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WO2025137267A1 - Modulateurs de l'activité de tnf-alpha - Google Patents

Modulateurs de l'activité de tnf-alpha Download PDF

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Publication number
WO2025137267A1
WO2025137267A1 PCT/US2024/061017 US2024061017W WO2025137267A1 WO 2025137267 A1 WO2025137267 A1 WO 2025137267A1 US 2024061017 W US2024061017 W US 2024061017W WO 2025137267 A1 WO2025137267 A1 WO 2025137267A1
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optionally substituted
pharmaceutically acceptable
solvate
oxide
compound
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Toufike Kanouni
Yoshiyuki Fukase
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Forward Therapeutics Inc
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Forward Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • TNF- ⁇ Tumor necrosis factor alpha
  • TNF- ⁇ is an inflammatory cytokine that is responsible for a wide range of signaling events within cells. Aberrant TNF- ⁇ signaling gives rise to inflammatory conditions and is thought to be an important component of inflammatory disease, such as rheumatoid arthritis.
  • One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof: wherein, W is N or C-R 10 ; X is N or C-R 11 ; Y is N or C-R 12 ; Z is N or C-R 13 ; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R 8 )(R 9 ), -S(O)(NH)R 8 , or -CH 2 -PO(R 8 )(R 9 ); R 1 is selected from hydrogen, optionally substituted C1
  • One embodiment provides a compound of Formula (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof: wherein, W is N or C-R 10 ; X is N or C-R 11 ; Y is N or C-R 12 ; Z is N or C-R 13 ; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, or - PO(R 8 )(R 9 ); R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen, optionally substituted C1 alkyl, or halogen; R 3 is hydrogen, or halogen; R 4 is hydrogen, optionally substituted C1 alkyl, or
  • Ring A is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, O or S;
  • R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R 8 )(R 9 ), -S(O)(NH)R 8 , or -CH 2 -PO(R 8 )(R 9 );
  • R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;
  • R 2 is hydrogen, optionally substituted C1 alkyl, or halogen;
  • R 3 is hydrogen, or
  • One embodiment provides a compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof: WSGR Ref: 53699-720.601 wherein, G is -CN, halogen, optionally substituted C1-C6 alkoxy, optionally substituted heteroarylalkoxy, optionally substituted C2-C6 alkynyl, (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2-C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl); R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen, optionally substituted C1 alkyl, or halogen; R 3 is hydrogen,
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, or N-oxide thereof, and at least one pharmaceutically acceptable excipient.
  • One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, or N-oxide thereof.
  • Another embodiment provides the method wherein the disease or disorder is rheumatoid arthritis.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl).
  • an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl WSGR Ref: 53699-720.601 comprises two to five carbon atoms (e.g., C2-C5 alkyl).
  • an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)tR 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 -CF 3 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
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)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(
  • 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 WSGR Ref: 53699-720.601 attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., 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) t R a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene).
  • an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene).
  • an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene).
  • an alkenylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkenylene).
  • an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, - N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)t
  • 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., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene).
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , - C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), WSGR Ref: 53699-720.601 -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from 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 -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -C(O)N(R a ) 2 , -R b
  • Aralkyl refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Aralkenyl refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • 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 -Re-aryl, where Re is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-Rc-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 spiro, fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, WSGR Ref: 53699-720.601 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-R
  • Carbocyclylalkyl refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • 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.
  • the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes WSGR Ref: 53699-720.601 spiro, 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 substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, 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-R c -C(O)N(
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, 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 –Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from 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 -C(O)R
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • 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: [0052]
  • the compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S.
  • Patent Nos.5,846,514 and 6,334,997 deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • 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 1H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds WSGR Ref: 53699-720.601 are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S.
  • 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.
  • CD 3 I 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 TNF- ⁇ 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, WSGR Ref: 53699-720.601 benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein 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.
  • WSGR Ref 53699-720.601
  • 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.
  • Tumor necrosis factor alpha (TNF ⁇ ) proteins are members of the TNF superfamily, comprising various transmembrane proteins with a homologous TNF domain forming trimers.
