There are multiple mechanisms that affect brain penetration of molecules. Compounds may enter the brain by transcellular passive diffusion, which is driven by a concentration gradient between the blood and the brain. Brain penetration of compounds may be enhanced by influx transporters, such as the large neutral amino acid transporter 1 (LAT1) for L-dopa and gabapentin (Ohtsuki,et al. Pharm. Res. 2007, 24, 1745-58; Gynther, et al. J. Med. Chem. 2008, 51(4), 932-936). This requires that the compounds have a certain structural motif to bind to the transporter. Only a few examples have been reported in which this pathway was purposely used to increase brain penetration. Efflux transporters move molecules out of cells. Of primary importance for brain penetration is the efflux transporter Pgp. 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. Overall, 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.
[0076] Bioanalytical methods and screening strategies provide the rationale for design and evaluation of compounds with desirable BBB distribution properties. (Di, L. et al. Expert Opinion on Drug Discovery (2008) 3:6, 677-687; Summerfield et al. J. Pharmacol. Exp. Ther. (2016) 358:294- 305) 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)
RAF Kinase Inhibitors
[0077] 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.
[0078] 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). Although the initial results of the clinical studies in B-RAF-mutant melanoma were encouraging, as clinical testing began in other B-RAF-mutated cancers (such as thyroid and colorectal cancers) it became apparent that tumors of different cell types harboring B-RAF mutations responded differently to selective B-RAF inhibition. Moreover, the existence of both primary and secondary resistance to RAF inhibition poses as one of the greatest challenge to the progress of RAF kinase inhibitor therapy. The mechanisms of resistance fall into two broad categories. Intrinsic/primary resistance is displayed by approximately 50% of patients. The other 50% of the patients initially respond (>30% tumor shrinkage) to RAF inhibitor but subsequently develop progressive disease associated with acquired/secondary resistance to RAF inhibitor. These two categories are not mutually exclusive because nearly all responders have remaining disease and, thus, may display intrinsic resistance. The determinants of primary RAF inhibitor resistance seem to vary with tumor type, with alteration in RTK signaling also being involved. Potential mechanisms of secondary B-RAF inhibitor resistance include, but are not limited to, reactivation of ERK1/2 pathways, upregulation of RTK signaling, the upregulation of receptor tyrosine kinases, mutations in RAS, and upregulation of COT. B- Raf alternative splicing and amplification of B-RAF-V600E have also been implicated in ~ 30 and 20% of patients, respectively. Moreover, RAF kinase inhibitors cause paradoxical activation of the MAPK pathway, which, in some instances, leads to the development of secondary RAS mutation-driven malignancies. As such, there is a need in the field for new RAF kinase inhibitors that overcome the existing pitfalls and challenges posed by the current inhibitors.
RAF Inhibitory Compounds
[0079] In one aspect, provided herein is a RAF inhibitory compound.
[0080] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):
Figure imgf000025_0001
wherein,
X is independently N or C-H; Y is independently N or C-H;
R is selected from H, -C(R1)(R2)(R3), optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
R1 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
R2 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
R3 is selected from H, -OH, -OR4, -NH2, -NHR4, -N(R4)2, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each R4 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R2 and R4 join to form a ring; and Z is an optionally substituted aryl or optionally substituted heteroaryl.
[0081] 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.
[0082] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R is H.
[0083] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R is -C(R1)(R2)(R3).
[0084] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is H.
[0085] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted C3-C7 cycloalkyl.
[0086] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 is optionally substituted Cl- C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 is optionally substituted C3-C7 cycloalkyl. [0087] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NH2. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NHR4. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R4)2. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR4. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted heterocyclyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted heteroaryl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C6 acyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R4 join to form a ring.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] In some embodiments, the RAF kinase inhibitory compound as described herein has a structure provided in Table 1. Table 1
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Preparation of Compounds
[0093] 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).
[0094] 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) "Modem 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" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[0095] 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
[0096] In certain embodiments, the RAF kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
[0097] Provided herein is 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.
[0098] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
[0099] 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.
[00100] In certain embodiments, 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.
[00101] 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)). [00102] In some embodiments, the RAF kinase inhibitory compound as described by Formula (I), 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.
[00103] 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.
[00104] 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.
[00105] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
Methods of Treatment
[00106] 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.
[00107] 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.
[00108] One embodiment provides 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.
[00109] 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.
[00110] In some embodiments is provided 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 embodimentsis provided 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.
[00111] In some embodiments described herein, 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. In some embodiments described herein, 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. In some embodiments, 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.
[00112] 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.
[00113] 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
[00114] In some embodiments, 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 δH chemical shift in parts per million downfield from tetramethylsilane
DCM di chloromethane (CH2Q2) 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 coupling constant (in NMR spectrometry)
LCMS liquid chromatography mass spectrometry micro m multiplet (spectral); meter(s); milli
M molar M+ parent molecular ion
Me methyl MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) 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
[00115] Intermediate 1 : 4- [5 -Chi oro-2-(prop- 1 -yn- 1 -yl)pyri din-3 -yl]morpholine
Figure imgf000066_0001
[00116] To a stirred mixture of 4-(2,5-dichloropyridin-3-yl)morpholine (300 mg, 1.287 mmol), propyne (2.57 mL, 2.574 mmol, 1 M THF solution), Cui (49 mg, 0.257 mmol) and Pd(PPh3)2Cl2 (90 mg, 0.129 mmol) in DMF (3 mL) was added TEA (0.6 mL). The reaction mixture was degassed with nitrogen atmosphere for three times and stirred for 16 h at 80 °C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers was washed with brine (2 x 50 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 PEZEA (1/1). The fractions contained desired product were combined and concentrated to afford 4-[5-chloro-2-(prop-l-yn-l-yl)pyridin-3- yl]morpholine (205 mg, 67%) as a yellow oil. MS ESI calculated for C12H13C1N2O [M + H]+, 237.07, 239.07, found 237.10, 239.10. 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J= 2.0 Hz, 1H), 7.21 (d, J= 2.0 Hz, 1H), 3.92-3.90 (m, 4H), 3.24-3.22 (m, 4H), 2.17 (s, 3H).
[00117] The following compounds in Table 2 were prepared using procedures similar to those described in Intermediate 1 using appropriate starting materials.
