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WO2024178304A1 - Modulateurs de kras - Google Patents

Modulateurs de kras Download PDF

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Publication number
WO2024178304A1
WO2024178304A1 PCT/US2024/017034 US2024017034W WO2024178304A1 WO 2024178304 A1 WO2024178304 A1 WO 2024178304A1 US 2024017034 W US2024017034 W US 2024017034W WO 2024178304 A1 WO2024178304 A1 WO 2024178304A1
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Prior art keywords
compound
pharmaceutically acceptable
solvate
acceptable salt
optionally substituted
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Inventor
Michael David Bartberger
Yi Fan
Eric Anthony MURPHY
Xuefeng Zhu
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Alterome Therapeutics Inc
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Alterome Therapeutics Inc
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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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • KRAS Zirsten rat sarcoma viral oncogene homologue
  • KRAS protein is a GTPase and involved in cellular signaling such as regulation of cell proliferation.
  • KRAS can activate cellular signaling pathways including, but not limited to, the mitogen-activated protein kinase (MAPK) pathway.
  • MAPK mitogen-activated protein kinase
  • X 1 is N or C-CN
  • X 2 is N, C-H, C-F, or C-Cl
  • X 3 is N, C-H, C-F, C-Cl, or C-CF3
  • X 4 is O, S, or NR 5
  • X is O, S, or NR 5
  • Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system
  • One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: WSGR Docket No. 62619-720.601 wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; X 3 is N, C-H, C-F, C-Cl, or C-CF 3 ; X 4 is O, S, or NR 5 ; X is O, S, or NR 5 ; Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system; R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected from hydrogen or optionally substituted C1-C4 alkyl; each R 5 is hydrogen or optionally substituted C1-C4 alkyl; W is a O, -CH
  • X 3 is N, C-H, C-F, C-Cl, or C-CF 3 ;
  • X 4 is O, S, or NR 5 ;
  • X is O, S, or NR 5 ;
  • Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system;
  • R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected from hydrogen, deuterium, or optionally substituted C1-C4 alkyl;
  • each R 5 is hydrogen or optionally substituted C1-C4 alkyl;
  • Y is a divalent moiety selected from: (a) , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms; (b) wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms;
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • One embodiment provides a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (II), (III), wherein the KRAS protein is contacted in an in vitro setting.
  • One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (II), (III), wherein the KRAS protein is contacted in an in vivo setting.
  • “Amino” refers to the –NH 2 radical.
  • “Cyano” refers to the -CN radical.
  • “Nitro” 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., C 1 -C 15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., C1-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., C 1 -C 4 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., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl).
  • an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec- butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , - C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(
  • an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.
  • 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.
  • an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.
  • the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, - N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)
  • 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, WSGR Docket No.
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., 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., C 3 -C 5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , - N(R a )S(O)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., C 2 -C 5 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., C 2 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) t R a (where t is 1 or 2),
  • 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). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkynylene).
  • 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)tR a (where t is 1 or
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) –electron system in accordance with the Hückel theory.
  • aryl groups 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 optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, - R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b
  • “Aralkyl” refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • “Aralkenyl” refers to a radical of the formula –R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • “Aralkynyl” refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms.
  • the carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as “cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as “cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted exocyclic alkylidene, halo, oxo, thioxo, cyano, nitro, -R b -OR a , -R b - OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b - C(O)N(R a )2, -R b -O-
  • each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain
  • R c is a straight or branched alkylene or alkenylene chain
  • each of the R a , R b , or R c substituents is unsubstituted unless otherwise indicated.
  • “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. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, 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 optionally substituted alkyl, optionally WSGR Docket No.
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, 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 WSGR Docket No. 62619-720.601 heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O- R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) –electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
  • 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.
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b - OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -N(R a ) 2 , -R b -N(R
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the WSGR Docket No. 62619-720.601 heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula –O- R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • tautomeric equilibrium includes: WSGR Docket No. 62619-720.601
  • 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, for example, 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, in some instances, improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated.
  • isotopic substitution with 18 F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • WSGR Docket No. 62619-720.601 [0068] 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.
  • Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate.
  • CD3I is illustrated, by way of example only, in the reaction schemes below.
  • Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4) are employed to transfer deuterium under reducing conditions to the reaction substrate.
  • LiAlD4 is 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.
  • the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the KRAS inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. Aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable.
  • salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results WSGR Docket No.
  • 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.
  • Ras proteins are important for activating signaling networks for controlling cell differentiation, proliferation, and survival, encoded by three genes HRAS, KRAS, and NRAS. The three genes share significant sequence homology and largely overlapping functions. Activation of RAS is facilitated by guanine nucleotide exchange factors (GEF), and activation causes conformational changes.
  • GEF guanine nucleotide exchange factors
  • the KRAS gene encodes two highly related protein isoforms, KRAS-4A and KRAS-4B, which comprise of 189 and 188 amino acids.
  • KRAS generally refers to KRAS-4B, because of the high level of mRNA encoding KRAS-4B in cells.
  • KRAS has two major domains, the catalytic G domain and a hypervariable region (HVR).
  • HVR hypervariable region
  • KRAS G domain is the basis of biological function of GTPase proteins.
  • the G domain comprises 6 beta-strands of the protein core, surrounded by five alpha-helices, and comprises residues 1-166.
  • the G domain also consists of other regions: switch I, switch II, and the P loop.
  • KRAS-GTP binding alters the conformation of the switches I and II in the G domain. When activated, KRAS binds to its downstream molecules as monomers or dimers to mediate series of signaling cascades.
  • KRAS also has a flexible C-terminal, the hypervariable region (HVR), which is important for localizing KRAS to the membrane.
  • HVR hypervariable region
  • the RAS family comprises three isoforms, but about 85% of RAS-related cancers are caused by mutations in the KRAS isoform.
  • the mutations in KRAS isoform occurs most frequently in solid tumors such as colorectal carcinoma, lung adenocarcinoma, and pancreatic ductal carcinoma.
  • nearly 80% of KRAS mutant tumors are located within codon 12, with the most common mutations being p.G12D, p.G12V, and p.G12C.
  • KRAS protein functions as a molecular switch in growth factor signaling pathways by regulating proliferation by alternating between a GDP-bound inactive form and a GTP-bound WSGR Docket No. 62619-720.601 active form.
  • the GTP-bound active form is capable of engaging downstream effector proteins to trigger a pro-proliferative response. This regulation cycle is impaired by mutations in codon 12 which disrupts association of GTPase activating proteins, which impairs the inactivation of KRAS, which leads to accumulation of the pro-proliferative form.
  • EGF epidermal growth factor
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factors
  • Upstream regulation can promote binding of GTP and KRAS, converting KRAS from an inactive to an active state.
  • Molecules upstream of KRAS mainly mediate the activation or inactivation of KRAS by regulating guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386).
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase-activating proteins
  • SHP2 Src homology phosphatase 2
  • SHP2 is a common signaling regulatory that mediates receptor tyrosine kinases signals to KRAS-ERK signaling, and dephosphorylation substrates of SHP2 have been shown to promote KRAS activation.
  • the RAF-MEK-ERK pathway is a downstream target of KRAS signaling.
  • Another pathway KRAS involved in is the PI3K-AKT-mTOR pathway (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386).
  • KRAS was previously considered to be an undruggable protein, but recently there have been advances in targeting codon 12, and specifically in G12C inhibitors. Many efforts have been focused on indirectly targeting KRAS, so there remains an unmet need of targeting KRAS, which the compounds provided herein fulfill. With the discovery of a new allosteric site of KRAS, G12C, several covalently binding inhibitors of KRAS have emerged and are under clinical investigation. However, KRAS inhibition is a complex issue with a lack of understanding of the underlying principles, and there still remains an unmet need for new inhibitors which target other KRAS mutations such as, but not limited to G12D and G12V.
  • KRAS mutations are frequently found in colorectal cancer, pancreatic cancer, and non- small cell lung cancer (M.H. Hofmann et al., Cancer Discov 2022; 12:924-37).
  • the KRAS allelic distribution varies between the tumor types, with G12C mutations in 13.6% of lung adenocarcinomas, whereas the G12D and G12V mutations are most common in colorectal and pancreatic cancer.
  • the G12D, G12V, and G12C mutations are the three most frequent allele mutations.
  • KRAS mutations, especially at codon 12 is strongly associated with cellular KRAS dependency, indicating that KRAS acts as an oncogenic driver.
  • KRAS G12C inhibitors such as sotorasib (AMG510) and adagrasib (MRTX849). Sotorasib is the first to be approved for clinical use. Both inhibitors rely on the interaction with the nucleophilic cysteine 12 in the GDP state and occupy the switch II pocket.
  • KRAS inhibitory compounds are KRAS inhibitory compounds.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; X 3 is N, C-H, C-F, C-Cl, or C-CF 3 ; X 4 is O, S, or NR 5 ; X is O, S, or NR 5 ; Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system; R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, ; and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected from hydrogen, deuterium, or optionally substituted C1-C4 alkyl; each R 5 is hydrogen or optionally
  • One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; WSGR Docket No.
  • X 3 is N, C-H, C-F, or C-Cl;
  • X 4 is O, S, or NR 5 ;
  • X is O, S, or NR 5 ;
  • Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system;
  • R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, ; and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected from hydrogen, deuterium, or optionally substituted C1-C4 alkyl;
  • each R 5 is hydrogen or optionally substituted C1-C4 alkyl;
  • Y is a divalent moiety selected from: (a) –(CH2)m-, wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms; (b) -(CH 2 )p-O-(CH 2 )q-, wherein up to 4
  • One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is –(CH 2 )m-. [0095] One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is –(CH2)-. [0096] One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is –(CH2CH2)-.
  • One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH 2 )p-O-(CH 2 )q-. [0098] One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH 2 )-O-(CH 2 )-. [0099] One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -( CH2CH2)-O-(CH2)-.
  • One embodiment provides the compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH 2 )-O-(CH 2 CH 2 )-.
  • One embodiment provides a compound having the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; X 3 is N, C-H, C-F, C-Cl, or C-CF 3 ; X 4 is O, S, or NR 5 ; X is O, S, or NR 5 ; Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system; R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, ; and G is an optionally substituted 5- to 10-membered heterocyclyl; WSGR Docket
  • each R is independently selected from hydrogen or optionally substituted C1-C4 alkyl; each R 5 is hydrogen or optionally substituted C1-C4 alkyl; Y is a divalent moiety selected from –(CH2)m-, or –(CH2)p-O-(CH2)q-; n is 0, 1, 2, 3, 4, 5, or 6; m is 1-9; p is 1-4; and q is 1-4.
  • One embodiment provides a compound having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; X 3 is N, C-H, C-F, or C-Cl; X 4 is O, S, or NR 5 ; X is O, S, or NR 5 ; Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system; R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, ; and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected from hydrogen or optionally substituted C1-C4 alkyl; each R 5 is hydrogen or optionally substituted C1-C4 alkyl; Y is a divalent moiety selected from –(CH2)m-, or –(CH2)p-O
  • One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is –(CH 2 )m-. [0104] One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is –(CH 2 )-. WSGR Docket No. 62619-720.601 [0105] One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is –(CH2CH2)-.
  • One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH 2 )p-O-(CH 2 )q-. [0107] One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH2)-O-(CH2)-. [0108] One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH2CH2)-O-(CH2)-.
  • One embodiment provides the compound of Formula (Ib) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -(CH 2 )-O-(CH 2 CH 2 )-.
  • One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; X 3 is N, C-H, C-F, C-Cl, or C-CF 3 ; X 4 is O, S, or NR 5 ; X is O, S, or NR 5 ; Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system; R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, ; and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected
  • R 3 is hydrogen, R 2 is alkyl, R 4 is alkyl, and R 2 and R 4 join to form a ring; or R 2 is hydrogen, R 3 is alkyl, R 4 is alkyl, and R 3 and R 4 join to form a ring; or R 2 is hydrogen, and R 3 and R 4 join to form a -CH2OCH2- group; or R 2 is hydrogen, and R 3 and R 4 join to form an -O- group; and n is 0, 1, 2, 3, 4, 5, or 6.
  • One embodiment provides a compound having the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: wherein: X 1 is N or C-CN; X 2 is N, C-H, C-F, or C-Cl; X 3 is N, C-H, C-F, or C-Cl; X 4 is O, S, or NR 5 ; X is O, S, or NR 5 ; Ar is a monocyclic or bicyclic optionally substituted aryl or heteroaryl ring system; R 1 is L-G; wherein L is a bond, optionally substituted C1-C4 alkylene, ; and G is an optionally substituted 5- to 10-membered heterocyclyl; each R is independently selected from hydrogen or optionally substituted C1-C4 alkyl; each R 5 is hydrogen or optionally substituted C1-C4 alkyl; W is a O, -CH 2 -, or -CD 2 -; R 3 is hydrogen, R
  • One embodiment provides a compound having the structure of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. [0113] One embodiment provides a compound having the structure of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is -CH2-, or -CD2-. WSGR Docket No. 62619-720.601 [0114] One embodiment provides a compound having the structure of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 and R 4 join together to form a - CH2CH2-.