  • the TNF superfamily comprises 19 family members, including, but not limited to tumor necrosis factor alpha (also known as tumor necrosis factor, or TNF), lymphotoxin alpha (TNF ⁇ ), lymphotoxin beta (TNF ⁇ ), OX40 ligand, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, CD137 ligand, CD137 ligand, and TNF-related apoptosis-inducing ligand.
  • TNF tumor necrosis factor alpha
  • TNF ⁇ lymphotoxin alpha
  • TNF ⁇ lymphotoxin beta
  • OX40 ligand CD40 ligand
  • Fas ligand CD27 ligand
  • CD30 ligand CD137 ligand
  • CD137 ligand CD137 ligand
  • TNF ⁇ proteins are cytokines and adipokines (cytokines secreted by adipose tissue).
  • TNF ⁇ is a transmembrane protein, with soluble TNF ⁇ (sTNF ⁇ ) released via protein cleavage.
  • the sTNF ⁇ can propagate signaling by binding to two receptors, TNFR1 and TNFR2.
  • TNF ⁇ is a regulator of immune responses for cell signaling and can mediate cell survival and cell death inducing signaling. There are two receptors for TNF signaling, TNFR1 and TNFR2.
  • sTNF ⁇ – TNFR1 signaling promotes immune cell activation and drives acute and chronic inflammation.
  • TNFR1 membrane TNF ⁇ – TNFR2 signaling promotes inflammation resolution, immune cell regulatory functions and cell survival.
  • TNFR1 and TNFR2 have four homologous cysteine-rich domains, but they have structurally different intracellular regions.
  • TNFR1 has a protein binding region called a death domain which allows homo- and hetero-typic interactions with other death domain-containing proteins.
  • TNFR2 has a TNF Receptor Associated Factor TRAF) that interacts with TRAF family of signaling adaptors.
  • TRAF TNF Receptor Associated Factor
  • the distinct profiles and differences of the two TNF receptors influence the cellular activity and physiological roles.
  • TNFR1 can activate NF- ⁇ B and MAPK signaling, and cell death, and is important to regulate for inflammatory diseases.
  • TNFR2 is highly regulated and restricted to specific cell types such as endothelial cells and T cells.
  • TNFR1 primarily promotes tissue degeneration and inflammation WSGR Ref: 53699-720.601 and TNFR2 typically mediates local homestatic effects such as tissue regeneration and cell survival (D. Fresegna et al., Cells, 2020, 9, 2290).
  • Binding of TNF ⁇ to TNFR1 can activate NF- ⁇ B for mediating transcription of various proteins involved in cell survival and proliferation, anti-apoptotic factors, and inflammatory response.
  • the MAPK pathway can also be activated by binding of TNF ⁇ to TNFR1, which is involved in cell differentiation and proliferation.
  • TNF When TNF binds to TNFR1, it triggers receptor trimerization, leading to the assembly of a TNFR1-associated signaling complex.
  • This complex recruits the receptor interacting protein 1 (RIP2) and TNF receptor associated death domain (TRADD) to the TNFR1 through the receptive death domains.
  • TRADD then recruits adaptor proteins TRAF2 and TRAF5, which can engage the E3 ligases cellular inhibitors of apoptosis (c-IAP1, c-IAP2).
  • C-IAP1/2 are important for TNFR1 complex signaling, which can eventually lead to the recruitment of the signaling kinase complexes of kinase IKK ⁇ and IKK ⁇ , which are inhibitors of kappa B kinase 1 and 2, and transforming growth factor beta- activated kinase 1 (TAK1) leading to activation of NF- ⁇ B and MAPK signaling.
  • TNF signaling is regulated by post-translational ubiquitination, which is essential for my biological processes.
  • TNF has long been known to be a key regulator of the inflammatory response, and recently has been known to be involved n brain functioning (D. Fresegna et al., Cells, 2020, 9, 2290). As a regulator of the inflammatory response, TNF can regulate many aspects of T cell biology including, but not limited to proliferation, survival, priming, and apoptotic fate.
  • TNF is also known to play a role in conclusion of lymphocyte response, by the ability to promote cell death in both CD4 and CD8P T cells, through TNFR1. Specific inflammatory conditions can also result in TNFR2 promoting or supporting T cell apoptosis.