Table 2
Figure imgf000066_0002
Figure imgf000067_0001
[00118] Intermediate 7: N-[2-Fluoro-4-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-di oxaborolan-2 -yl)phenyl]-2- (trifluoromethyl)pyridine-4-carboxamide
[00119] To a stirred solution of 2 -fluoro-4-methyl-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol) and 2-(trifluoromethyl)pyridine-4-carboxylic acid (1.67 g, 8.761 mmol) in CH3CN (15 mL) were added HATU (4.54 g, 11.947 mmol) and TEA (1.61 g, 15.930 mmol). The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 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/ EtOAc (1/1). The fractions contained desired product were combined and concentrated to afford A-[2-fhioro-4-methyl-5-(4, 4,5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide (1.50 g, 44%) as a yellow solid. MS ESI calculated for C20H21BF4N2O3 [M + H]+, 425.16, found 425.05. 'H NMR (400 MHz, Chloroform-d ) δ 8.95-8.94 (m, 1H), 8.58-8.55 (d, J = 8.9 Hz, 1H), 8.16 (s, 1H), 7.98-7.93 (m, 2H), 7.02-6.97 (m, 1H), 2.55 (s, 3H), 1.36 (s, 12H).
[00120] The following compounds in Table 3 were prepared using procedures similar to those described in Intermediate 7 using appropriate starting materials.
Table 3
Figure imgf000068_0002
[00121] Intermediate 9: 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridin-3-yl]aniline
Figure imgf000068_0001
[00122] To a stirred mixture of 4-[5-chloro-2-(prop-l-yn-l-yl)pyridin-3-yl]morpholine (1.16 g, 4.901 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.23 g, 4.901 mmol), K3PO4 (2.08 g, 9.802 mmol) in THF (10 mL) and H2O (1 mL) was added XPhos palladium(II) biphenyl-2-amine chloride (0.39 g, 0.490 mmol). 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 fractions contained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridin-3-yl]aniline (1.10 g, 68%) as a light brown solid. MS ESI calculated for C19H20FN3O [M + H]+, 326.16, found 326.15. 1H NMR (400 MHz, DMSO ) 6 8.03, (d, J= 2.0 Hz, 1H), 7.23, (d, J= 2.0 Hz, 1H), 6.96, (d, J= 12.4 Hz, 1H), 6.68, (d, J= 9.6 Hz, 1H), 5.02 (s, 2H), 3.77, (t, J= 4.8 Hz, 4H), 3.15, (t, J= 4.8 Hz, 4H), 2.14 (s, 3H), 2.08 (s, 3H). 19F NMR (376 MHz, DMSO-d 6) δ -135.98 (IF).
[00123] The following compounds in Table 4 were prepared using procedures similar to those described in Intermediate 9 using appropriate starting materials.
Table 4
Figure imgf000069_0003
[00124] Intermediate 11 : 4-(5-Chloro-2-ethynylpyridin-3-yl)morpholine
Figure imgf000069_0001
[00125] To a stirred mixture of 4-{5-chloro-2-[2-(trimethylsilyl)ethynyl]pyridin-3-yl}morpholine (2 g, 6.783 mmol), K2CO3 (1.87 g, 13.566 mmol) and CH3OH (20 mL) was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with CH3OH (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1). The fractions contained desired product were combined and concentrated to afford 4-(5-chloro-2-ethynylpyridin-3- yl)morpholine (1.4 g, 93%) as a light yellow solid. MS ESI calculated for C11H11CIN2O [M + H]+, 223.06, found 222.90. 'H NMR (400 MHz, Chloroform-d) 8.20 (d, J= 2.0 Hz, 1H), 7.24 (d, J= 2.0 Hz, 1H), 3.91-3.89 (m, 4H), 3.53 (s, 1H), 3.26-3.24 (m, 4H).
[00126] Intermediate 12: Methyl 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylate
Figure imgf000069_0002
, , , step 1
[00127] To a stirred mixture of methyl 2-bromopyridine-4-carboxylate (1.00 g, 4.629 mmol), 1,1,1- trifluoro-2-iodoethane (1.94 g, 9.258 mmol), IR[DF(CF3)PPY]2(DTBPY)PF6 (0.10 g, 0.093 mmol, 0.02 equiv), 1,2-dimethoxy ethane dihydrochloride nickel (0.02 g, 0.093 mmol), 4-terL butyl-2-(4-tert-butylpyridin-2-yl)pyridine (0.01 g, 0.046 mmol) in DME (20 mL) was added 2,6- dimethylpyridine (0.99 g, 9.258 mmol). The reaction mixture was stirred for 10 min at room temperature under a argon atmosphere. To the above mixture was added 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 Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1). The fractions contained desired product were combined and concentrated to afford methyl 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (0.04 g, crude) as light yellow oil. MS ESI calculated for C9H8F3NO2 [M + H]+, 220.05, found 220.10. 'H NMR (400 MHz, Chloroform-d) 8 8.79 (dd, J= 0.8, 4.4 Hz, 1H), 7.93 (s, 1H), 7.86 (dd, J= 1.6, 3.2 Hz, 1H), 4.00 (s, 3H), 3.77-3.68 (m, 2H). 19F NMR (376 MHz, Chloroform-d) 8 -64.64 (3F).
[00128] Intermediate 13: Methyl 2-(l,l-difluoroethyl)pyridine-4-carboxylate
Figure imgf000070_0001
[00129] To a stirred solution of DAST (9.00 g, 55.810 mmol) in DCM (5 mL) was added methyl 2- acetylpyridine-4-carboxylate (1.00 g, 5.581 mmol) in DCM (5 mL) at 0 °C under argon atmosphere. The resulting mixture was stirred for 16 h at room temperature under argon atmosphere. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (80 mL) at °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 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 (3/1). The fractions contained desired product were combined and concentrated to afford methyl 2-(l,l-difluoroethyl)pyridine-4-carboxylate (0.80 g, 71%) as a reddish solid. MS ESI calculated for C9H9F2NO2 [M + H]+, 202.06, found 202.05. 'H NMR (400 MHz, DMSO- d6) 8 8.92-8.90 (m, 1H), 8.05-8.04 (m, 1H), 8.01-7.99 (m, 1H), 3.94 (s, 3H), 2.04 (t, J= 19.2 Hz, 3H). 19F NMR (376 MHz, DMSO ) 8 -88.94 (2F).