  • One embodiment provides a compound having the structure of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 join together to form a - CH2CH2-.
  • One embodiment provides a compound having the structure of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 join together to form a - CH2CH2CH2-.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms. [0119] One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is , wherein up to 4 hydrogen atoms are optionally replaced with deuterium or fluorine atoms.
  • One embodiment provides the compound wherein W is oxo.
  • One embodiment provides the compound wherein W is oximo.
  • One embodiment provides the compound wherein W is optionally substituted alkyl oximo.
  • One embodiment provides the compound wherein W is O-methyl oximo.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is an optionally substituted C1 alkyl.
  • One embodiment provides a compound having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2; and q is 1 or 2. [0128] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is N. [0129] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is C-CN.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is N.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 is C-H, C-F, or C-Cl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is N.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is C-H, C-F, or C-Cl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 3 is C-CF 3 .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X 4 is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted aryl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is an optionally substituted naphthyl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted naphthyl is an optionally substituted 1-naphthyl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 1-naphthyl is further substituted at the 8-position.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted aryl is described by Formula (a): wherein: R 12 is hydrogen; R 13 is -OH, -NH2, Cl, -OCONHMe, -NHCO2Me; R 14 is hydrogen; R 15 is hydrogen or F; R 16 is hydrogen or F; R 17 is fluorine or -CN; and R 18 3, -OCD3, -OCH2F, or -OCD2F.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: WSGR Docket No. 62619-720.601 [0144] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: [0145] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: [0147]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is: .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: [0150]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a bicyclic optionally substituted heteroaryl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is described by Formula (b): wherein: R 12 is hydrogen; R 13 is -OH, -NH2, Cl, -OCONHMe, -NHCO2Me; R 14 is hydrogen; R 16 is hydrogen or F; R 17 is fluorine or -CN; and R 18 3 , -OCD 3 , -OCH 2 F, or -OCD 2 F.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from: WSGR Docket No. 62619-720.601 .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic optionally substituted heteroaryl is selected from: [0155]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is an optionally substituted phenyl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted phenyl is substituted with an -OH group at the 3-position.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from:
  • WSGR Docket No. 62619-720.601 One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: .
  • WSGR Docket No. 62619-720.601 One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: [0162]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is selected from: WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is a bond.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1-C4 alkylene.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is optionally substituted C1 alkylene.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III),or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is an optionally substituted 5- to 10-membered heterocyclyl.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: WSGR Docket No. 62619-720.601 [0171] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: .
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is described by Formula (c): wherein, each R 20 -R 30 is independently selected from hydrogen or deuterium.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is described by Formula (d): wherein, R 31 is selected from hydrogen, F, Cl, -CN, -OH, or optionally substituted C1-C4 alkyl; R 32 is hydrogen, deuterium or optionally substituted C1-C4 alkyl; and R 33 is hydrogen, deuterium, or F.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: [0176]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from:
  • [0177] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: [0179]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: [0180]
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein G is selected from: Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O. [0182] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: . Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O. WSGR Docket No.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O. [0184] One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: , WSGR Docket No. 62619-720.601 .
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: , .
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III),or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: .
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • WSGR Docket No. 62619-720.601 One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: .
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: WSGR Docket No. 62619-720.601 embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • R 1 is selected from: , .
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: WSGR Docket No. 62619-720.601 .
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: , , , , , , . provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • R 1 is selected from: WSGR Docket No.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X is O.
  • One embodiment provides the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from: [0197]
  • One embodiment provides a compound of the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having a structure represented in Fig.1.
  • One embodiment provides a compound of the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having a structure represented in Fig.2.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, WSGR Docket No. 62619-720.601 Formula (I), wherein the portion of the structure of Formula (I) enclosed within the box is provided in Fig.3, Fig.4, Fig.5, or Fig.6.
  • One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Formula (II), wherein the portion of the structure of Formula (II) enclosed within the box is provided in Fig.7, Fig.8, Fig.9, or Fig.10.
  • One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.
  • WSGR Docket No. 62619-720.601 Table 1 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-
  • WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601
  • WSGR Docket No. 62619-720.601 WSGR Docket No. 62619-720.601
  • One embodiment provides a KRAS inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.
  • Table 2 WSGR Docket No. 62619-720.601
  • WSGR Docket No. 62619-720.601 Preparation of Compounds [0203]
  • the compounds used in the synthetic chemistry 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.
  • 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,” 2 nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2 nd Ed., W. A. Benjamin, Inc. Menlo WSGR Docket No. 62619-720.601 Park, Calif.1972; T. L.
  • the KRAS inhibitory compound described herein is administered as a pure chemical.
  • the KRAS 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) WSGR Docket No. 62619-720.601 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 KRAS 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)
  • the carrier(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 comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), 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), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the KRAS inhibitory compound as described by Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, 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.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any of Figures 1-10, or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the KRAS inhibitory compound as described by Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, 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.
  • 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 KRAS inhibitory compound as described by Formula (I), or Table 1 or Table 2, 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 KRAS 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.
  • 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.
  • 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. [0218] 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), (Ia), (Ib), (Ic), (II), (IIa), or (III), 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), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.
  • WSGR Docket No. 62619-720.601 Another embodiment provides the method wherein the cancer is lung cancer, non-small cell lung cancer, or colorectal cancer.
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a use of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), 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), (Ia), (Ib), (Ic), (II), (IIa), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • Another embodiment provides the method wherein the cancer is lung cancer, non-small cell lung cancer, or colorectal cancer.
  • One embodiment provides a compound of Table 1 or Table 2, 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 Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer.
  • Another embodiment provides the method wherein the cancer is lung cancer, non-small cell lung cancer, or colorectal cancer.
  • One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a use of a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Table 1 or Table 2, 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 Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate WSGR Docket No. 62619-720.601 thereof, and a pharmaceutically acceptable excipient.
  • Another embodiment provides the method wherein the cancer is lung cancer, non-small cell lung cancer, or colorectal cancer.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of any one of Figures 1-10, 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 any one of Figures 1-10, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • Another embodiment provides the method wherein the cancer is lung cancer, non-small cell lung cancer, or colorectal cancer.
  • One embodiment provides a method of inhibiting KRAS protein activity comprising contacting the KRAS protein with a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), or (III), or Table 1 or Table 2. Another embodiment provides the method of inhibiting KRAS protein activity, wherein the KRAS protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting KRAS protein activity, wherein the KRAS protein is contacted in an in vitro setting.
  • Step 2 2,6-Dichloro-3-fluoro-5-iodopyridin-4-amine
  • 2-iodopyrrolidine-2,5-dione 112 g, 497 mmol
  • 4-methylbenzenesulfonic acid monohydrate 3.94 g, 20.7 mmol
  • the reaction mixture was stirred at 70 °C for 4 h.
  • the reaction mixture was quenched with Na2SO3 (200 mL) at 20 °C and extracted with EtOAc (500 mL x 3).
  • Step 3 Ethyl 4-amino-2,6-dichloro-5-fluoronicotinate WSGR Docket No. 62619-720.601 [0240] To a mixture of 2,6-dichloro-3-fluoro-5-iodo-pyridin-4-amine (42 g, 137 mmol), TEA (66. 7 mL, 479 mmol) and dichloropalladiumtriphenylphosphane (4.80 g, 6.84 mmol) in EtOH (1050 mL) was purged with CO three times, and the mixture was stirred under CO (1.5 Mpa) at 100 °C for 40 h in a 2000 mL of autoclave.
  • Step 5 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione
  • ethyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate 50.6 g, 115 mmol
  • MeOH 500 mL
  • NH3 in MeOH 7 M, 45.81 mL
  • Step 6 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol
  • 5 To a solution of 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (10 g, 40.0 mmol) in POCl3 (100 mL) was added DIPEA (20.9 mL, 120 mmol). The mixture was stirred at 105 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 1,4-dioxane (40 mL) and the resulting solution was added dropwise to aq. K2CO3 (20%, 200 mL).
  • Step 2 2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [0251] To a solution of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- 10% purity). The suspension was degassed, purged with H2 three times, and stirred at 25 °C for 16 h under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure.
  • Step 2 2-(8-(Ethynyl-d)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane
  • 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.9 g, 5.334 mmol) in MeCN (30 mL) under nitrogen atmosphere were added K2CO3 (2.21 g, 16.002 mmol) and D2O (3.0 mL, 164.778 mmol) at room temperature.
  • Step 3 2-(8-(Ethyl-d5)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane [0258] To a solution of 2-(8-(ethynyl-d)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.5 g, 4.199 mmol) in EtOAc (38 mL) under nitrogen atmosphere was added PtO 2 (0.14 g, 0.630 mmol) at room temperature.
  • Step 2 2-(7-Fluoro-3-(methoxymethoxy)-8-vinylnaphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane
  • 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 13.0 g, 36.5 mmol
  • quinoline (6.00 g, 46.5 mmol, 5.48 mL) in methanol (50.0 mL) was added Lindlar catalyst (7.80 g, 37.8 mmol).
  • Step 1 tert-Butyl (S)-2-(hydroxymethyl)azepane-1-carboxylate
  • BH 3 61.72 mL, 61.72 mmol, 1M in THF
  • Step 2 (S)-Azepan-2-ylmethanol [0268] To an ice-cooled solution of tert-butyl (S)-2-(hydroxymethyl)azepane-1-carboxylate (30 g, 130.82 mmol) in DCM (300 mL) was added 4N HCl (gas) in 1,4-dioxane (300 mL, 9873.83 mmol) dropwise. The reaction mixture was stirred in an ice bath for 1.5 hours. The ice bath was removed, and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL), and Amberlyst-A-21 resin (8 g) was added at room temperature.
  • Step 3 (S)-5-(Azepan-2-ylmethoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol
  • NaH 0.89 g, 37.25 mmol, 60% in mineral oil
  • Step 3 (S)-5-(Azepan-2-ylmethoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol
  • Step 4 (S)-2,5-Dichloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene [0272] To an ice-cooled solution of (S)-5-(azepan-2-ylmethoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-ol (1.9 g, 5.26 mmol) and DIEA (4.08 g, 31.56 mmol) in DCM (380 mL) under nitrogen atmosphere was added POCl3 (4.03 g, 26.30 mmol) dropwise.
  • Step 5 (S)-5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0274] To a mixture of (S)-2,5-dichloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- pyrrolizin-7a(5H)-yl)methanol (556.69 mg
  • Step 1 1-(tert-Butyl) 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2- dicarboxylate
  • TBSCl adazole-6.25 g, 91.734 mmol
  • the ice bath was removed, and the reaction mixture was stirred at room temperature for 16 hours.
  • Step 2 1-(tert-Butyl) 2-methyl (4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2- (chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate
  • 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate 15 g, 41.720 mmol
  • THF 300 mL
  • LiHMDS 54.24 mL, 54.236 mmol, 1M in THF
  • Step 3 1-(tert-Butyl) 2-methyl (4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2- dicarboxylate
  • 1-tert-butyl 2-methyl (4R)-4-[(tert-butyldimethylsilyl)oxy]-2-[2- (chloromethyl)prop-2-en-1-yl]pyrrolidine-1,2-dicarboxylate 36 g, 80.345 mmol
  • TBAF 96.41 mL, 96.414 mmol, 1M in THF
  • Step 4 1-(tert-Butyl) 2-methyl (4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2- dicarboxylate
  • 1-(tert-butyl) 2-methyl (4R)-2-(2-(chloromethyl)allyl)-4- hydroxypyrrolidine-1,2-dicarboxylate 7.8 g, 23.367 mmol
  • DCM DCM
  • BAST 7.75 g, 35.050 mmol
  • Step 7 ((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol & ((2S,7aS)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol [0289] To an ice-cooled solution of methyl (2S)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate (7.5 g, 37.646 mmol) in THF (75 mL) under N 2 atmosphere was added LiAlH 4 (37.65 mL, 75.292 mmol, 2M in THF) dropwise.
  • Step 1 (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H- pyrrolizine
  • TBDPSCl TBDPSCl
  • Step 2 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one & (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-3H- pyrrolizin-3-one (a mixture) [0294] To an ice-cooled solution of (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2- fluorohexahydro-1H-pyrrolizine (10 g, 25.15 mmol) and RuCl 3 .H 2 O (2.83 g, 12.57 mmol) in CCl 4 (50 mL) and H 2 O (50 mL) was added NaIO 4 (26.90 g, 125.75 mmol).