  • TNF is expressed at low levels, and it is believed that the expression could be influenced by presence or absence of cytokines that can cross the blood brain barrier.
  • TNFRs in the brain are expressed by glia and neurons cells, and have regulatory functions, including, but not limited to homeostatic synaptic plasticity, astrocyte-mediated synaptic transmission, and neurogenesis. These functions are useful for regulating learning and memory functions amongst other roles.
  • TNF is recognized to be physiological gliotransmitter for the communication between neurons and glial cells, which in turn affects synaptic regulation. Glial TNF is important for maintenance of normal surface expression of AMPA receptors, and for homeostatic synaptic scaling, which allows for adjustment of the strength of all synapses on a neuron.
  • Prior Art Small Molecules Inhibitors [0076] Diseases treated with biologic TNF ⁇ inhibitors include, but are not limited to rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis.
  • Patients with neuroinflammatory conditions and degenerative disease may benefit from treatment with oral CNS sTNF ⁇ inhibitors by disrupting the sTNF ⁇ signaling and sparing the mTNF ⁇ signaling.
  • Previous reports have also indicated targeting TNFR2 for treating Alzheimer’s Disease (N. Orti-Casa ⁇ et al., Front Neurosci.2019; 13: 49).
  • Small molecules have been developed for treatment of rheumatoid arthritis as some patients have responded poorly to monotherapy of approved anti-TNF ⁇ drugs (J. D. Dietrich et al., J. Med.
  • Anti-TNF ⁇ drugs have also been expanded for use in other chronic autoimmune diseases, including, but not limited to, Crohn’s disease, psoriasis, psoriatic arthritis, ulcerative colitis inflammatory bowel disease, ankylosing spondylitis, and juvenile rheumatoid arthritis. Small molecules have been developed as an alternative to anti- TNF ⁇ biologics since the long-term clinical response rate is generally around 60-70% for rheumatoid arthritis. [0078] Previous research has also indicated that TNF ⁇ inhibitors can be therapeutic for treatment of multiple sclerosis (D. Fresegna et al., Cells, 2020, 9, 2290).
  • TNF ⁇ inhibitors have the potential for treatment of multiple sclerosis, other potential chronic neurodegenerative diseases of the central nervous system.
  • TNF ⁇ is necessary for noise-induced neuroinflammation and synaptic imbalance (W. Wang et al., PLoS Biol.2019 Jun 18; 17(6):e3000307; A. Shulman et al., Curr Top Behav Neurosci.2021;51:161-174).
  • TNF ⁇ inhibitors can be used alone or in combination for treatment with inflammatory bowel disease (S. F. Fowler Braga and K. J. Clark, US Pharm. 2021; 46(5):34-37).
  • TNF ⁇ is a mediator of the abnormal immune response of inflammatory WSGR Ref: 53699-720.601 bowel disease, which leads to disruption of the intestinal mucosa and epithelial wall barrier.
  • the anti-TNF agents can block TNF-mediated activation of the proinflammatory pathways to result in decreased immune-mediated inflammation.
  • Small molecule sTNF ⁇ inhibitors are active in pharmacology models of sTNF ⁇ /TNFR1 signaling in addition to demonstrating efficacy in a model of collagen antibody induced arthritis. There is currently limited data in the public domain for small molecule sTNF ⁇ inhibitors.
  • Some TNF ⁇ inhibitors include, but are not limited to XPro1595, Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumamb, and other inhibitors described in “TNF- ⁇ : The Shape of Small Molecules to Come?” (A. Dömling and X.
  • TNF- ⁇ inhibitory compounds are provided herein.
  • One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof: wherein, W is N or C-R 10 ; X is N or C-R 11 ; Y is N or C-R 12 ; WSGR Ref: 53699-720.601 Z is N or C-R 13 ; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R 8 )(R 9 ), -S(O)(NH)R 8 , or -CH2-PO(R 8 )(R 9 ); R 1 is selected from hydrogen, optionally substituted C1-C
  • One embodiment provides a compound of Formula (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof: wherein, W is N or C-R 10 ; X is N or C-R 11 ; Y is N or C-R 12 ; Z is N or C-R 13 ; R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, or - PO(R 8 )(R 9 ); WSGR Ref: 53699-720.601 R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen, optionally substituted C1 alkyl, or halogen; R 3 is hydrogen, or halogen; R 4 is
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is N.