[00130] Intermediate 14: Methyl 2-(l,l,2,2,2-pentaflu oroethyl)pyridine-4-carboxylate
Figure imgf000071_0001
[00131] To a stirred mixture of methyl 2-bromopyridine-4-carboxylate (1.00 g, 4.629 mmol) and NaOAc (1.52 g, 18.516 mmol) were added tris(trimethylsilyl)silane (2.07 g, 8.332 mmol) and CuBr (0.13 g, 0.926 mmol), 4-tert-butyl-2-(4-tert-butylpyri din-2 -yl)pyri dine (0.31 g, 1.157 mmol), IR[DF(CF3)PPY]2(DTBPY)PF6 (0.03 g, 0.023 mmol), trimethyl(l,l,2,2,2- pentafluoroethyl)silane (2.67 g, 13.887 mmol) in MeCN (30 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 16 h at 25 °C under blue LED. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers was washed with brine (100 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, Cl 8; mobile phase, MeCN in water (plus 10 mM NH4HCO3), 5% to 95% gradient in 45 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford methyl 2-(l,l,2,2,2-pentafluoroethyl)pyridine-4-carboxylate (0.16 g, 13%) as a brown solid. MS ESI calculated for C9H6F5NO2 [M + H]+, 256.03, found 255.05. 'H NMR (400 MHz, DMSO-d6) δ 9.06-9.05, (m, 1H), 8.22-8.19, (m, 2H), 3.96 (s, 3H). 19F NMR (376 MHz, DMSO- d6) δ -77.20, (3F), 115.74 (2F).
[00132] Intermediate 15: Methyl 5-fluoro-2-isopropylpyridine-4-carboxylate
Figure imgf000071_0002
[00133] Step 1 : 5-Fluoro-2-(prop-l-en-2-yl)pyridine-4-carboxylate
Figure imgf000071_0003
[00134] To a stirred solution of methyl 2-bromo-5-fluoropyridine-4-carboxylate (2 g, 8.546 mmol), Pd(PPh3)4 (0.99 g, 0.855 mmol) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (1.58 g, 9.401 mmol) in dioxane (16 mL) and H2O (4 mL) was added K2CO3 (3.54 g, 25.638 mmol). The reaction mixture was degassed with nitrogen for 3 times and stirred for 3 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers was washed with brine (2 x 150 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; mobile phase, C LCN in water (10 mM NH4HCO3), 25% to 75% gradient in 20 min; detector, UV 300 nm. The fractions contained desired product were combined and concentrated to afford methyl 5-fluoro-2-(prop-l-en-2-yl)pyridine-4-carboxylate (880 mg, 53%) as a yellow oil. MS ESI calculated for Chemical Formula: C10H10FNO2 [M + H]+, 196.07, found 195.90. TH NMR (400 MHz, Chloroforms/) δ 8.57-8.56 (d, J= 2.1 Hz, 1H), 7.95-7.93 (d, J= 5.6 Hz, 1H), 5.90- 5.89 (m, 1H), 5.37 (s, 1H), 4.00 (s, 3H), 2.23-2.22 (m, 3H). 19F NMR (376 MHz, Chloroforms/) 6 -128.50 (IF).
[00135] Step 2: Methyl 5-fluoro-2-isopropylpyridine-4-carboxylate
Figure imgf000072_0001
[00136] To a solution of methyl 5-fluoro-2-(prop-l-en-2-yl)pyridine-4-carboxylate (800 mg, 4.099 mmol) in 10 mL EtOH was added Pd/C (10%, 400 mg) in a pressure tank. The reaction mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure overnight. The resulting mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford methyl 5-fluoro-2-isopropylpyridine-4-carboxylate (905 mg, crude) as a yellow oil.. The crude product was used in the next step directly without further purification. MS ESI calculated for Chemical Formula: C10H12FNO2 [M + H]+, 198.09, found 197.90. 'H NMR (400 MHz, Chloroforms/) δ 7.80-7.61 (m, 1H), 7.33-7.27 (d, J= 16.6 Hz, 1H), 4.04-3.98 (m, 1H), 3.79-3.70 (m, 3H), 1.40-1.26 (m, 6H). 19F NMR (376 MHz, Chloroform-d), -130.70. (IF).
[00137] The following compounds in Table 5 were prepared using procedures similar to those described in Intermediate 15 using appropriate starting materials.
Table 5
Figure imgf000072_0002
[00138] Intermediate 17: 2-(2,2,2-Trifluoroethyl)pyridine-4-carboxylic acid
Figure imgf000073_0001
step 1
[00139] To a stirred mixture of methyl 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylate (40 mg, 0.183 mmol, crude) in THE (1 mL), CH3OH (1 mL) and H2O (1 mL) was added LiOHH2O (38 mg, 0.915 mmol). The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was acidified with 1 M HC1 (aq.) (10 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers was washed with saturated brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (15 mg, 40%) as a light yellow solid. MS ESI calculated for C8H6F3NO2 [M + H]+, 206.04, found 206.05. 1H NMR (400 MHz, DMSO-d6 ) 5 8.52 (d, J= 5.2 Hz, 1H), 7.78 (s, 1H), 7.66 (dd, J= 1.6, 3.6 Hz, 1H), 3.85- 3.77 (m, 2H). 19F NMR (376 MHz, DMSO-d6 ) 5 -63.12 (3F).
[00140] The following compounds in Table 6 were prepared using procedures similar to those described in Intermediate 17 using appropriate starting materials.
Figure imgf000073_0002
Figure imgf000074_0002
[00141] 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
Figure imgf000074_0001
[00142] To a stirred mixture of 4-[5-chloro-2-(prop-l-yn-l-yl)pyridin-3-yl]morpholine (100 mg, 0.422 mmol), N -[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-2- (trifluoromethyl)pyridine-4-carboxamide (161 mg, 0.380 mmol) and 2nd Generation XPhos Precatalyst (33 mg, 0.042 mmol) in THF (0.8 mL) was added K3PO4 (1.7 mL, 7.904 mmol, 0.5 M in H2O). 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. The fractions contained desired product were combined and concentrated to afford A-{2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn- l-yl)pyridin-3-yl]phenyl}-2-(trifluoromethyl)pyridine-4-carboxamide (97.4 mg, 46%) as a white solid. MS ESI calculated for C26H22F4N4O2 [M + H]+, 499.17; found 499.25. 1H NMR (400 MHz, DMSO-d6 ) δ 10.69 (s, 1H), 9.01 (d, J= 5.2 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J= 4.4 Hz, 1H), 8.12 (d, J= 2.0 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.37-7.32 (m, 2H), 3.78-3.74 (m, 4H), 3.19-3.17 (m, 4H), 2.28 (s, 3H), 2.15 (s, 3H).19F NMR (376 MHz, Chloroform-d) δ -66.53 (3F), -122.33 (IF). [00143] The following compounds in Table 7 were prepared using procedures similar to those described in Example 1 using appropriate starting materials.