  • Step 3 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one & (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-3H- pyrrolizin-3-one & [0296] A mixture of (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one & (2R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-3H- pyrrolizin-3-one (6 g) was separated by Prep-Achiral-SFC with the following conditions: Column: 2, Mobile Phase B
  • Step 2 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-3,3-d2)methanol
  • (2R,7aS)-2-fluoro-7a-(hydroxymethyl)hexahydro-3H- pyrrolizin-3-one 400 mg, 2.310 mmol
  • LiAlD4 4.85 mL, 4.85 mmol, 1M in THF
  • Step 2 ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methanol
  • 6R,7aS -6-fluoro-7a-(hydroxymethyl)-tetrahydro-1H- pyrrolizin-3-one
  • LiAlD4 (1.82 mL, 1.819 mmol, 1M in THF
  • Step 2 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-ol
  • (2R,7aS)-2-fluoro-hexahydropyrrolizine-7a-carboxylic acid 200 mg, 1.155 mmol
  • Me-THF Me-THF
  • LiAlD4 2.43 mL, 2.425 mmol, 1M in THF
  • Step 2 ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-5,5-d2)methan-d2-ol
  • (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- carboxylic-5,5-d 2 acid 80 mg, 0.457 mmol
  • LiAlD4 0.96 mL, 0.960 mmol, 1M in THF
  • Step 2 4-(3,4-Difluorophenyl)-3-oxobutanoic acid [0321] To a stirred solution of 1,3-ditrimethylsilyl propanedioate (3.91 g, 15.74 mmol) in THF (50 mL) under nitrogen atmosphere was added n-BuLi (5.2 mL, 13.08 mmol, 2.5 M in n-Hexane) dropwise at -78 °C.
  • Step 3 6,7-Difluoronaphthalene-1,3-diol
  • a solution of 4-(3,4-difluorophenyl)-3-oxobutanoic acid (800 mg, 3.73 mmol) in trifluoromethanesulfonic acid (8 mL) under nitrogen atmosphere was stirred at 25°C for 16 hours.
  • the resulting mixture was diluted with EA (150 mL), washed with water (4 x 60 mL) and brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 6,7-Difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
  • 6 mL 1,4-dioxane
  • [Ru(p-cymene)Cl2]2 162.34 mg, 0.26 mmol
  • KOAc 520.35 mg, 5.30 mmol
  • Step 5 6,7-Difluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol
  • 627 To an ice-cooled solution of 6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (600 mg, 1.59 mmol) and DIEA (267.75 mg, 2.07 mmol) in DCM (6 mL) under nitrogen atmosphere was added bromo(methoxy)methane (189.18 mg, 1.51 mmol) dropwise.
  • Step 6 6,7-Difluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate
  • DCM dimethyl methoxycarbonate
  • Step 7 ((2,3-Difluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane [0331] To a stirred solution of 6,7-difluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (500 mg, 0.90 mmol) and WSGR Docket No.
  • Step 2 4-(3-Bromo-4-fluorophenyl)-3-oxobutanoic acid
  • 1,3-ditrimethylsilyl propanedioate 23.71 g, 95.43 mmol
  • THF 250 mL
  • n-BuLi 2.5 M in n-hexane, 32 mL, 80 mmol
  • Step 3 6-Bromo-7-fluoronaphthalene-1,3-diol
  • Step 4 ((6-Bromo-7-fluoronaphthalene-1,3-diyl)bis(oxy))bis(tert-butyldimethylsilane) [0340] To an ice-cooled solution of 6-bromo-7-fluoronaphthalene-1,3-diol (5.0 g, 19.44 mmol) in DCM (50 mL) under nitrogen atmosphere were added Et3N (13.52 mL, 97.24 mmol) and TBSOTf (17.88 mL, 77.80 mmol) dropwise. The ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours.
  • Step 5 ((7-Fluoronaphthalene-1,3-diyl-6-d)bis(oxy))bis(tert-butyldimethylsilane)
  • Step 5 To a stirred solution of ((6-bromo-7-fluoronaphthalene-1,3-diyl)bis(oxy))bis(tert- butyldimethylsilane) (4.4 g, 9.06 mmol) in CH3OD (50 mL) under D2 atmosphere was added Pd/C (4.4 g, 10% wt) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under D 2 atmosphere. The resulting mixture was filtered and concentrated under reduced pressure.
  • Step 7 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-6-d-1,3-diol
  • Step 7 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-6-d-1,3-diol
  • Step 8 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-6-d-1-ol
  • Step 8 To an ice-cooled solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-6-d-1,3-diol (630 mg, 1.75 mmol) and DIEA (0.23 g, 1.75 mmol) in DCM (10 mL) under nitrogen atmosphere was added bromo(methoxy)methane (0.20 g, 1.58 mmol) dropwise.
  • Step 9 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl-6-d trifluoromethanesulfonate
  • DCM dimethyl methoxycarbonate
  • Step 10 ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl-3-d)ethynyl)triisopropylsilane [0352] To a stirred solution of 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl-6-d trifluoromethanesulfonate (610 mg, crude) and B2Pin2 (347.03 mg, 1.37 mmol) in 1,4-dioxane (7 mL) under nitrogen atmosphere were added KOAc (335.30 mg, 3.42 mmol) and Pd(dppf)Cl2.CH2Cl2 (83.33.
  • Step 1 6-Bromo-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
  • 6-bromo-7-fluoronaphthalene-1,3-diol (refer to Intermediate 15 for detail procedures, 2 g, 7.780 mmol) and [Ru(p-Cymene)Cl2]2 (0.48 g, 0.778 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere were added (2-bromoethynyl)tris(propan-2-yl)silane (2.24 g, 8.558 mmol) and KOAc (1.53 g, 15.560 mmol) at room temperature.
  • Step 2 6-Bromo-7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- ol
  • 6-bromo-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene- 1,3-diol (2 g, 4.572 mmol) and DIEA (768.23 mg, 5.944 mmol) in DCM (20 mL) under nitrogen atmosphere was added bromo(methoxy)methane (542.80 mg, 4.343 mmol) dropwise.
  • Step 3 3-Fluoro-5-hydroxy-7-(methoxymethoxy)-4-((triisopropylsilyl)ethynyl)-2- naphthonitrile
  • 6-bromo-7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-ol (1 g, 2.077 mmol) and Pd(PPh3)4 (1.20 g, 1.038 mmol) in DMF (10 mL) under nitrogen atmosphere was added Zn(CN) 2 (0.27 g, 2.285 mmol) at room temperature.
  • Step 4 6-Cyano-7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl trifluoromethanesulfonate
  • 3-fluoro-5-hydroxy-7-(methoxymethoxy)-4- ((triisopropylsilyl)ethynyl)-2-naphthonitrile 500 mg, 1.169 mmol
  • DIEA 453.40 mg, 3.507 mmol
  • Tf2O 494.88 mg, 1.754 mmol
  • Step 5 3-Fluoro-7-(methoxymethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- ((triisopropylsilyl)ethynyl)-2-naphthonitrile
  • 6-cyano-7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate 700 mg, crude
  • B 2 Pin 2 594.05 mg, 2.340 mmol
  • Pd(dppf)Cl2.CH2Cl2 85.59 mg, 0.117 mmol
  • KOAc 344.38 mg, 3.510 mmol
  • Step 2 (S)-Azepan-2-ylmethanol [0372] To a solution of (S)-azepane-2-carboxylic acid (2.2 g, 12.2 mmol) in THF (40 mL) was added dropwise LiAlH 4 (2.5 M in n-hexane, 24.5 mL) at 0 °C under N 2 atmosphere. The reaction was warmed up to 20 °C slowly and stirred for 1 h. Na 2 SO 4 ⁇ 10H 2 O (29.5 g, 90 mmol) was added into the mixture slowly at 0 °C, and the mixture was stirred for 30 min.
  • LiAlH 4 2.5 M in n-hexane, 24.5 mL
  • Step 1 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
  • Step 1 To a solution of 7-fluoronaphthalene-1,3-diol (50 g, 281 mmol) and 2- bromoethynyl(triisopropyl)silane (77 g, 295 mmol) in 1,4-dioxane (334 mL) were added KOAc (55.1 g, 561 mmol) and dichlororuthenium:1-isopropyl-4-methyl-benzene (17.2 g, 28.1 mmol).
  • Step 2 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3- diylbis(trifluoromethanesulfonate) [0377] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (140 g, 390 mmol) and DIPEA (408 mL, 2.34 mol) in CH2Cl2 (3.5 L) was added Tf2O (258 ml, 1.56 mol) dropwise under N 2 atmosphere at 0 °C.
  • Step 3 3-((Diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl trifluoromethanesulfonate WSGR Docket No.
  • Step 1 (2R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-fluoro-2,3,5,7a-tetrahydro- 1H-pyrrolizine
  • 6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro- 5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one (refer to Intermediate 36 for detail procedures, 1 g, 2.44 mmol) in DCM (100 mL) under nitrogen atmosphere was added tetrafluoroboranuide; trimethyloxidanium (1.81 g, 12.21 mmol) at room temperature.
  • Step 2 ((2R,7aR)-2-Fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluoro- 2,3,5,7a-tetrahydro-1H-pyrrolizine 200 mg, 0.50 mmol
  • TBAF 0.75 mL, 0.75 mmol, 1 M solution in THF
  • Step 1 (S)-5-Chloro-2,4-difluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene [0389] A solution of (S)-2,5-dichloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene (refer to Intermediate 5 for detail procedures, 1.2 g, 3.49 mmol) and KF (304.72 mg, 5.24 mmol) in DMSO (60 mL) under nitrogen atmosphere was heated at 80 °C for 16 hours.
  • Step 2 (S)-2,4-difluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene [0391] To a stirred mixture of (S)-5-chloro-2,4-difluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene (200 mg, 0.61 mmol) and ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y
  • Step 1 A mixture of ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate-2-d & ethyl (2R,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate- 2-d [0394] To an ice-cooled solution of ethyl 2,5-dioxo-tetrahydropyrrolizine-7a-carboxylate (20 g, 94.68 mmol) in ethyl alcohol (150 mL) was added NaBD4 (796.53 mg, 18.93 mmol).
  • Step 2 A mixture of ethyl (2S,7aR)-2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate-2-d & ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate-2-d [0396] To a stirred solution of ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate-2-d & ethyl (2R,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate- WSGR Docket No.
  • Step 3 A mixture of (6S,7aR)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolizin-3-one- 6-d & (6R,7aS)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolizin-3-one-6-d.
  • Step 4 A mixture of (6S,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro- 3H-pyrrolizin-3-one-6-d & (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro- 3H-pyrrolizin-3-one-6-d [0400] To an ice-cooled solution of a mixture of (6S,7aR)-6-fluoro-7a-(hydroxymethyl)hexahydro- 3H-pyrrolizin-3-one-6-d & (6R,7aS)-6-fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolizin-3-one- 6-d (500 mg, 2.87 mmol) and imidazole (390.81 mg, 5.74 mmol) in DMF (5 mL) under nitrogen atmosphere was added
  • Step 5 (6S,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one-6-d & (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one-6-d [0402] A mixture of (6S,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one-6-d & (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one-6-d (2.5 g, 6.06 mmol
  • the first eluting peak (RT1: 6.63 min) was concentrated under reduced pressure to give the title compound (Intermediate 24, 1 g, 40% yield) as a white solid.
  • 1 H NMR (400 MHz, DMSO-d6) 1H), 2.81 - 2.56 (m, 1H), 2.28 - 1.78 (m, 5H), 0.99 (s, 9H).
  • the second eluting peak (RT1: 8.07 min) was concentrated under reduced pressure to give the title compound (Intermediate 25, 1 g, 40% yield) as a white solid.
  • Step 2 ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2-d)methanol
  • 6R,7aS -6-fluoro-7a-(hydroxymethyl)hexahydro-3H- pyrrolizin-3-one-6-d
  • LiAlH4 4.8 mL, 4.8 mmol, 1 M in THF
  • Step 2 4-(3-Chloro-4-fluorophenyl)-3-oxobutanoic acid
  • 2-(3-chloro-4-fluorophenyl)acetyl chloride (10.9 g, crude) in THF (110 mL) under nitrogen atmosphere was added n-butyllithium (2.5 M in n-hexane, 25.2 mL, 63.17 mmol) dropwise at -78 °C.
  • the resulting mixture was stirred in an ice bath for 0.5 hours.
  • the reaction was quenched with sat. aq. NH 4 Cl (500 mL) in an ice bath and concentrated under reduced pressure.
  • the combined organic layers were washed with brine (500 mL), dried over WSGR Docket No. 62619-720.601 anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the residue was purified by silica gel flash chromatography, eluted with 0-50% EA in PE to afford the title compound (8 g, 65% yield for two steps) as a black oil.