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein X is N.
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Y is N.
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Z is N.
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is C-R 10 .
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein X is C-R 11 .
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Y is C-R 12 .
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Z is C-R 13 .
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein each R 10 , R 11 , R 12 , and R 13 is independently selected from hydrogen or halogen.
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is N, Z is N, X is C-R 11 , WSGR Ref: 53699-720.601 and Y is C-R 12 .
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is N, Z is C-R 13 , X is C-R 11 , and Y is C-R 12 .
  • Another embodiment provides the compound of Formula (I) or (Ia), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein W is C-R 10 , Z is C-R 13 , X is C-R 11 , and Y is C-R 12 .
  • Ring A is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, O or S;
  • R is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkoxy, - PO(R 8 )(R 9 ), -S(O)(NH)R 8 , or -CH2-PO(R 8 )(R 9 );
  • R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl;
  • R 2 is hydrogen, optionally substituted C1 alkyl, or halogen;
  • R 3 is hydrogen, or halogen
  • Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein Ring A is selected from an optionally substituted imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, or triazole.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 1 is selected from hydrogen, or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 1 is CH 3 or CD 3 .
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 2 is hydrogen or halogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 3 is hydrogen or halogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 4 is hydrogen or halogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is hydrogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is optionally substituted C1 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is CH3.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C3 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkyl is substituted with at least an - OH or -NH 2 group.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C3-C6 carbocyclyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C5 carbocyclyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or WSGR Ref: 53699-720.601 deuteroisotope thereof, wherein R is optionally substituted C4 carbocyclyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted carbocyclyl is substituted with at least one group selected from -OH, -NH2, -CH3, -CN, or a halogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted heterocyclyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted 4- or 5-membered oxygen-containing heterocyclyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted oxetanyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted heterocyclyl is substituted with at least one group selected from -OH, -NH 2 , -CH 3 , -CN, or a halogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is 3-aminooxetan-3-yl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C6 alkoxy.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is optionally substituted C1-C2 alkoxy.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkoxy is substituted with at least one halogen.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein the optionally substituted alkoxy is substituted with at least one fluoro.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R is - PO(R 8 )(R 9 ).
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 8 and R 9 are each independently selected from optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, WSGR Ref: 53699-720.601 N-oxide, or deuteroisotope thereof, wherein R 8 and R 9 are each independently selected from optionally substituted C1-C3 alkyl.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 8 and R 9 are each CH3.
  • Another embodiment provides the compound of Formula (I), (Ia), or (II), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 8 and R 9 join to form a phosphorous-containing heterocyclic ring.
  • One embodiment provides a compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof: wherein, G is -CN, halogen, optionally substituted C1-C6 alkoxy, optionally substituted heteroarylalkoxy, optionally substituted C2-C6 alkynyl, (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2-C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl); R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C4-C7 cycloalkylalkyl; R 2 is hydrogen, optionally substituted C1 alkyl, or halogen; R 3 is hydrogen, or halogen; R 4 is hydrogen, optionally substituted optionally
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is -CN. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is halogen. Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is optionally substituted C1-C6 alkoxy.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is optionally substituted WSGR Ref: 53699-720.601 heteroarylalkoxy.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is - CH 2 -heteroaryl.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is - CH2-pyrazole.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is optionally substituted C2-C6 alkynyl.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein G is (optionally substituted C2-C6 alkynylene)-NH-(optionally substituted C3-C6 cycloalkyl), or (optionally substituted C2- C6 alkynylene)-O-(optionally substituted C3-C6 cycloalkyl).
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 1 is selected from hydrogen, or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 1 is CH3 or CD3.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 2 is hydrogen or halogen.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 3 is hydrogen or halogen.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 4 is hydrogen or halogen.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is hydrogen.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is optionally substituted C1 alkyl.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is CH3.
  • Another embodiment provides the compound of Formula (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, wherein R 5 is optionally substituted heterocyclyl.
  • WSGR Ref 53699-720.601
  • TNF- ⁇ inhibitory compound or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, having a structure presented in Table 1.