Table 7
Figure imgf000075_0001
Figure imgf000076_0002
[00144] 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
Figure imgf000076_0001
[00145] To a stirred solution of 2-(trifluoromethyl)pyridine-4-carboxylic acid (52 mg, 0.271 mmol) and HATU (140 mg, 0.369 mmol) in CH3CN (1 mL) was added TEA (100 mg, 0.984 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at room temperature under nitrogen atmosphere. To the above mixture was added 2-fluoro-4- methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridin-3-yl]aniline (80 mg, 0.246 mmol). The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture 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 95% gradient in 30 min; detector, UV 254 nm. The fractions contained desired product were combined and cocnentrated to afford N-{2-fluoro-4-methyl-5-[5- (morpholin-4-yl)-6-(prop- 1 -yn- 1 -yl)pyri din-3 -yl]phenyl } -2-(trifluoromethyl)pyridine-4- carboxamide (69.8 mg, 57%) as an off-white solid. MS ESI calculated for C26H22F4N4O2 [M + H]+, 499.17, found 499.30. 1H NMR (400 MHz, Chloroform-d) δ 9.31 (d, J= 2.4 Hz, 1H), 9.09 (d, = 2.0 Hz, 1H), 8.47 (s, 1H), 8.26-8.12 (m, 3H), 7.19-7.13 (m, 2H), 3.94-3.92 (m, 4H), 3.29- 3.27 (m, 4H), 2.28 (s, 3H), 2.20 (s, 3H). 19F NMR (376 MHz, Chloroform-d) δ -62.51 (3F), - 130.98 (IF).
[00146] The following compounds in Table 8 were prepared using procedures similar to those described in Example 7 using appropriate starting materials.
Table 8
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0002
[00147] Example 23: N-{5-[6-ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylphenyl}-3-
(trifluoromethyl)benzamide
Figure imgf000082_0001
[00148] To a stirred solution of 5-[6-ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylaniline (100 mg, 0.321 mmol) in DCM (0.5 mL) were added DIE A (124 mg, 0.963 mmol) and 3- (trifluoromethyl)benzoyl chloride (74 mg, 0.353 mmol) in DCM (0.5 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc/EtOH=8/3/l) to afford crude product. The crude product was further purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, CH3CN 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. MS ESI calculated for C26H21F4N3O2 [M + H]+, 484.16, found 484.30. 1H NMR (400 MHz, Chloroform- d) δ 8.31 (d, J= 8.0 Hz, 1H), 8.23 (d, J= 2.0 Hz, 1H), 8.17 (s, 1H), 8.09-8.07 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.23 (d, J= 2.0 Hz, 1H), 7.13 (d, J= 11.6 Hz, 1H), 3.94- 3.91 (m, 4H), 3.54 (s, 1H), 3.31-3.29 (m, 4H), 2.27 (s, 3H). 19F NMR (376 MHz, Chloroforms/) δ -62.81 (3F), -131.34 (IF).
[00149] The following compounds in Table 9 were prepared using procedures similar to those described in Example 23 using appropriate starting materials.
Table 9
Figure imgf000083_0001
[00150] Example 25: N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl)-2-
(trifluoromethyl)isonicotinamide
Figure imgf000084_0001
step 3
[00151] Preparation 25A: 4-(5-bromo-2-chloropyridin-3-yl)morpholine
Figure imgf000084_0002
step 1
[00152] A mixture of 4-(5-bromo-2-iodopyridin-3-yl)morpholine (1.0 g, 2.70 mmol), ethynyltrimethyl silane ( 0.4 mL, 3.20 mmol), Pd(PPh3)2Cl2 (280 mg, 0.40 mmol) , Cui (51 mg, 0.27mmol) and TEA (1.1 mL, 8.10 mmol) in THF (40 mL) was stirred for 2h at 60 °C under nitrogen atmosphere. The resulting mixture was addd water (100 mL), extracted with EA (200 mL). The organic layer dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by FCC with PE/EtOAc (3/1) to afford 4-(5-bromo-2- ((trimethylsilyl)ethynyl)pyridin-3-yl)morpholin (880 mg, 88%) as yellow oil. MS ESI calculated for C14H19BrN2OSi [M + H]+ , 339.05, found 339.10.
[00153] Preparation 25B : N-(2-fluoro-4-methyl-5-(5-morpholino-6-((trimethylsilyl)ethynyl)pyridin-3- yl)phenyl)-2-(trifluoromethyl)isonicotinamide
Figure imgf000085_0001
step 2
[00154] A mixture of 4-(5-bromo-2-((trimethylsilyl)ethynyl)pyridin-3-yl)morpholine (240 mg, 0.71 mmol), N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- (trifluoromethyl)isonicotinamide (300 mg, 0.71 mmol), Pd(dppf)C12 (51 mg, 0.07 mmol) and CS2CO3 (456 mg, 1.40 mmol) in dioxane (30 mL) and H2O (6 mL) was stirred for 2h at 80 °C under nitrogen atmosphere. To the resulting mixture was addd water (50 mL), extracted with EA (100 mL). The organic layer dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by FCC with PE/EtOAc (2/1) to afford N-(2-fluoro-4-methyl-5-(5- morpholino-6-((trimethylsilyl)ethynyl)pyridin-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide (200 mg, 51%) as a yellow solid. MS ESI calculated for C28H28F4N4O2Si [M + H]+ , 557.19, found 557.20.
[00155] Example 25: N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide
Figure imgf000085_0002
step 3
[00156] A mixture of N-(2-fluoro-4-methyl-5-(5-morpholino-6-((trimethylsilyl)ethynyl)pyri din-3- yl)phenyl)-2-(trifluoromethyl)isonicotinamide (200 mg, 0.36 mmol) and TBAF (0.40 mL, 1.0 M in THF, 0.40 mmol) in THF (10 mL) was stirred at RT for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by re -HPLC to afford N-(5-(6- ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide (54.5 mg, 31%) as a white solid. MS ESI calculated for C25H20F4N4O2 [M + H]+, 485.15, found 485.20. 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J= 4.8 Hz, 1H), 8.28 (s, 1H), 8.12-8.11 (m, 2H), 7.68 (d, J = 6.8 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J = 11.2 Hz, 1H), 4.12 (s, 1H), 3.89-3.86 (m, 4H), 3.29-3.26 (m, 4H), 2.29 (s, 3H).