  • Step 3 6-Chloro-7-fluoronaphthalene-1,3-diol
  • 4-(3-Chloro-4-fluorophenyl)-3-oxobutanoic acid (8 g, 34.68 mmol) was dissolved in CF3SO3H (150 mL) at room temperature, and the mixture was stirred at this temperature for 16 hours under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (800 mL), washed with water (4 x 300 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step 4 6-Chloro-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol
  • 6-chloro-7-fluoronaphthalene-1,3-diol 6.5 g, 30.57 mmol
  • 1,4- dioxane 65 mL
  • (2-bromoethynyl)triisopropylsilane 8787.10 mg, 33.63 mmol
  • [Ru(p-cymene)Cl2]2 (1872.31 mg, 3.05 mmol
  • KOAc (6001.16 mg, 61.14 mmol) at room temperature.
  • Step 5 6-Chloro-7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- ol
  • 6-chloro-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene- 1,3-diol (6 g, 15.26 mmol) and DIEA (2565.40 mg, 19.84 mmol) in DCM (60 mL) under nitrogen atmosphere was added bromo(methoxy)methane (1717.19 mg, 13.74 mmol) dropwise.
  • Step 6 6-Chloro-7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl trifluoromethanesulfonate WSGR Docket No.
  • Step 7 ((3-Chloro-2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane [0425] To a stirred solution of 6-chloro-7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5 g, crude) and bis(pinacolato)diboron (4462.29 mg, 17.57 mmol) in 1,4-dioxane (50 mL) under nitrogen atmosphere were added AcOK (2586.86 mg, 26.358 mmol) and Pd(dppf)Cl2•CH2Cl2 (715.73 mg, 0.87 mmol) at room temperature.
  • Step 2 A mixture of (6S,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 )-6- fluorohexahydro-3H-pyrrolizin-3-one-6-d & (6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl-d2)- 6-fluorohexahydro-3H-pyrrolizin-3-one-6-d [0430] To an ice-cooled solution of (6S,7aR)-6-fluoro-7a-(hydroxymethyl-d 2 )hexahydro-3H- pyrrolizin-3-one-6-d & (6R,7aS)-6-fluoro-7a-(hydroxymethyl-d2)hexahydro-3H-pyrrolizin-3-one-6- d (2.1 g mixture, 11.91 mmol) and 1H-imidazole (1.62 g, 23.83 mmol)
  • Step 2 ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-2,5,5-d3)methan-d2-ol
  • ((6R,7aS)-6-fluoro-7a-(hydroxymethyl-d2)hexahydro-3H- pyrrolizin-3-one-6-d (380 mg, 2.15 mmol) in 2-methyl-THF (4 mL) under nitrogen atmosphere was added LiAlD4 (4.53 mL, 4.53 mmol) dropwise. The ice bath was removed, and the resulting mixture was stirred at room temperature for 1 hour.
  • Step 2 (6R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluoro-5,6,7,7a-tetrahydro- 3H-pyrrolizin-3-one
  • 6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-2- (phenylselanyl)hexahydro-3H-pyrrolizin-3-one 5.2 g, 9.177 mmol
  • DCM 80 mL
  • H 2 O 2 (20 mL, 30% w/w
  • Step 3 ((6R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluoro-3-oxohexahydro-1H- pyrrolizin-1-yl)boronic acid
  • 6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro- 5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one 800 mg, 1.953 mmol) in EtOH (20 mL) were added 2- (Dicyclohexylphosphino)biphenyl (68.46 mg, 0.195 mmol), CuCl (19.34 mg, 0.195 mmol), (dihydroxyboranyl)boronic acid (210.13 mg, 2.344 mmol) and t-BuONa (56.31 mg, 0.586 mmol) at room temperature
  • Step 4 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,6-difluorohexahydro-3H- pyrrolizin-3-one
  • ((6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-3- oxohexahydro-1H-pyrrolizin-1-yl)boronic acid 600 mg, 1.317 mmol
  • AgNO 3 (223.81 mg, 1.317 mmol
  • Selectfluor (2.80 g, 7.902 mmol) in DCM (9 mL) were added H2O (9 mL), H3PO4 (1.2 mL, 20.634 mmol) and TFA (4.8 mL, 64.623 mmol) under nitrogen atmosphere.
  • the resulting mixture was quenched with MeOH (40 mL) and 2 M HCl (40 mL) in an ice bath, and then heated at 60 °C for another 1 hour. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was diluted with EtOAc (80 mL) and saturated aqueous NaHCO 3 (100 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step 6 ((6R,7aS)-1,6-Difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6- difluorohexahydro-1H-pyrrolizine (680 mg, 1.636 mmol) in THF (7 mL) was added pyridine hydrofluoride (347.48 mg, 2.454 mmol, 70% w/w) at room temperature.
  • the reaction mixture was stirred at room temperature for 2 hours.
  • the resulting mixture was concentrated under reduced pressure.
  • Step 2 (2R)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,6-difluorohexahydro-1H- pyrrolizine
  • 6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6- difluorohexahydro-3H-pyrrolizin-3-one (2 g, 4.65 mmol) in THF (50 mL) under nitrogen atmosphere was added BH 3 •Me 2 S (2.33 mL, 23.3 mmol) dropwise.
  • the reaction mixture was heated at 60 °C for 16 hours.
  • Step 3 ((2R)-2,6-Difluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6- difluorohexahydro-1H-pyrrolizine (1.5 g, 3.60 mmol) in THF (30 mL) under nitrogen atmosphere was added TBAF (5.41 mL, 5.41 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure.
  • Step 1 (8aS)-5-Chloro-2-(((2R,7aS)-2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8- ab]heptalene [0466] To an ice-cooled solution of Intermediate 37 (182.2 mg, 1.02 mmol) in THF (5 mL) under nitrogen atmosphere was added NaH (51.41 mg, 1.28 mmol, 60% dispersion in mineral oil).
  • Step 2 (S)-5-Chloro-2-(((2R,6S,7as)-2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8- ab]heptalene & (S)-5-chloro-2-(((2R,6R)-2,6-difluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8- ab]heptalene [0468] (8aS)-5-Chloro-2-(((2R,7as)-2
  • the first eluting peak (RT1: 10.136 min) was concentrated and lyophilized to give the title compound (Intermediate 38, 48 mg, 20% yield) as an off-white solid.
  • the second eluting peak (RT2: 13.282 min) was concentrated and lyophilized to give the title compound (Intermediate 39, 130 mg, 54% yield) as an off-white solid.
  • Step 1 5-Chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene
  • 1-bromo-3-chloro-2,4-difluorobenzene 10 g, 43.97 mmol
  • furan 6.02 g, 88.38 mmol
  • n-BuLi 2.5 M in n-hexane, 21.00 mL, 52.5 mmol
  • the resulting mixture was stirred at -15 °C for 30 min. Then the resulting mixture was warmed to room temperature and stirred for another 16 hours.
  • Step 4 8-Chloro-7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl pivalate
  • 8-chloro-7-fluoronaphthalen-1-yl pivalate 2.5 g, 8.90 mmol
  • bis(pinacolato)diboron 2.26 g, 8.90 mmol
  • n-hexane 75 mL
  • Step 5 8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl pivalate
  • H2O2 4.87 g, 42.96 mmol, 30% aq.
  • AcOH 21.08 g, 350.99 mmol
  • Step 8 8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate
  • DCM 7.5 mL
  • DIEA 546.24 mg, 4.22 mmol
  • Tf2O 604.18 mg, 2.14 mmol
  • the resulting mixture was stirred at -40 °C for 1.5 hours.
  • the resulting mixture was diluted with H2O (15 mL) and extracted with EtOAc (3 x 80 mL).
  • Step 9 2-(8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane [0492] To a solution of 8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.05 g, crude) and AcOK (795.32 mg, 8.10 mmol) in 1,4-dioxane (12 mL) under nitrogen atmosphere were added bis(pinacolato)diboron (1.37g, 5.40 mmol) and Pd(dppf)Cl2•CH2Cl2 (220.05 mg, 0.27 mmol) at room temperature.
  • Step 2 3-((Diphenylmethylene)amino)-6,7-difluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate [0497] To a stirred solution of 6,7-difluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate) (3 g, crude), Pd2(dba)3 (428.83 mg, 0.468 mmol), XantPhos (812.90 mg, 1.405 mmol) and Cs 2 CO 3 (3051.55 mg, 9.366 mmol) in toluene (30 mL) was added diphenylmethanimine (933.59 mg, 5.151 mmol) at room temperature under nitrogen atmosphere.
  • Step 3 N-(6,7-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine [0499] To a stirred solution of 3-((diphenylmethylene)amino)-6,7-difluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2 g, 2.977 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.512 g, 5.954 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere were added KOAc (876.53 mg
  • Step 2 tert-Butyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate
  • a solution of 2,2-dimethyl-5-(2-(2,4,5-trifluorophenyl)acetyl)-1,3-dioxane-4,6-dione (40 g, 126.48 mmol) in 2-methyl-2-propanol (680 mL) was heated at 88 °C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with 0-10% EA in PE to afford the title compound (30 g, 82% yield) as a white oil.
  • Step 5 5,7,8-Trifluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol
  • DIEA 1,3-diol
  • chlorotriisopropylsilane 734.85 mg, 3.81 mmol
  • Step 7 Triisopropyl((5,6,8-trifluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-yl)oxy)silane
  • 514 To a stirred mixture of 5,7,8-trifluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (750 mg, 1.49 mmol), bis(pinacolato)diboron (757.97 mg, 2.98 mmol) and Pd(dppf)Cl 2 .DCM (121.58 mg, 0.14 mmol) in 1,4-dioxane (8 mL) was added KOAc (439.41 mg, 4.47 mmol) at room temperature under argon atmosphere.
  • Step 2 (5R,6aR)-6a-(((tert-Butyldiphenylsilyl)oxy)methyl)-5- fluorooctahydrocyclopropa[a]pyrrolizine
  • 5R,6aR -6a-(((tert-butyldiphenylsilyl)oxy)methyl)-5- fluorohexahydrocyclopropa[a]pyrrolizin-2(1H)-one
  • BH3•Me2S 0.413 mL, 4.13 mmol, 10M in DMS
  • Step 3 ((5R,6aR)-5-Fluorohexahydrocyclopropa[a]pyrrolizin-6a(4H)-yl)methanol
  • 5R,6aR -6a-(((tert-butyldiphenylsilyl)oxy)methyl)-5- fluorooctahydrocyclopropa[a]pyrrolizine (230 mg, 0.56 mmol) in THF (3.5 mL) was added TBAF (1 M in THF, 0.84 mL, 0.84 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure.
  • Step 1 (2R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H- pyrrolizine-3,3-d2
  • TBDPSCl 736.52 mg, 2.68 mmol
  • Step 3 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-3H- pyrrolizin-3-one-5,5-d 2
  • the mixture was separated by prep-Achiral-HPLC with the following conditions: Column: 2; Mobile Phase B: MeOH(0.1% 2 M NH 3 WSGR Docket No. 62619-720.601 Back Pressure(bar): 100; Detector: UV 220 nm; RT1 (min): 5.17; RT2 (min): 7.97.
  • Step 4 (6R,7aS)-6-Fluoro-7a-(hydroxymethyl)hexahydro-3H-pyrrolizin-3-one-5,5-d 2
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6- fluorohexahydro-3H-pyrrolizin-3-one-5,5-d 2 550 mg, 1.33 mmol
  • THF 5.5 mL
  • TBAF (1 M in THF, 1.46 mL, 1.463 mmol
  • Step 1 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluoro-2-hydroxyhexahydro- 3H-pyrrolizin-3-one
  • LDA 9.11 mL, 18.222 mmol
  • Step 2 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-1H- pyrrolizin-2-ol
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6- fluoro-2-hydroxyhexahydro-3H-pyrrolizin-3-one 100 mg, 0.234 mmol
  • THF 10 mL
  • BH 3 -Me 2 S (0.12 mL, 1.170 mmol
  • Step 3 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluorotetrahydro-1H- pyrrolizin-2(3H)-one
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6- fluorohexahydro-1H-pyrrolizin-2-ol 500 mg, 1.209 mmol
  • TEA 366.99 mg, 3.627 mmol
  • DCM 5 mL
  • DMSO DMSO
  • Step 4 (6R,7aS)-6-fluoro-7a-(hydroxymethyl)tetrahydro-1H-pyrrolizin-2(3H)-one
  • 6R,7aS -6-fluoro-7a-(hydroxymethyl)tetrahydro-1H-pyrrolizin-2(3H)-one
  • TBAF 0.0573 mL, 0.729 mmol
  • Step 2 ((2R,7aS)-2-Fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • (2R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-fluoro-6- methylenehexahydro-1H-pyrrolizine (298 mg, 0.728 mmol) in THF (3 mL) was added TBAF (1.09 mL, 1.092 mmol, 1M in THF) at room temperature. The mixture was stirred at room temperature for 1 hour.