[00157] Example 26: N-(2-fluoro-5-(6-(3-hydroxy-3-methylbut-l-yn-l-yl)-5-morpholinopyridin-3-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide
Figure imgf000086_0001
[00158] Preparation 26A: 4-(5-bromo-3-morpholinopyridin-2-yl)-2-methylbut-3-yn-2-ol
Figure imgf000086_0002
[00159] A mixture of 4-(5-bromo-2-iodopyridin-3-yl)morpholine (400 mg, 1.10 mmol), 2-methylbut-3- yn-2-ol ( 110 mg, 1.30 mmol), Pd(PPh3)2Cl2 (115 mg, 0.17 mmol), CuI (21 mg, 0.11 mmol) and TEA (300 mg, 3.30 mmol) in THF (30 mL) was stirred for 4h at 60 °C under nitrogen atmosphere. The resulting mixture was filtered, concentrated under reduced pressure. The residue was purified by FCC with PEZEtOAc (3/1) to afford 4-(5-bromo-3-morpholinopyridin-2- yl)-2-methylbut-3-yn-2-ol (170 mg, 42%) as a yellow solid. MS ESI calculated for C14H17BrN2O2 [M + H]+ , 324.05, found 324.10.
[00160] Example 26: N-(2-fluoro-5-(6-(3-hydroxy-3-methylbut-l-yn-l-yl)-5-morpholinopyridin-3-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide
Figure imgf000087_0001
A mixture of 4-(5-bromo-3-morpholinopyridin-2-yl)-2-methylbut-3-yn-2-ol (170 mg, 0.50 mmol), N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- (trifluoromethyl)isonicotinamide (200 mg, 0.50 mmol) Pd(dppf)C12 (36 mg, 0.05 mmol) and CS2CO3 (480 mg, 1.50 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred for 2h at 80 °C under nitrogen atmosphere. The resulting mixture was addd water (100 mL), extracted with EA (200 mL). The organic layer was dried over Na2SO4 , filtered, concentrated under reduced pressure. The residue was purified by FCC with PEZEtOAc (1/1) to afford N-(2-fluoro-4-methyl- 5-(5-morpholino-6-((trimethylsilyl)ethynyl)pyridin-3-yl)phenyl)-2- (trifluoromethyl)isonicotinamide (87.9 mg, 34%) as a white solid. MS ESI calculated for C28H26F4N4O3 [M + H]+ , 543.19, found 543.20. 'H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.05 (d, J= 6.8 Hz, 1H), 8.43 (s, 1H), 8.24 (d, J= 6.8 Hz, 1H), 8.18 (s, 1H), 7.61 (d, J= 10.4 Hz, 1H), 7.43-7.38 (m, 2H), 5.62 (s, 1H), 3.84-3.82 (m, 4H), 3.26-3.24 (m, 4H), 2.32 (s, 3H), 1.54 (s, 6H).
[00161] Example 27: 2-cyclobutyl-N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl) isonicotinamide
Figure imgf000088_0001
Synthetic Scheme
Figure imgf000088_0002
[00162] Example 27A: methyl 2-cyclobutylisonicotinate
Figure imgf000088_0003
[00163] A suspension of methyl isonicotinate (1.5 g, 10.9 mmol), cyclobutanecarboxylic acid (2.1 mL,
21.8 mmol), Selectflour (7.7 g, 21.8 mmol), AgNO3 (0.37 g, 2.18 mmol) and TFA (0.8 mL, 21.8 mmol) in DCE (30 mL) and H2O (30 mL) was stirred at 50 °C for 3 h. The reaction was diluted with DCM (500 mL), washed with saturated NaHCO3 solution to adjust pH 8. The organic layer was dried over NaSO4, filtered and concentrated to give residue, which was purified by FCC with PEZEA (2: 1) to afford 2-cyclobutylisoni cotinate (1.3 g, 62%) as colorless oil. MS ESI calculated for C11H13NO2 [M + H]+, 192.23, Found: 192.10.
[00164] Example 27B: 2-cyclobutylisonicotinic acid
Figure imgf000089_0001
[00165] A mixture of 2-cyclobutylisonicotinate (1.3 g, 6.80 mmol) and LiOH (857 mg, 20.4 mmol) in THF (10 mL), MeOH (10 mL) and H2O (10 mL) was stirred for 3h at rt. The resulting mixture was concentrated, added IN HC1 to adjust pH 6. Then the precipiatated was filtered and dried to afford 2-cyclobutylisonicotinic acid (900 mg, 75%) as a white solid. MS ESI calculated for C10H11NO2 [M + H]+ , 178.08, Found: 178.10.
[00166] Example 27C: 2-cyclobutyl-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl) phenyl)isonicotinamide
Figure imgf000089_0002
[00167] A mixture of 2-cyclobutylisonicotinic acid (425 mg, 1.69 mmol), 2-fluoro-4-methyl-5-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (300 mg, 1.69 mmol), HATU (964 mg, 2.53 mmol) and DIEA (0.55 ml, 3.38 mmol) in DMF (30 mL) was stirred at rt for 3h . To the resulting mixture was addd water (100 mL) and extracted with EA (100 mL*2). The organic layeres washed with H2O (100 mL*2) and brine EA (100 mL), dried over Na2SO 4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PEZEA = 2: 1) to obtain 2-cyclobutyl-N-(2-fluoro-4-methyl-5-(4, 4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl)isoni cotinamide (490 mg, 75% yield) as colorless liquid. MS ESI calculated for C23H28BFN2O3 [M + H]+, 411.29, found:411.30. [00168] Example 27D:4-(5-bromo-2-ethynylpyridin-3-yl)morpholine
Figure imgf000090_0001
Step 4
[00169] A mixture of 4-(5-bromo-2-((trimethylsilyl)ethynyl)pyridin-3-yl)morpholine (750 mg, 2.22 mmol), and TBAF (2.6 mL, 1.0 M in THF, 2.6 mmol) in THF (15 mL) was stirred at RT for 2 h. The resulting mixture was added H2O (100 mL) and extracted with EA (100 mL), the organic layer was dried over Na2 SO4, filtered and concentrated to give crude residue. The residue was purified by silica gel column chromatography with (PEZEA = 2/1) to afford 4-(5-bromo-2- ethynylpyridin-3-yl)morpholine (370 mg, 62%) as a light brown solid. MS ESI calculated for CiiHiiBrN2O [M + H]+, 267.01, found 267.00.
[00170] Example 27: 2-cyclobutyl-N-(5-(6-ethynyl-5-morpholinopyridin-3-yl)-2-fluoro-4- methylphenyl)isonicotinamide
Figure imgf000090_0002
[00171] A mixture of 4-(5-bromo-2-ethynylpyridin-3-yl)morpholine (85 mg, 0.31 mmol), 2-cyclobutyl- N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide (130 mg, 0.31 mmol), Pd(dppf)C12 (23 mg, 0.03 mmol) and CS2CO3 (207 mg, 0.63 mmol) in dioxane (15 mL) and H2O (3 mL) was stirred at 75 °C for Ih under nitrogen atmosphere. The resulting mixture was added water (50 mL) and extracted with EA (100 mL). The organic layer dried over Na2SO4, filtered and concentrated under reduced pressure to give crude residue. The residue was purified by Prep-HPLC (HCOOH) with to afford 2-cyclobutyl-N-(5-(6-ethynyl-5- morpholinopyridin-3-yl)-2-fluoro-4-methylphenyl)isonicotinamide (12.4 mg, 8.2%) as a white solid. MS ESI calculated for C28H27FN4O2 [M + H]+ , 471.21, found 471.20. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, IH), 8.70 (d, J= 4.8 Hz, IH), 8.16 (d, J= 1.6 Hz, IH), 7.73 (s, 1H), 7.68-7.66 (m, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.37 (d, = 1.6 Hz, 1H), 7.33 (d, J= 11.2 Hz, 1H), 4.59 (s, 1H), 3.76-3.72 (m, 5H), 3.21-3.19 (m, 4H), 2.35-2.27 (m, 7H), 2.04-2.02 (m, 1H), 1.89-1.85 (m, 1H).
[00172] 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
Figure imgf000091_0001
[00173] Preparation 28A: methyl 2-fluoro-6-(l-methylcyclopropyl)isonicotinate
F
Figure imgf000091_0002
[00174] To a mixture of AgNO3 (982 mg, 5.81 mmol), (NH4)2S208 (8.8 g, 38.70 mmol) in H2O (30 mL) was added to a mixture of methyl 2-fluoroisonicotinate (3.0 g, 19.35 mmol), 1- methylcyclopropanecarboxylic acid (8.7 g, 87.08 mmol) in 20% H2SO4 (15 mL) at 0 °C. Then the mixture was stirred at rt overnight. The reaction mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (200 mL*2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase column chromatography (Column: Spherical C18, 20-40 pm, 480 g; Mobile Phase A: water (10 mM NH4HCO3); Mobile Phase B: CH3CN; Flow rate: 80 mL/min; Gradient: 5% to 95% B, Detector: 214 nm) to afford methyl 2-fluoro-6-(l-methylcyclopropyl)isonicotinate (180 mg, 4%) as a yellow semi-solid. MS ESI calculated for C11H12FNO2 [M + H]+, 210.09, found 210.10.
[00175] Preparation 28B: 2-fluoro-6-(l-methylcyclopropyl)isonicotinic acid
Figure imgf000092_0001
[00176] To a solution of methyl 2-fluoro-6-(l-methylcyclopropyl)isonicotinate (180 mg, 0.86 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH.H2O (72 mg, 1.72 mmol) and then stirred at rt ovemighgt. THF was removed under reduced pressure. IN HC1 was added drop-wise to the solution until pH 2. Filtered and the precipitate was dried under vaccum to afford 2-fluoro-6-(l- methylcyclopropyl)isonicotinic acid (HC1 salt, 185 mg, 93%) as a white solid. MS ESI calculated for C10H10FNO2 [M + H]+, 196.07, found 196.10.
[00177] Preparation 28C: 2-fluoro-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-6-(l-methylcyclopropyl)isonicotinamide
Figure imgf000092_0002
[00178] To a solution of 2-fluoro-6-(l-methylcyclopropyl)isonicotinic acid (185 mg, 0.8 mmol), 2- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (201 mg, 0.8 mmol) and DIE A (206 mg, 1.6 mmol) in DMF (15 mL) was added HATU (334 mg, 0.88 mmol) and stirred at rt for 3h. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated in PE (10 mL). Filtered and the precipitate was dried under vaccum to afford 2-fluoro-A-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-6-(l-methylcyclopropyl)isonicotinamide (174 mg, 51%) as a off-white solid. MS ESI calculated for C23H27BF2N2O3 [M + H]+, 429.21, found 429.20.
[00179] 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
Figure imgf000093_0001
[00180] A mixture of 2-fluoro-A-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-6-(l-methylcyclopropyl)isonicotinamide (70 mg, 0.16 mmol), 4-(5-bromo-2-(prop-l- yn-l-yl)pyri din-3 -yl)morpholine (45 mg, 0.16 mmoL), CS2CO3 (104 mg, 0.32 mmol) and Pd(dppf)C12 (15 mg, 0.02 mmol) in dioxane/EEO (10 mL/2 mL) was stirred at 80 °C for 2 h under N2. To the reaction mixture was added water (30 mL), extracted with EtOAc (30 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pr ep-HPLC to afford 2-fluoro-A-(2-fluoro-4-methyl-5-(5-morpholino-6-(prop-l-yn-l-yl)pyridin-3-yl)phenyl)- 6-(l-methylcyclopropyl)isonicotinamide (15.9 mg, 20%) as a white solid. MS ESI calculated for C29H28F2N4O2 [M + H]+, 503.22, found 503.20. 1H NMR (400 MHz, DMSO-d6 ): δ 10.51 (s, 1H), 8.11 (d, J= 1.6 Hz, 1H), 7.75 (s, 1H), 7.51 (d, = 7.6 Hz, 1H), 7.36-7.31 (m, 3H), 3.76 (t, J = 4.0 Hz, 4H), 3.18 (t, J= 4.0 Hz, 4H), 2.27 (s, 3H), 2.14 (s, 3H), 1.52 (s, 3H), 1.19-1.17 (m, 2H), 0.93-091 (m, 2H).
[00181] 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
Figure imgf000094_0002
[00182] Step 1 : 4-(3,6-Dichloropyridazin-4-yl)morpholine step 1
Figure imgf000094_0001
[00183] To a stirred solution of 3,4,6-trichloropyridazine (10 g, 54.52 mmol) in EtOH (40 mL) was added morpholine (10.88 g, 124.85 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with water (3 x 80 mL) and concentrated under reduced pressure to afford 4-(3,6-dichloropyridazin-4- yl)morpholine (10.47 g, 82%) as a white solid. MS ESI calculated for C8H9Cl2N3O [M + H]+, 234.01, 236.01, found 234.15, 236.15; 'H NMR (400 MHz, Chloroform-d δ 6.90 (s, 1H), 3.92- 3.90 (m, 4H), 3.35-3.33 (m, 4H).