  • Step 2 (2-Bromoethyl)diphenylsulfonium trifluoromethanesulfonate
  • the crude was purified by RP-Flash with the following conditions: Column: C18, 40 g, 4HCO3; Mobile Phase B: MeCN; Gradient: 0% B hold 5 min, up to 95% B within 30 min, 95% B hold 10 min; Flow rate: 35 mL/min; Detector: UV 210 nm.
  • the product-containing fractions were collected and evaporated in vacuo and then lyophilized overnight to give the title compound (170 mg, 19% yield) as a yellow oil.
  • Step 2 (6'R,7a'S)-7a'-(((tert-Butyldiphenylsilyl)oxy)methyl)-6'-fluorotetrahydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizine]
  • 6'R,7a'S)-7a'-(((tert-butyldiphenylsilyl)oxy)methyl)-6'- fluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-3'-one (170 mg, 0.38 mmol) in THF (5 mL) was added BH3•Me2S (0.19 mL, 1.94 mmol) dropwise under nitrogen atmosphere.
  • the ice bath was removed, and the resulting mixture was heated at 60 °C for 16 hours.
  • the reaction mixture was cooled to room temperature and quenched with MeOH (5 mL) and 2 M HCl aq. (5 mL) at room temperature.
  • the resulting mixture was heated at 60 °C for 1 hour.
  • the mixture was WSGR Docket No. 62619-720.601 cooled to room temperature and concentrated under reduced pressure.
  • the mixture was diluted with EtOAc (30 mL) and saturated aqueous NaHCO3 (20 mL). After separation, the aqueous phase was extracted with EtOAc (3 x 20 mL).
  • Step 3 ((6'R,7a'S)-6'-Fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)- yl)methanol
  • 6'R,7'aS)-7'a- ⁇ [(tert-butyldiphenylsilyl)oxy]methyl ⁇ -6'-fluoro- tetrahydro-1'H-spiro[cyclopropane-1,2'-pyrrolizine] (116 mg, 0.27 mmol) in THF (1.5 mL) was added TBAF (1 M solution in THF, 0.41 mL, 0.41 mmol) at room temperature.
  • Step 2 (6R,7aS)-7a-((((S)-5-chloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-2-yl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-ol [0565] To a stirred solution of (6R,7aS)-6-fluoro-7a-(hydroxymethyl)-hexahydropyrrolizin-2-ol (135 mg, 0.77 mmol) and Cs2CO3 (131.53 mg, 0.40 mmol) in 1,4-dioxane (5 mL) under argon atmosphere was added (S)-2,5-dichloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,
  • Step 3 (2S,6R,7aS)-7a-(((S)-5-chloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-2-yl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-ol & (2R,6R,7aS)-7a-(((S)-5-chloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalen-2-yl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-ol [0567] (6R,7aS)-7a-((((S)-5-chloro-4-
  • the first eluting peak (RT1: 7.089) was collected and concentrated to give the title compound (Intermediate 51, 30 mg, 13% yield) as light-yellow lyophilized powder.
  • the second eluting peak (RT2: 8.309 min) was collected and concentrated to give the title compound (Intermediate 52, 150 mg, 65% yield) as light-yellow lyophilized powder.
  • MS: m/z 482.20 [M + H] + .
  • Step 2 (2R,6S,7R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H- pyrrolizine-6,7-d2
  • Step 3 ((2R,6S,7R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-6,7-d 2 )methanol
  • Step 1 tert-Butyl (S)-2-(methoxy(methyl)carbamoyl)azepane-1-carboxylate
  • (2S)-1-(tert-butoxycarbonyl)azepane-2-carboxylic acid (2 g, 8.220 mmol)
  • N,O-dimethylhydroxylaminehydrochloride (1.20 g, 12.330 mmol) in DCM (20 mL) under nitrogen atmosphere were added DIEA (4.25 g, 32.880 mmo) and HATU (4.69 g, 12.330 mmol).
  • Step 2 tert-Butyl (2S)-2-acetylazepane-1-carboxylate
  • tert-butyl (S)-2-(methoxy(methyl)carbamoyl)azepane-1-carboxylate 2.2 g, 7.682 mmol
  • bromo(methyl) magnesium 11.5 mL, 1.362 mmol
  • the reaction was quenched with NH4Cl (sat) (30 mL) in an ice bath and extracted with EA (3 x 50 mL).
  • Step 3 tert-Butyl (2S)-2-(1-hydroxyethyl)azepane-1-carboxylate
  • BH 3 .THF 12 mL, 12.000 mmol, 1 M in DMS.
  • the ice bath was removed, and the resulting mixture was stirred at room temperature for 16 hours.
  • the reaction was quenched with water (10 mL) in an ice bath and extracted with EtOAc (3 x 15 mL).
  • Step 4 (S)-1-(Azepan-2-yl)ethan-1-ol WSGR Docket No. 62619-720.601 [0583] To an ice-cooled stirred solution of tert-butyl (2S)-2-(1-hydroxyethyl)azepane-1- carboxylate (1.9 g, 7.808 mmol) in DCM (20 mL) was added HCl (20 mL, 4 M in 1,4-dioxane) dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure.
  • Step 5 (S)-5-(1-(Azepan-2-yl)ethoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol
  • (S)-1-(azepan-2-yl)ethan-1-ol (1.17 g, 8.195 mmol) in THF (40 mL) under nitrogen atmosphere was added NaH (1.19 g, 29.800 mmol, 60% dispersion in mineral oil). The mixture was stirred in an ice bath for 0.5 hours. Intermediate 1 (2 g, 7.450 mmol) was added to the above mixture, and the reaction mixture was stirred at room temperature for 2.5 hours.
  • Step 6 (S)-2,5-Dichloro-4-fluoro-8-methyl-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0587] To an ice-cooled solution of (S)-5-(1-(azepan-2-yl)ethoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-ol (1.7 g, 4.531 mmol) and DIEA (3.51 g, 27.186 mmol) in DCM (340 mL) under nitrogen atmosphere was added POCl3 (3.47 g, 22.655 mmol) dropwise.
  • Step 7 (S)-5-Chloro-2,4-difluoro-8-methyl-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0589] To a stirred solution of (S)-2,5-dichloro-4-fluoro-8-methyl-8a,9,10,11,12,13-hexahydro-8H- 7-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene (1.1 g, 3.079 mmol) in DMSO (20 mL) was added KF (0.30 g, 5.234 mmol) at room temperature under nitrogen atmosphere.
  • Step 8 (8S,8aS)-5-Chloro-2,4-difluoro-8-methyl-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene & (8R,8aS)-5-chloro-2,4-difluoro-8-methyl- 8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0591] (S)-5-Chloro-2,4-difluoro-8-methyl-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene (850 mg, 2.494 mmol) was separated
  • the first eluting peak (RT1: 1.731 min) was concentrated and lyophilized to give the title compound (Intermediate 54, 280 mg, 32% yield) as a yellow lyophilized powder.
  • MS: m/z 341.05 [M + H] + .
  • the second eluting peak (RT2: 1.995 min) was concentrated and lyophilized to give the title compound (Intermediate 55, 380 mg, 44% yield) as a yellow lyophilized powder.
  • MS: m/z 341.05 [M + H] + .
  • Step 2 (2R,6S,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-fluoro-6-methylhexahydro- 1H-pyrrolizine
  • (2S,6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6- fluoro-2-methylhexahydro-3H-pyrrolizin-3-one 550 mg, 1.29 mmol
  • THF 6 mL
  • BH 3 •Me 2 S (0.65 mL, 6.46 mmol
  • the reaction mixture was heated at 60 °C for 16 hours.
  • the resulting mixture was cooled in an ice bath, quenched with MeOH (7 mL) and 2 M HCl (7 mL).
  • the resulting mixture was heated at 60 °C for another 1 hour.
  • the resulting mixture was cooled and concentrated under reduced pressure.
  • the resulting mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (3 x 50 mL) and brine (50 mL).
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 3 ((2R,6S,7aS)-2-Fluoro-6-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • (2R,6S,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluoro-6- methylhexahydro-1H-pyrrolizine 350 mg, 0.85 mmol
  • MeOH 4 mL
  • NH4F (1259.65 mg, 34.00 mmol
  • the ice bath was removed, and the reaction mixture was heated at 60 °C for 16 hours.
  • the reaction mixture was cooled in an ice bath, then MeOH (10 mL) and HCl aq. (2 M, 10 mL) were added.
  • the resulting mixture was heated at 60 °C for 1 hour.
  • the resulting mixture was cooled, quenched with saturated aq. NaHCO3 (50 mL) in an ice bath, and extracted with EA (3 x 50 mL).
  • the combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 3 ((6R,7aR)-2,6-difluoro-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • 6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-difluoro-2- methylhexahydro-1H-pyrrolizine 300 mg, 0.69 mmol
  • NH4F (1034.49 mg, 27.92 mmol)
  • Step 2 (R)-(1,4-Oxazepan-3-yl)methanol [0610] To a solution of (R)-3-(hydroxymethyl)-1,4-oxazepan-5-one (200 mg, 1.38 mmol) in THF (5 mL) was added LiAlH4 (2.5 M in THF, 1.10 mL) at 0 °C.
  • Step 3 (S)-5-((1,4-Oxazepan-3-yl)methoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin- 4(3H)-one
  • (R)-(1,4-oxazepan-3-yl)methanol 130 mg, 991 ⁇ mol
  • THF 10 mL
  • NaH 176 mg, 4.40 mmol, 60% purity
  • Step 4 (S)-2,5-Dichloro-4-fluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene [0614] To a solution of (S)-5-((1,4-oxazepan-3-yl)methoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4(3H)-one (400 mg, 1.10 mmol) in CH 2 Cl 2 (150 mL) were added DIEA (6.61 mmol, 1.15 mL) and POCl3 hr.
  • Example 59 (S)-5-Chloro-2,4-difluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene WSGR Docket No. 62619-720.601 [0616] To a stirred solution of Intermediate 58 (900 mg, 2.60 mmol) in DMSO (9 mL) under nitrogen atmosphere was added KF (227.23 mg, 3.91 mmol) at room temperature, and the mixture was heated at 80 °C for 16 hours.
  • Step 2 (6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-1H- pyrrolizin-2-yl-2-d 4-methylbenzenesulfonate
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6- fluorohexahydro-1H-pyrrolizin-2-d-2-ol 400 mg, crude
  • DMAP 17.68 mg, 0.14 mmol
  • TEA 292.88 mg, 2.89 mmol
  • 4-methylbenzene- 1-sulfonyl chloride 275.89 mg, 1.44 mmol.
  • Step 3 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl-6,6-d2)methanol
  • Step 3 4-(4-Bromophenyl)-3-oxobutanoic acid [0630] To a stirred solution of tert-butyl 4-(4-bromophenyl)-3-oxobutanoate (12.5 g, 39.91 mmol) in DCM (125 mL) was added TFA (125 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours.
  • Step 5 6,8-Dihydroxynaphthalene-2-carbonitrile
  • Step 6 6,8-Dihydroxy-1-((triisopropylsilyl)ethynyl)-2-naphthonitrile WSGR Docket No. 62619-720.601
  • To a stirred solution of 6,8-dihydroxynaphthalene-2-carbonitrile (4.3 g, 23.22 mmol) and (2-bromoethynyl)triisopropylsilane (6.67 g, 25.54 mmol) in 1,4-dioxane (43 mL) under nitrogen atmosphere were added bis(1-methyl-4-(propan-2-yl)benzene); bis(dichlororuthenium) (1421.99 mg, 2.32 mmol) and KOAc (4.56 g, 46.44 mmol) at room temperature.
  • Step 7 8-Hydroxy-6-(methoxymethoxy)-1-((triisopropylsilyl)ethynyl)-2-naphthonitrile
  • 6-38 To an ice-cooled solution of 6,8-dihydroxy-1-((triisopropylsilyl)ethynyl)-2-naphthonitrile (4 g, 10.94 mmol) and DIEA (3.54 g, 27.35 mmol) in DCM (80 mL) under nitrogen atmosphere was added bromo(methoxymethoxy)methane (1.37 g, 10.94 mmol) dropwise. The reaction mixture was stirred in an ice bath for 1 hour.
  • Step 8 7-Cyano-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate
  • DCM 8-Hydroxy-6-(methoxymethoxy)-1-((triisopropylsilyl)ethynyl)-2- naphthonitrile
  • Step 9 6-(Methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((triisopropylsilyl)ethynyl)-2-naphthonitrile
  • 7-cyano-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate 1.0 g, crude
  • bis(pinacolato)diboron 937.64 mg, 3.69 mmol
  • 1,4-dioxane 10 mL
  • Pd(dppf)Cl 2 •CH 2 Cl 2 150.39 mg, 0.18 mmol
  • KOAc 543.56 mg, 5.53 mmol
  • Step 2 (6R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluoro-2-methyl-2- (phenylselanyl)hexahydro-3H-pyrrolizin-3-one
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-2- methylhexahydro-3H-pyrrolizin-3-one 550 mg, 1.29 mmol
  • LiHMDS 1.5 mL, 1 M in THF
  • Step 3 (6R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluoro-2-methyl-5,6,7,7a- tetrahydro-3H-pyrrolizin-3-one
  • (6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6- fluoro-2-methyl-2-(phenylselanyl)hexahydro-3H-pyrrolizin-3-one 500 mg, 0.86 mmol
  • CH2Cl2 6 mL
  • hydrogen peroxide 1.5 mL, 30wt%) dropwise.
  • Step 4 (2R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-fluoro-6-methyl-2,3,5,7a- tetrahydro-1H-pyrrolizine
  • 6R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-2- methyl-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one 300 mg, 0.70 mmol
  • 9-BBN 6 mL, 3 mmol, 0.5 M in THF
  • Step 2 (1R,6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,6-difluorohexahydro-1H- pyrrolizine
  • (1R,6R,7aS)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)- 1,6-difluorohexahydro-3H-pyrrolizin-3-one 330 mg, 0.768 mmol
  • THF 8 mL
  • BH 3 - Me2S (0.38 mL, 3.840 mmol
  • Step 2 (6R,7aS)-6-fluoro-7a-(hydroxymethyl)-2-methylhexahydro-1H-pyrrolizin-2-ol
  • 6R,7aS)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-2- methylhexahydro-1H-pyrrolizin-2-ol (414.8 mg, 0.97 mmol) in CH 3 OH (4.2 mL) under nitrogen atmosphere was added NH4F (1437.37 mg, 38.81 mmol) at room temperature. The reaction mixture was heated at 65 °C for 8 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure.
  • Step 2 ((6R,7aR)-6-Fluoro-1-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • 6R,7aR)-7a-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-fluoro-1- methylenehexahydro-1H-pyrrolizine (170 mg, 0.41 mmol) and NH4F (614.84 mg, 16.60 mmol) in MeOH (2 mL) under nitrogen atmosphere was heated at 65 °C for 4 hours. The resulting mixture was cooled to room temperature, filtered and concentrated under reduced pressure.
  • Step 3 Benzyl (S)-3-(1-hydroxypropyl)-1,4-oxazepane-4-carboxylate [0686] To a solution of (S)-benzyl 3-formyl-1,4-oxazepane-4-carboxylate (810 mg, 3.08 mmol) in THF (10 mL) was stirred at -78 °C for 10 min under N2 atmosphere, and then EtMgBr (3 M, 2 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 20 °C for 1 hr under N 2 atmosphere.
  • Step 4 (S)-1-(1,4-Oxazepan-3-yl)propan-1-ol [0688] To a solution of (S)-benzyl 3-(1-hydroxypropyl)-1,4-oxazepane-4-carboxylate (450 mg, 1.53 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 10% purity). The mixture was degassed, purged with H 2 three times, and stirred at 25 °C for 4 hr under H 2 (15 Psi) atmosphere. The reaction mixture was filtered and concentrated to give the title compound (230 mg, yield: 94%) as a colorless oil.
  • Step 5 (S)-5-(1-(1,4-Oxazepan-3-yl)propoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin- 4(3H)-one
  • (S)-1-(1,4-oxazepan-3-yl)propan-1-ol (220 mg, 1.38 mmol) in THF (20 mL) was degassed, purged with N2 three times. NaH (221 mg, 5.53 mmol, 60% purity) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 hr.
  • Step 6 (8R,8aS)-2,5-Dichloro-8-ethyl-4-fluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0692] To a solution of (S)-5-(1-(1,4-oxazepan-3-yl)propoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4(3H)-one (450 mg, 1.15 mmol) in CH2Cl2 (100 mL) was added dropwise DIPEA (1.2 mL, 6.90 mmol) at 0 °C.
  • Step 2 (S)-4-Benzyl-3-(chloromethyl)-1,4-oxazepane [0699] To a solution of (R)-(4-benzyl-1,4-oxazepan-3-yl)methanol (4.5 g, 20.3 mmol), TEA (6.17 g, 61.0 mmol) in THF (45 mL) was added MsCl (2.4 g, 21.0 mmol) at -10 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL x 3).
  • Step 3 (R)-3-(Azidomethyl)-4-benzyl-1,4-oxazepane [0701] To a solution of (S)-4-benzyl-3-(chloromethyl)-1,4-oxazepane (2.9 g, 12.1 mmol) in DMF (30 mL) was added NaN3 (2.3 g, 35.2 mmol). The mixture was stirred at 70 °C for 3 hr. The reaction mixture was diluted with H 2 O (200 mL) and extracted with EtOAc (100 mL x 2).
  • Step 4 tert-Butyl (R)-((4-benzyl-1,4-oxazepan-3-yl)methyl)carbamate [0703] To a solution of (R)-3-(azidomethyl)-4-benzyl-1,4-oxazepane (2.7 g, 11.0 mmol) in MeOH (30 mL) was added Pd/C (500 mg, 10% purity). The mixture was stirred at 25 °C for 2 hr under H2 (15 Psi). Then the mixture was filtered and concentrated under reduced pressure. Then THF (20 mL), DIPEA (1.46 g, 11.3 mmol) and Boc 2 O (1.98 g, 9.06 mmol) were added.
  • Step 5 tert-Butyl (R)-((4-benzyl-1,4-oxazepan-3-yl)methyl)(methyl)carbamate
  • a solution of tert-butyl (R)-((4-benzyl-1,4-oxazepan-3-yl)methyl)carbamate (1.6 g, 4.99 mmol) in THF (5 mL) was degassed and purged with N2 three times. NaH (599 mg, 15.0 mmol, 60% purity) was added at 0 °C, and the mixture was stirred at 25 °C for 0.5 hr under N 2 atmosphere.
  • Step 6 tert-Butyl (R)-((1,4-oxazepan-3-yl)methyl)(methyl)carbamate
  • tert-butyl (R)-((4-benzyl-1,4-oxazepan-3-yl)methyl)(methyl)carbamate 745 mg, 2.23 mmol
  • Pd(OH)2 745 mg, 20% purity
  • the mixture was stirred at 25 °C for 3 hr under H2 (15 Psi).
  • the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (600 mg, yield: 77%) as a colourless oil.
  • Step 7 tert-Butyl (R)-((4-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4- yl)-1,4-oxazepan-3-yl)methyl)(methyl)carbamate
  • DIPEA 2.5 g, 19.5 mmol
  • POCl3 2.8 g, 18.2 mmol
  • Step 8 (R)-5-Chloro-4-fluoro-7-methyl-2-(methylthio)-7,8,8a,9,12,13-hexahydro-11H-10- oxa-1,3,6,7,13a-pentaazanaphtho[1,8-ab]heptalene [0711] To a solution of tert-butyl (R)-((4-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-3-yl)methyl)(methyl)carbamate (800 mg, 1.58 mmol) in MeCN (55 mL) was added HCl/1,4-dioxane (4 M, 9 mL).
  • Step 1 Methyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-serinate
  • Step 1 Methyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-serinate
  • Step 2 tert-Butyl (R)-(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropan-2-yl-3,3- d 2 )carbamate
  • methyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-serinate 17.1 g, 24.5 mmol
  • LiAlD4 3.26 g, 85.8 mmol
  • Step 3 tert-Butyl (R)-(1-(benzyloxy)-3-((tert-butyldiphenylsilyl)oxy)propan-2-yl-1,1- d 2 )carbamate WSGR Docket No. 62619-720.601 [0718] To a solution of tert-butyl (R)-(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropan-2-yl-3,3- d2)carbamate (7.7 g, 17.8 mmol) in DMF (90 mL) was added NaH (460 mg, 11.5 mmol, 60% purity in oil) at 0 °C under N2 atmosphere.
  • Step 4 tert-Butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl-1,1-d 2 )carbamate
  • tert-butyl (R)-(1-(benzyloxy)-3-((tert-butyldiphenylsilyl)oxy)propan-2-yl- 1,1-d 2 )carbamate 3.5 g, 6.71 mmol
  • THF 26 mL
  • TBAF 1,3.4 mL, 1 M in THF
  • Step 5 tert-Butyl (S)-3-(3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propoxy-3,3- d2)propanoate
  • tert-butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl-1,1-d 2 )carbamate 1.7 g, 6.00 mmol
  • t-BuOH 18 mL
  • Cs2CO3 2.35 g, 7.20 mmol
  • tert-butyl acrylate 18.8 g, 146 mmol
  • Step 7 (S)-3-((Benzyloxy)methyl-d2)-1,4-oxazepan-5-one [0726] To a solution of (S)-3-(2-amino-3-(benzyloxy)propoxy-3,3-d2)propanoic acid (1.5 g, 5.88 mmol) in CH 2 Cl 2 (150 mL) were added HATU (2.68 g, 7.05 mmol) and TEA (2.97 g, 29.4 mmol). The mixture was stirred at 25 °C for 3 hr. The mixture was diluted with H2O (500 mL) and extracted with CH2Cl2 (500 mL ⁇ 2).
  • Step 8 (R)-3-(Hydroxymethyl-d 2 )-1,4-oxazepan-5-one
  • (S)-3-((benzyloxy)methyl-d2)-1,4-oxazepan-5-one 900 mg, 3.79 mmol
  • CH2Cl2 20 mL
  • BCl3 1 M in CH2Cl2, 7.59 mL
  • the reaction mixture was stirred at 25 °C for 1 hr.
  • the reaction mixture quenched with MeOH (100 mL) and concentrated under reduced pressure.
  • the resulting residue neutralized with NH3 H2O (pH ⁇ 7-8).
  • Step 9 (R)-(1,4-Oxazepan-3-yl)methan-d2-ol [0730] To a solution of (R)-3-(hydroxymethyl-d 2 )-1,4-oxazepan-5-one (470 mg, 3.19 mmol) in THF (5 mL) was added LiAlH4 (242 mg, 6.39 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H 2 O (0.24 mL), 15% NaOH (0.24 mL), and H 2 O (0.72 mL).
  • Step 10 (S)-5-((1,4-Oxazepan-3-yl)methoxy-d2)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4(3H)-one [0732] To a solution of NaH (336 mg, 8.41 mmol, 60% purity in oil) in THF (8 mL) was added (R)-(1,4-oxazepan-3-yl)methan-d 2 -ol (280 mg, 2.10 mmol) in THF (3 mL) at 0 °C under N 2 atmosphere.
  • Step 11 (S)-2,5-Dichloro-4-fluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene-8,8-d 2 .
  • Step 2 (S)-5-((1,4-Oxazepan-3-yl-5,5-d2)methoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4(3H)-one
  • (R)-(1,4-oxazepan-3-yl-5,5-d2)methanol 130 mg, 976 ⁇ mol
  • NaH 156 mg, 3.90 mmol, 60% purity
  • Step 3 (S)-2,5-Dichloro-4-fluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene-13,13-d 2 [0743] To a solution of (S)-5-((1,4-oxazepan-3-yl-5,5-d2)methoxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4(3H)-one (400 mg, 1.1 mmol) in CH 2 Cl 2 (150 mL) were added DIEA (849 mg, 6.57 mmol) and POCl 3 (839 mg, 5.48 mmol) at 0 °C.
  • Step 1 tert-Butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl-3,3-d2)carbamate
  • (R)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanoic acid 5 g, 16.9 mmol
  • LiAlD 4 2.73 g, 59.3 mmol
  • the mixture was stirred at 25 °C for 2 hr.
  • Step 2 tert- Butyl (R)-3-(3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propoxy-1,1- d 2 )propanoate
  • tert-butyl (S)-(1-(benzyloxy)-3-hydroxypropan-2-yl-3,3-d2)carbamate 3. g, 10.9 mmol
  • Cs2CO3 4.28 g, 13.1 mmol
  • tert-butyl acrylate (26.5 g, 207 mmol). The mixture was stirred at 25 °C for 16 hr.
  • Step 3 (R)-3-(2-Amino-3-(benzyloxy)propoxy-1,1-d2)propanoic acid
  • tert-butyl (R)-3-(3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propoxy- 1,1-d 2 )propanoate 3.0 g, 7.53 mmol
  • CH 2 Cl 2 35 mL
  • TFA 35 mL
  • the mixture WSGR Docket No. 62619-720.601 was stirred at 25 °C for 2 hr.
  • the reaction mixture was concentrated under reduced pressure.
  • the title compound (2.78 g, TFA salt) was obtained as a yellow oil.
  • Step 4 (R)-3-((Benzyloxy)methyl)-1,4-oxazepan-5-one-2,2-d2 [0754] To a solution of (R)-3-(2-amino-3-(benzyloxy)propoxy-1,1-d 2 )propanoic acid (2.78 g, 10.9 mmol) in CH2Cl2 (300 mL) were added HATU (4.97 g, 13.1 mmol) and TEA (5.51 g, 54.4 mmol). The mixture was stirred at 25 °C for 3 hr.