[00184] Step 2: 4-[6-Chl oro-3 -(prop- l-yn-l-yl)pyridazin-4-yl]morpholine step 2
Figure imgf000095_0001
[00185] To a stirred solution of 4-(3,6-dichloropyridazin-4-yl)morpholine (1 g, 4.27 mmol), Cui (0.16 g,
0.85 mmol), TEA (2.07 mL, 14.95 mmol) and Pd(PPh3)2C12 (0.30 g, 0.43 mmol) in DMF (10 mL) was added propyne (0.21 g, 5.13 mmol, 1 mol/L in THF) dropwise at room temperature. The reaction mixture was degassed with argon for three times and stirred for 3 h at 80 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers was washed with brine (2 x 100 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 PEZEA (1/2). The fractions containing desired product were combined and concentrated to afford 4-[6-chl oro-3 -(prop- l-yn-l-yl)pyridazin-4-yl]morpholine (0.74 g, 73%) as a reddish brown solid. MS ESI calculated for C11H12CIN3O [M + H]+,238.07, 240.07, found 238.10, 240.10. 1H NMR (400 MHz, Chloroform-d) δ 6.76 (s, 1H), 3.89-3.87 (m, 4H), 3.49-3.47 (m, 4H), 2.18 (s, 3H)
[00186] Step 3: 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3-yl]aniline
Figure imgf000095_0002
[00187] To a stirred mixture of 4-[6-chloro-3-(prop-l-yn-l-yl)pyridazin-4-yl]morpholine (0.60 g, 2.52 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.69 g, 2.77 mmol), 2 nd Generation XPhos precatalyst (199 mg, 0.25 mmol) in THF (6 mL) was added K3PO4 (12 mL, 0.5 M in H2O). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 40 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers was washed with brine (60 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/EtOAc/EtOH (4/3/1). The fractions containing desired product were combined and concentrated to afford 2-fluoro-4- methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3-yl]aniline (0.50 g, 61%) as a light yellow solid. MS ESI calculated for C18H19FN4O [M + H]+, 327.15, found 327.15. 'H NMR (400 MHz, Chloroform-d ) δ 6.95-6.89 (m, 2H), 6.79 (s, 1H), 3.92-3.90 (m, 4H), 3.48-3.46 (m, 4H), 2.25-2.22 (m, 6H). 19F NMR (376 MHz, Chloroform-d) δ -134.62 (IF)
[00188] 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
Figure imgf000096_0001
4
[00189] To a stirred solution of 3-methyl-l,3-benzodiazole-5-carboxylic acid (65 mg, 0.37 mmol) and HATU (175 mg, 0.46 mmol) in DMF (1 mL) was added TEA (124 mg, 1.22 mmol) dropwise at 0 °C. The reaction mixture was stirred for 0.5 h at room temperature. To the above mixture was added 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3-yl]aniline (100 mg, 0.31 mmol). The resulting mixture was stirred for additional 5 h at 60 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers was washed with brine (30 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/EtOAc/EtOH = 4/3/1) to afford the crude product. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 5% to 95% gradient in 10 min; detector, UV 254 nm. The fractions containing desired product were combined and concentrated to afford /V-{2-fluoro-4- methyl-5-[5-(morpholin-4-yl)-6-(prop-l-yn-l-yl)pyridazin-3-yl]phenyl}-3-methyl-l,3- benzodiazole-5-carboxamide (36.7 mg, 24%) as an off-white solid. MS ESI calculated for C27H25FN6O2 [M + H]+, 485.20, found 485.15; 'H NMR (400 MHz, DMSO-d6 ) δ 10.7 (s, 1H), 8.37-8.29 (m, 2H), 7.88 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.34 (d, J= 11.2 Hz, 1H), 7.14 (s, 1H), 3.92 (s, 3H), 3.77-3.75 (m, 4H), 3.48-3.46 (m, 4H), 2.35 (s, 3H), 2.20 (s, 3H). 19F NMR (376 MHz, DMSO-d6 ) δ -120.93 (IF).
[00190] 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
Figure imgf000097_0002
[00191] Step 1 : 4-(2-Bromo-5-chloropyridin-3-yl)morpholine
Figure imgf000097_0001
[00192] To a stirred mixture of 2-bromo-5-chloropyridin-3-amine (5 g, 24.10 mmol) in N,N- dimethylformamide (50.00 mL) was added 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). The fractions containing desired product were combined and concentrated to afford 4-(2- bromo-5-chloropyridin-3-yl)morpholine (6 g, 89%) as a yellow solid. MS ESI calculated for C9H10BrC1N2O [M + H]+, 276.97, 278.97, found 277.05, 279.05; 'H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J= 2.3 Hz, 1H), 7.27 (d, J= 2.3 Hz, 1H), 3.95-3.88 (m, 4H), 3.14-3.08 (m, 4H).
[00193] Step 2: 4-{5-Chloro-2-[2-(trimethylsilyl)ethynyl]pyridin-3-yl}morpholine step 2
Figure imgf000098_0001
[00194] To a stirred mixture of 4-(2-bromo-5-chloropyridin-3-yl)morpholine (2.5 g, 9.00 mmol), Cui (0.34 g, 1.80 mmol) and Pd(PPh3)2Cl2 (0.63 g, 0.90 mmol) in N,N -di methyl form am ide (25 mL) were added TEA (2.73 g, 27.02 mmol) and trimethylsilylacetylene (1.33 g, 13.51 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/ EA (10/1). The fractions containing desired product were combined and concentrated to afford 4-{5-chloro-2-[2- (trimethylsilyl)ethynyl]pyridin-3-yl}morpholine (2.3 g, 86%) as a yellow oil. MS ESI calculated for C14H19C1N2OSi. [M + H]+, 295.10, found 295.10; 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J= 2.0 Hz, 1H), 7.21 (d, J= 2.1 Hz, 1H), 3.93-3.87 (m, 4H), 3.31-3.24 (m, 4H), 0.30 (s, 9H).
[00195] Step 3: 2-Fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(trimethylsilyl)ethynyl]pyridin-3- yl]aniline
Figure imgf000099_0001
[00196] To a stirred mixture of 4-{5-chloro-2-[2-(trimethylsilyl)ethynyl]pyridin-3-yl]morpholine (2 g, 6.78 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.7 g, 6.78 mmol) in tetrahydrofuran (20 mL) and water (2 mL) were added 2nd Generation XPhos Precatalyst (0.53 g, 0.67 mmol), K3PO4 (2.8 g, 13.56 mmol) at room temperature. 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). The fractions containing desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[5-(morpholin- 4-yl)-6-[2-(trimethylsilyl)ethynyl]pyridin-3-yl]aniline (1 g, 38%) as a yellow oil. MS ESI calculated for C21H26FN3OSi [M + H]+, 384.18, found 384.20.