  • Step 5 (R)-3-(Hydroxymethyl)-1,4-oxazepan-5-one-2,2-d2
  • (R)-3-((benzyloxy)methyl)-1,4-oxazepan-5-one-2,2-d2 was added dropwise a solution of BCl 3 (1 M in CH 2 Cl 2 , 10.5 mL) at 0 - 5 °C under N2 over 10 min.
  • the mixture was stirred at 25 °C for 1 hr.
  • the reaction mixture quenched with MeOH (100 mL) and concentrated under reduced pressure.
  • Step 6 (R)-(1,4-Oxazepan-3-yl-2,2-d2)methanol [0758] To a solution of (R)-3-(hydroxymethyl)-1,4-oxazepan-5-one-2,2-d2 (630 mg, 4.28 mmol) in THF (10 mL) was added LiAlH 4 (325 mg, 8.56 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (0.33 mL), 15% NaOH (0.33 mL), and H 2 O (1 mL).
  • Step 7 (S)-5-((1,4-Oxazepan-3-yl-2,2-d 2 )methoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4(3H)-one [0760] To a solution of (R)-(1,4-oxazepan-3-yl-2,2-d2)methanol (300 mg, 2.25 mmol) in THF (20 mL) was added NaH (360 mg, 9.01 mmol, 60% purity) at 0 °C.
  • Step 8 (S)-2,5-Dichloro-4-fluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene-9,9-d2 [0762] To a solution of (S)-5-((1,4-oxazepan-3-yl-2,2-d 2 )methoxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4(3H)-one (780 mg, 2.14 mmol) in CH 2 Cl 2 (130 mL) was added DIEA (2.23 mL, 12.8 mmol) and POCl3 (1 mL, 10.7 mmol).
  • Step 2 tert -Butyl (R)-6,6-difluoro-3-(hydroxymethyl)-1,4-oxazepane-4-carboxylate
  • a mixture of tert-butyl (R)-3-((benzyloxy)methyl)-6,6-difluoro-1,4-oxazepane-4- 2 MeOH (30 mL) was degassed and purged with H2 for three times, and the mixture was stirred at 25 °C for 3 hr under H 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure.
  • Step 3 (R)-(6,6-Difluoro-1,4-oxazepan-3-yl)methanol
  • a mixture of tert-butyl (R)-6,6-difluoro-3-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1.34 g, 5.01 mmol) in HCl/EtOAc (2 M, 10.3 mL) was stirred at 25 °C for 0.5 hr.
  • the reaction WSGR Docket No. 62619-720.601 mixture was concentrated under reduced pressure.
  • the crude product was dissolved in CH 3 CN : MeOH (5 mL : 1 mL).
  • Step 5 (S)-2,5-Dichloro-4,12,12-trifluoro-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa- 1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0775] To a solution of (S)-2,7-dichloro-5-((6,6-difluoro-1,4-oxazepan-3-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4(3H)-one (1.1 g, 2.76 mmol) in CH2Cl2 (300 mL) were added DIEA (2.40 mL, 13.7 mmol) and POCl 3 (1.54 mL, 16.5 mmol) at 0 °C.
  • Step 2 tert-Butyl (2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodoazepane-1- carboxylate
  • Step 3 tert-Butyl (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2,3,6,7-tetrahydro-1H- azepine-1-carboxylate & tert-butyl (S)-7-(((tert-butyldiphenylsilyl)oxy)methyl)-2,3,4,7-tetrahydro- 1H-azepine-1-carboxylate [0784] To a solution of tert-butyl (2S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-iodoazepane-1- carboxylate (5.1 g, 8.59 mmol) in xylene (100 mL) was added DBU (25.5 mL, 169 mmol).
  • Step 4 (S)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H-azepine [0787] To a solution of Intermediate 82 (700 mg, 1.50 mmol) in CH 2 Cl 2 (6 mL) was added TFA (2.33 mL, 31.4 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture concentrated under reduced pressure.
  • Step 2 (S)-4-(7-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H-azepin-1-yl)- 2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine [0789] To a solution of 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (455 mg, 1.59 mmol) in MeCN (8 mL) was added DIPEA (0.83 mL, 4.70 mmol) and (S)-2-(((tert- butyldiphenylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H N 2 , and the mixture was stirred at 25 °C for 16 h.
  • Step 3 4-((S)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H-azepin-1-yl)- 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine WSGR Docket No.
  • Step 4 (S)-5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8a,9,10,13-tetrahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene [0793] To a solution of 4-((S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H- azepin-1-yl)-5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- in THF, 2.98 mL) and stirred at 25 °C for 16 h.
  • Step 2 (S)-(2,3,6,7-Tetrahydro-1H-azepin-2-yl)methanol
  • a mixture of tert-butyl (S)-2-(hydroxymethyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (369 mg, 1.62 mmol) in HCl (2M in EtOAc, 3 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to dryness. The residue was dissolved in MeCN (5mL) and MeOH (1mL), and then K2CO3 was added to adjust the pH to around 8.
  • Step 3 (S)-2,7-Dichloro-8-fluoro-5-((2,3,6,7-tetrahydro-1H-azepin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4(3H)-one [0800] To a solution of (S)-(2,3,6,7-tetrahydro-1H-azepin-2-yl)methanol (200 mg, 1.57 mmol) in THF (5 mL) was added NaH (252 mg, 6.29 mmol, 60% purity) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h under N 2 .
  • Step 4 (S)-2,5-Dichloro-4-fluoro-8a,9,12,13-tetrahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene [0802] To a solution of (S)-2,7-dichloro-8-fluoro-5-((2,3,6,7-tetrahydro-1H-azepin-2- yl)methoxy)pyrido[4,3-d]pyrimidin-4(3H 2 Cl 2 (70 mL) were added 3 2. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with sat.
  • Step 2 tert-Butyl (S)-2-propionylazepane-1-carboxylate
  • a mixture of of tert-butyl (S)-2-(methoxy(methyl)carbamoyl)azepane-1-carboxylate (2.10 g, 7.33 mmol) in THF (20 mL) was degassed and purged with N2 three times.
  • CH3CH2MgBr (3 M, 7.30 mL) was added dropwise at -78 °C under N 2 atmosphere. The reaction was slowly warmed up to 20 °C and stirred for 1 h. The reaction mixture was quenched with sat.
  • Step 3 (S)-1-(Azepan-2-yl)propan-1-one [0811] To a solution of tert-butyl (S)-2-propionylazepane-1-carboxylate (1.54 g, 6.03 mmol) in CH2Cl2 (20 mL) was added HCl/EtOAc (4 M, 10 mL), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.15 g, HCl salt) as a white solid, which was used in the next step without further purification.
  • Step 5 5-(1-((S)-Azepan-2-yl)propoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin- 4(3H)-one
  • N2 atmosphere a solution of 1-((S)-azepan-2-yl)propan-1-ol (300 mg, 1.91 mmol) in THF (18 mL) was added NaH (305 mg, 7.63 mmol, 60% purity) at 0 °C, and the mixture was stirred at 30 °C for 1 h under N2 atmosphere.
  • Step 7 (8S,8aS)-5-Chloro-8-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8- ab]heptalene & (8R,8aS)-5-chloro-8-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8- ab]heptalene [0819] A mixture of (8aS)-2-fluorote
  • Step 2 tert-Butyl (S)-4,4-difluoro-2-(hydroxymethyl)azepane-1-carboxylate
  • tert-butyl (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4,4-difluoroazepane- 1-carboxylate 753 mg, 1.49 mmol
  • THF 10 mL
  • TBAF (1 M in THF, 2.24 mL
  • Step 5 (S)-2,5-Dichloro-4,10,10-trifluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene WSGR Docket No.
  • Step 6 (S)-5-Chloro-4,10,10-trifluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a-tetraazanaphtho[1,8- ab]heptalene [0832] A solution of (S)-2,5-dichloro-4,10,10-trifluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa- 1,3,6,13a-tetraazanaphtho[1,8-ab ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H (5 mL) was stirred at 110 °C under N2 for 16 h.
  • Step 2 8-Bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime
  • NBS 10.6 g, 59.6 mmol
  • Pd(OAc) 2 1.49 g, 6.6 mmol
  • the reaction mixture was concentrated under reduced pressure, diluted with H2O (100 mL), and extracted with EtOAc (100 mL x 3).
  • Step 3 8-Bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one
  • O-methyl oxime 16 g, 56.31 mmol
  • HCl 6 M, 160 mL
  • EtOAc 200 mL x 3
  • Step 4 8-Bromo-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one
  • H 2 SO 4 3.36 mL, 63.03 mmol
  • SelectFluor 80 g, 225.8 mmol
  • Step 3 N-(6-Fluoro-5-(fluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-yl)-1,1-diphenylmethanimine
  • Step 2 tert-Butyl (3S)-8,8-difluoro-3-(hydroxymethyl)-4-azabicyclo[5.1.0]octane-4- carboxylate
  • the residue was purified by silica gel flash chromatography (eluent: 0 ⁇ 30% of EtOAc in petroleum ether) to give the title compound (160 mg, 74% yield) as a colorless WSGR Docket No. 62619-720.601 oil.
  • Step 3 ((3S)-8,8-Difluoro-4-azabicyclo[5.1.0]octan-3-yl)methanol [0865] To a solution of tert-butyl (3S)-8,8-difluoro-3-(hydroxymethyl)-4-azabicyclo[5.1.0]octane- reaction mixture was concentrated to dryness. The residue was dissolved in MeCN (10 mL) and MeOH (2 mL), and K2CO3 was added to adjust the pH to around 8. The mixture was filtered and concentrated under reduced pressure to give the title compound (90 mg, crude) as a colorless oil, which was used in the next step without further purification.
  • Step 4 2,7-Dichloro-5-(((3S)-8,8-difluoro-4-azabicyclo[5.1.0]octan-3-yl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4(3H)-one
  • ((3S)-8,8-difluoro-4-azabicyclo[5.1.0]octan-3-yl)methanol 90 mg, 508 2
  • the mixture was stirred at 0 °C under N 2 for 0.5 h.
  • a solution of Intermediate 1 167 mg, 559 h under N2 atmosphere.
  • the reaction mixture was quenched with sat. NaHCO3 aq.
  • Step 5 (8aS)-2,5-Dichloro-4,10,10-trifluoro-8,8a,9,9a,10,10a,11,12-octahydro-7-oxa- 1,3,6,12a-tetraazacyclopropa[h]naphtho[1,8-ab]heptalene [0869] To a solution of 2,7-dichloro-5-(((3S)-8,8-difluoro-4-azabicyclo[5.1.0]octan-3-yl)methoxy)- 8-fluoropyrido[4,3-d]pyrimidin-4(3H 2 Cl 2 (80 mL) was added 3 0 °C under N2 for 2 h.
  • Step 6 (8aS)-5-Chloro-4,10,10-trifluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,9a,10,10a,11,12-octahydro-7-oxa-1,3,6,12a- tetraazacyclopropa[h]naphtho[1,8-ab]heptalene [0871] A mixture of (8aS)-2,5-dichloro-4,10,10-trifluoro-8,8a,9,9a,10,10a,11,12-octahydro-7-oxa- 1,3,6,12a-tetraazacyclopropa[h]naphtho[1,8-ab R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5
  • Step 2 (S)-7-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,5,6,7-tetrahydro-2H-azepin-2-one
  • (S)-N-(1-((tert-butyldiphenylsilyl)oxy)hex-5-en-2-yl)acrylamide (13.4 g, 32.9 mmol) in CH 2 Cl 2 (1400 mL) was added Grubb's II (2.79 g, 3.29 mmol) at 25 °C under N 2 .
  • the mixture was stirred at 40 °C for 1 h under N2.
  • the reaction mixture was concentrated under reduced pressure.
  • Step 3 (S)-7-(((tert-Butyldiphenylsilyl)oxy)methyl)azepan-2-one [0889] To a solution of (S)-7-(((tert-butyldiphenylsilyl)oxy)methyl)-1,5,6,7-tetrahydro-2H-azepin- 2-one (9 g, 23.7 mmol) in MeOH (180 mL) was added 10% Pd/C (4 g, 60% purity) under Ar2. The suspension was degassed and purged with H2 three times. The mixture was stirred at 25 °C for 2 h under H 2 (15 Psi).
  • Step 4 (S)-7-(hydroxymethyl)azepan-2-one [0891] To a solution of (S)-7-(((tert-butyldiphenylsilyl)oxy)methyl)azepan-2-one (3 g, 7.86 mmol) in THF (30 mL) was added TBAF (7.86 mL, 1 M in THF) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between H 2 O (100 mL) and EtOAc (120 mL).
  • Step 5 (S)-(Azepan-2-yl-7,7-d 2 )methanol
  • (S)-7-(hydroxymethyl)azepan-2-one 1.1 g, 7.68 mmol
  • LiAlD4 530 mg, 11.5 mmol
  • the mixture was stirred at 0 °C for 2 h under N 2 .
  • D 2 O (0.53 mL) was added dropwise to the reaction mixture at 0 °C. 15 wt% NaOH (0.53 mL) was added dropwise and then water (1.5 mL) was added.
  • Step 6 (S)-5-((Azepan-2-yl-7,7-d2)methoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin- 4(3H)-one [0895] To a solution of (S)-(azepan-2-yl-7,7-d2)methanol (900 mg, 6.86 mmol) in THF (18 mL) was added NaH (1.10 g, 27.4 mmol, 60% purity) at 0 °C under N 2 , and the mixture was stirred for 30 min at 0 °C under N 2 .
  • Step 7 (S)-2,5-Dichloro-4-fluoro-8a,9,10,11,12,13-hexahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene-13,13-d2 [0897] To a solution of (S)-5-((azepan-2-yl-7,7-d 2 )methoxy)-2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4(3H)-one (380 mg, 1.05 mmol) in CH2Cl2 (120 mL) was added DIPEA (811 mg, 6.28 mmol, 1.09 mL) and POCl 3 2 .
  • Step 2 2,5-Dichloro-4-fluoro-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene
  • DIEA 640 mg, 4.96 mmol
  • POCl 3 633 mg, 4.13 mmol
  • Step 2 tert-Butyl (S)-(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl-1,1-d2)carbamate
  • tert-butyl (S)-(1-hydroxypent-4-en-2-yl-1,1-d 2 )carbamate 7.16 g, 35.2 mmol
  • CH2Cl2 30 mL
  • imidazole 2.40 g, 35.2 mmol
  • TBDPSCl 11.62 g, 42.27 mmol
  • Step 3 (S)-1-((tert-Butyldiphenylsilyl)oxy)pent-4-en-1,1-d2-2-amine [0913] To a solution of tert-butyl (S)-(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl-1,1- d 2 )carbamate (8.6 g, 19.47 mmol) in CH 2 Cl 2 (20 mL) was added TFA (5 mL, 67.3 mmol). The mixture was stirred at 25 °C for 2 h. The reation mixture was concentrated under reduced pressure.
  • Step 4 (S)-N-(but-3-en-1-yl-1,1-d2)-1-((tert-butyldiphenylsilyl)oxy)pent-4-en-1,1-d2-2- amine
  • (S)-1-((tert-butyldiphenylsilyl)oxy)pent-4-en-1,1-d2-2-amine (2 g, 5.86 mmol) in DMF (40 mL) were added K2CO3 (4.05 g, 29.3 mmol) and NaI (4.39 g, 29.3 mmol).
  • Step 5 tert-Butyl (S)-(but-3-en-1-yl-1,1-d 2 )(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl- 1,1-d2)carbamate [0917] To a solution of (S)-N-(but-3-en-1-yl-1,1-d2)-1-((tert-butyldiphenylsilyl)oxy)pent-4-en-1,1- d 2 -2-amine (3.48 g, 8.75 mmol) and K 2 CO 3 (4.05 g, 29.3 mmol) in DMF (50 mL) was added Boc2O (2.86 g, 13.1 mmol).
  • Step 6 tert-Butyl (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl-d2)-2,3,6,7-tetrahydro-1H- azepine-1-carboxylate-7,7-d 2
  • tert-butyl (S)-(but-3-en-1-yl-1,1-d 2 )(1-((tert-butyldiphenylsilyl)oxy)pent-4- en-2-yl-1,1-d2)carbamate (2.8 g, 5.63 mmol) in CH2Cl2 (470 mL) under N2 was added Grubb’s II 2 three times and stirred at 40 °C for 1 h under N 2 .
  • Step 7 tert-Butyl (S)-2-(hydroxymethyl-d 2 )-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate- 7,7-d2
  • tert-butyl (S)-2-(((tert-butyldiphenylsilyl)oxy)methyl-d 2 )-2,3,6,7- tetrahydro-1H-azepine-1-carboxylate-7,7-d 2 (1.6 g, 3.41 mmol) in THF (10 mL) was added TBAF (4.09 mL, 1 M in THF). The mixture was stirred at 25 °C for 16 h.
  • Step 8 (S)-(2,3,6,7-Tetrahydro-1H-azepin-2-yl-7,7-d 2 )methan-d 2 -ol WSGR Docket No. 62619-720.601 [0923] To a solution of tert-butyl (S)-2-(hydroxymethyl-d 2 )-2,3,6,7-tetrahydro-1H-azepine-1- carboxylate-7,7-d2 (490 mg, 2.12 mmol) in CH2Cl2 (5 mL) at 25 °C was added HCl (2.40 mL, 2 M in EtOAc), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure.
  • Step 9 (S)-2,7-Dichloro-8-fluoro-5-((2,3,6,7-tetrahydro-1H-azepin-2-yl-7,7-d2)methoxy- d 2 )pyrido[4,3-d]pyrimidin-4(3H)-one [0925] To a solution of (S)-(2,3,6,7-tetrahydro-1H-azepin-2-yl-7,7-d2)methan-d2-ol (260 mg, 1.98 mmol) in THF (15 mL) and DMF (2 mL) was added NaH (317 mg, 7.93 mmol, 60% purity) at 0 °C under N 2 .
  • Step 10 (S)-2,5-Dichloro-4-fluoro-8a,9,12,13-tetrahydro-8H-7-oxa-1,3,6,13a- tetraazanaphtho[1,8-ab]heptalene-8,8,13,13-d 4 [0927] To a solution of (S)-2,7-dichloro-8-fluoro-5-((2,3,6,7-tetrahydro-1H-azepin-2-yl-7,7- d2)methoxy-d2)pyrido[4,3-d]pyrimidin-4(3H)-one (719 mg, 1.98 mmol) in CH2Cl2 (216 mL) were added DIPEA (2.07 mL,11.9 mmol) and POCl 3 2 , and then the mixture was stirred at 0 °C for 1 h under N2.
  • Step 2 5-Allyl-1,2-difluoro-3-(methoxy-d 3 )benzene
  • Step 7 4-(2-Bromo-3,4-difluoro-5-(methoxy-d3)phenyl)-3-oxobutanoic acid [0944] To a solution of tert-butyl 4-(2-bromo-3,4-difluoro-5-(methoxy-d3)phenyl)-3-oxobutanoate (18 g, 41.4 mmol) in CH 2 Cl 2 (50 mL) was added TFA (66.0 mL, 888 mmol).
  • Step 8 5-Bromo-6,7-difluoro-8-(methoxy-d3)naphthalene-1,3-diol
  • a solution of 4-(2-bromo-3,4-difluoro-5-(methoxy-d3)phenyl)-3-oxobutanoic acid (18 g, 55.2 mmol) in trifluoromethanesulfonic acid (150 mL) was stirred at 20 °C for 16 h.
  • the reaction mixture was poured into ice water (200 mL) slowly, and the precipitate was filtered, and the filter cake was washed with water (50 ml x 3), sat. NaHCO3 aq.
  • Step 10 6,7-Difluoro-8-(methoxy-d 3 )naphthalene-1,3-diyl bis(trifluoromethanesulfonate) [0950] To a solution of 6,7-difluoro-8-(trideuteriomethoxy)naphthalene-1,3-diol (7.6 g, 33.16 mmol) and DIPEA (35 mL, 199 mmol) in CH2Cl2 (140 mL) was added dropwise Tf2O (22 mL, 133 mmol) at 0 °C under N 2 .
  • Step 12 N-(6,7-Difluoro-5-(methoxy-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-yl)-1,1-diphenylmethanimine
  • a solution of 3-((diphenylmethylene)amino)-6,7-difluoro-8-(methoxy-d3)naphthalen-1-yl trifluoromethanesulfonate (4 g, 7.63 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (2.32 g, 9.15 mmol), AcOK (2.25 g, 22.9 mmol)
  • Step 13 6,7-Difluoro-5-(methoxy-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-amine
  • N-(6,7-difluoro-5-(methoxy-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-2-yl)-1,1-diphenylmethanimine (18 g, 16.1 mmol) in EtOH (135 mL) was added hydroxylamine;hydrochloride (2.24 g, 32.3 mmol) and AcOK (4.75 g, 48.4 mmol).
  • Step 1 Methylene-d 2 bis(4-methylbenzenesulfonate) [0959] To a solution of (tosyloxy)silver (15.7 g, 56.3 mmol) in ACN (50 mL) was added dibromomethane-d2 (4.5 g, 25.6 mmol). The mixture was stirred at 81 °C for 16 h under N2. The reaction mixture was filtered to remove all the salts, and the mixture was concentrated. The residue was dissolved in CH2Cl2 (500 mL) and precipitate formed. The precipitate was filtered off to remove all the salts.
  • Step 2 Fluoromethyl-d24-methylbenzenesulfonate
  • methylene-d 2 bis(4-methylbenzenesulfonate) (2 g, 5.58 mmol)
  • ACN 20 mL
  • CsF 1.27 g, 8.37 mmol
  • hexaetheylene glycol (2.22 mL , 8.37 mmol, 95% purity).
  • the mixture was stirred at 81 °C for 16 h under N 2 .
  • the reaction mixture was quenched with H 2 O (50 mL) at 25 °C and extracted with EtOAc (50 mL x 3).
  • Step 2 Methyl 2-(2-(chloromethyl)allyl)-4-methylenepyrrolidine-2-carboxylate [0970] To an ice-cooled solution of 1-(tert-butyl) 2-methyl 2-(2-(chloromethyl)allyl)-4- methylenepyrrolidine-1,2-dicarboxylate (18 g, 54.57 mmol) in MeCN (180 mL) was added HCl (4 M in 1,4-dioxane, 179.96 mL, 719.84 mmol) under nitrogen atmosphere. The resulting mixture stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give the title compound (12 g, crude) as a yellow solid.
  • Step 3 Methyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate
  • Step 4 (2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol
  • 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate 2.3 g, 11.90 mmol
  • LiAlH4 11.85 mL, 2 mmol
  • the resulting mixture was heated at room temperature for 1 hour.
  • the resulting mixture was quenched with water (0.076 mL), NaOH (15% in water, 0.76 mL) and water (0.228 mL) at 0 °C.
  • Example 1 5-Ethynyl-6-fluoro-4-((R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazabenzo[4,5]cycloocta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol
  • Step 1 (R)-2,7-Dichloro-8-fluoro-5-(2-(piperidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin- 4(3H)-one [0981] To a solution of (R)-2-(piperidin-2-yl)ethan-1-ol (288 mg, 2.23 mmol) in THF (30 mL) was added NaH (297 mg, 7.45 mmol, 60% purity) at 0 °C under N 2 atmosphere, and the mixture was stirred for 0.5 h.
  • Step 3 (R)-2-Chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cycloocta[1,2,3- de]naphthalene [0985] A mixture of (R)-2,12-dichloro-1-fluoro-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazabenzo[4,5]cycloocta[1,2,3-de R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H 2 three times, and then the mixture was stirred at 100 °C for 16 h under N
  • Step 4 6-Fluoro-4-((R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cycloocta[1,2,3- de]naphthalen-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol [0987] A mixture of (R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-t
  • Step 5 5-Ethynyl-6-fluoro-4-((R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazabenzo[4,5]cycloocta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol WSGR Docket No.
  • Step 3 (S)-5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3- de]naphthalene [0996] A mixture of (S)-2,5-dichloro-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (700 mg, 2.13 mmol), ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (677.13 mg, 4.25 mmol
  • Step 4 6-Fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3- de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol [0998] A mixture of (S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8,8a,9,10,11,12-hexahydr
  • Step 5 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol [1000] To a solution of 6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3
  • Step 2 5-Ethyl-6-fluoro-4-((R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13- tetraazabenzo[4,5]cycloocta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol [1005] To a solution of (R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-
  • Example 6 5-Ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol [1011] Example 6 was prepared in a similar manner to Example 1.
  • Example 7 5-Ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol [1013] Example 7 was prepared in a similar manner to Example 1.
  • Step 2 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-yl dimethylcarbamate [1020] To a solution of 6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cycloh
  • Step 2 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-yl isobutyrate [1025] To a solution of 6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a- WSGR Docket No.

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Abstract

L'invention concerne des inhibiteurs de KRAS, des compositions pharmaceutiques comprenant les composés inhibiteurs, et des procédés d'utilisation des composés inhibiteurs de KRAS pour le traitement de maladies ou de troubles.
PCT/US2024/017034 2023-02-24 2024-02-23 Modulateurs de kras Ceased WO2024178304A1 (fr)

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US202363500469P 2023-05-05 2023-05-05
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WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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Publication number Priority date Publication date Assignee Title
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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