[00197] Step 4: 5-[6-Ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylaniline
Figure imgf000099_0002
[00198] To a stirred mixture of 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2- (trimethylsilyl)ethynyl]pyridin-3-yl]aniline (2 g, 5.22 mmol) in methyl alcohol (20 mL) was added potassium carbonate (1.44 g, 10.44 mmol) in portions at room temperature. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/ EA (1/1). The fractions containing desired product were combined and concentrated to afford 5-[6-ethynyl-5-(morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylaniline (0.77 g, 47%) as a light yellow solid. MS ESI calculated for C18H18FN3O [M + H]+, 312.14, found 312.05; 1H NMR (400 MHz, DMSO-d6 ) 6 8.09 (d, J= 1.8 Hz, 1H), 7.29 (d, J= 1.9 Hz, 1H), 6.97 (d, J= 12.3 Hz, 1H), 6.69 (d, J= 9.3 Hz, 1H), 5.03 (s, 2H), 4.56 (s, 1H), 3.76 (dd, J= 5.9, 3.3 Hz, 4H), 3.21-3.15 (m, 4H), 2.09 (s, 3H).
[00199] 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
Figure imgf000100_0001
[00200] To a stirred mixture of 4-fluoro-3-(2-fluoropropan-2-yl)benzoic acid (75.50 mg, 0.32 mmol) in Propylphosphonic anhydride (1 mL) and Pyridine (1 mL) was added 5-[6-ethynyl-5-(morpholin- 4-yl)pyridin-3-yl]-2-fluoro-4-methylaniline (100 mg, 0.32 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. 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. The fractions containing desired product were combined and concentrated to afford A-{5-[6-ethynyl-5- (morpholin-4-yl)pyridin-3-yl]-2-fluoro-4-methylphenyl}-4-fluoro-3-(2-fluoropropan-2- yl)benzamide (21.7 mg, 13%) as a white solid. MS ESI calculated for C28H26F3N3O2 [M + H]+, 494.20, found 494.20. 'H NMR (400 MHz, CDCh) δ 8.32 (d, J= 8.0 Hz, 1H), 8.24 (d, J= 2.0 Hz, 1H), 8.07-8.04 (m, 1H), 8.00 (s, 1H), 7.90-7.86 (m, 1H), 7.22-7.17 (m, 2H), 7.12 (d, J= 11.6 Hz, 1H), 3.94-3.91 (m, 4H), 3.53 (s, 1H), 3.31-3.28 (m, 4H), 2.27 (s, 3H), 1.83 (d, J= 1.2 Hz, 3H), 1.77 (d, J = 1.2 Hz, 3H). [00201] The following compounds in Table 10 were prepared using procedures similar to those described in Example 25, 26, 27, 28 using appropriate starting materials.
Table 10
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0002
II. Biological Evaluation
[00202] Example 1: Kinase assay protocol
Enzymatic BRAF and RAF1 Kinase Activity Determination:
Small molecule inhibition of the BRAF and RAFI kinases was measured using ADP-Glo assay. In the 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. 14-420) were incubated with 3 pM ATP, 10 mM MgC12, 0.003% Brij-35, 2 mM DTT, 0.05% BSA, 1 mM EGTA, and 50 mM HEPES for 90 minutes at room temp prior to addition of ADP-Glo reagent (Promega, Cat. V9102) for 40 minutes, and detection reagent for 45 minutes. Luminescence was read on an Envision plate reader (PerkinElmer) and percent remaining activity was used to calculate IC50 using a four-parameter fit model using Dotmatics Knowledge Solutions Studies curve fitting (Dotmatics, Bishops Stortford, UK, CM23).
[00203] Representative data for exemplary compounds is presented in Table 11.
Table 11
Figure imgf000123_0001
Figure imgf000124_0001
III. Preparation of Pharmaceutical Dosage Forms
Example 1: Oral capsule
[00204] 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.
Example 2: Solution for injection
[00205] 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.
[00206] 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):
Figure imgf000126_0001
wherein,
X is independently N or C-H;
Y is independently N or C-H;
R is selected from H, -C(R1)(R2)(R3), optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
R1 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
R2 is selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl;
R3 is selected from H, -OH, -OR4, -NH2, -NHR4, -N(R4)2, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each R4 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl or optionally, R2 and R4 join to form a ring; and
Z is an optionally substituted aryl or optionally substituted heteroaryl.
2. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein X is N, and Y is C-H.
3. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein X is N, and Y is N.
4. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H, and Y is N.
5. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, wherein X is C-H, and Y is C-H.
6. The compound of any one of claims 1-5, or pharmaceutically acceptable salt or solvate thereof, wherein R is H. The compound of any one of claims 1-5, or pharmaceutically acceptable salt or solvate thereof, wherein R is -C(R1)(R2)(R3). The compound of claim 7, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is H. The compound of claim 7, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted C1-C6 alkyl. The compound of claim 7, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted C3-C7 cycloalkyl. The compound of any one of claims 7-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. The compound of any one of claims 7-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is optionally substituted C1-C6 alkyl. The compound of any one of claims 7-10, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is optionally substituted C3-C7 cycloalkyl. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NH2. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NHR4. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R4)2. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR4. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted heterocyclyl. The compound of any one of claims 7-13, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted heteroaryl. The compound of any one of claims 16-18, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C6 alkyl. The compound of any one of claims 16-18, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C6 acyl. The compound of any one of claims 16-18, or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R4 join to form a ring. The compound of any one of claims 1-5, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted cycloalkyl. The compound of claim 24, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkyl is an optionally substituted C3-C6 cycloalkyl. The compound of claim 24, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted cycloalkyl is an optionally substituted cyclopropyl. The compound of any one of claims 1-5, or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted heterocyclyl. The compound of claim 27, 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. The compound of claim 28, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted O-containing heterocyclyl. The compound of claim 29, 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. The compound of claim 28, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted N-containing heterocyclyl. The compound of claim 29, 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. The compound of claim 28, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heterocyclyl is an optionally substituted S-containing heterocyclyl. The compound of any one of the preceding claims, or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted aryl. The compound of claim 34, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl. The compound of claim 35, 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. The compound of any one of claims 1-33, or pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted heteroaryl. The compound of claim 37, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted six-membered heteroaryl. The compound of claim 38, 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. The compound of claim 38 or 39, 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. A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1 - 41 and a pharmaceutically acceptable excipient. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1 - 41, and a pharmaceutically acceptable carrier. A compound of any one of claims 1 - 41, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. A compound of any one of claims 1 - 41, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. Use of a compound of any one of claims 1 - 41, or 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 as described in any one of claims 1 - 41, or 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 as described in any one of claims 1 - 41, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
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