  • Table 1 WSGR Ref: 53699-720.601
  • WSGR Ref 53699-720.601
  • compositions [0127]
  • the TNF- ⁇ inhibitory compound described herein is administered as a pure chemical.
  • the TNF- ⁇ inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one TNF- ⁇ inhibitory compound as described herein, or pharmaceutically acceptable salt, solvate, or N- oxide thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.
  • the TNF- ⁇ inhibitory compound as described by Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope 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.
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.
  • the TNF- ⁇ inhibitory compound as described by Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope 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.
  • 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.
  • the TNF- ⁇ 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 TNF- ⁇ 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 WSGR Ref: 53699-720.601 generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • One embodiment provides a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder.
  • Another embodiment provides a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of inflammatory disease or disorder.
  • Yet another embodiment provides a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of autoimmune disease or disorder.
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.
  • One embodiment provides a use of a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.
  • a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof comprising administering to the patient a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt, solvate, or N- oxide thereof.
  • a method of treating inflammatory or autoimmune disease or disorder, in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a method of treating an inflammatory disease or disorder.
  • Another embodiment provides a method of treating an autoimmune disease or disorder.
  • One embodiment provides a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope 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 pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder.
  • One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder.
  • One embodiment provides a use of a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder.
  • a method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof comprising administering to the patient a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof.
  • a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Table 2, or pharmaceutically acceptable salt, solvate, N-oxide, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.
  • the inflammatory and autoimmune disease or disorder is selected from, but are not limited to: rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer’s disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout, and gouty arthritis, ulcerative TNF receptor associated periodic syndrome (TRAPS), Wegener’s granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills.
  • rheumatoid arthritis psoriatic arthritis, systemic onset juvenile
  • One embodiment provides a method of inhibiting TNF- ⁇ activity comprising contacting the TNF- ⁇ protein with a compound of Formula (I), (Ia), (II), or (III), or Table 1, or Table 2.
  • WSGR Ref: 53699-720.601 Another embodiment provides the method of inhibiting TNF- ⁇ activity, wherein the TNF- ⁇ protein is contacted in an in vivo setting.
  • Another embodiment provides the method of inhibiting TNF- ⁇ activity, wherein the TNF- ⁇ protein is contacted in an in vitro setting.
  • Example 1 (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • 7R,14R -11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one (50 mg, 0.078 mmol) in THF (2 mL) was added TBAF (93 uL, 0.094 mmol, 1
  • Example 3 (7R,14R)-1-ethynyl-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one
  • Preparation 3A (7R,14R)-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one
  • Example 4 (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one WSGR Ref: 53699-720.601
  • Example 10 (7R,14R)-11-(4-(aminomethyl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 10A tert-butyl (2-fluoro-4-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)benzyl)carbamate To a stirred mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((triisopropylsilyl)
  • the reaction was diluted by the addition of water (10 mL) at room temperature and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was WSGR Ref: 53699-720.601 concentrated under reduced pressure.
  • Example 11 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • a solution of (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one 40 mg, 0.072 mmol
  • THF mL
  • TBAF 23 mg, 0.086 mmol
  • Example 12 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 12A (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- WSGR Ref: 53699-720.601 a][1,4]diazocin-5(14H)-one
  • Example 12 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-pyrazol-3-yl)-6,7-dihydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • TBAF TBAF
  • Example 13 (7R,14R)-11-(4-(3-aminooxetan-3-yl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one WSGR Ref: 53699-720.601
  • Preparation 13A N-[3-(4-bromophenyl) oxetan-3-yl]-2-methylpropane-2-sulfinamide
  • n-butyllithium solution 8 mL, 20.000 mmol, 2.5 M in THF
  • Example 13 (7R,14R)-11-(4-(3-aminooxetan-3-yl)phenyl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • a solution of (7R,14R)-11-(4-(3-aminooxetan-3-yl)phenyl)-6-(methyl-d3)-1-((triisopropylsilyl) ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one 35 mg, 0.056 mmol) in THF (1 mL) was added TBAF (68 uL, 0.067 mmol, 1M in THF) at room
  • the resulting mixture was stirred for 2 h at room temperature.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous Na 2 SO 4 .
  • Example 14 (7R,14R)-11-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 18 (7R,14R)-11-(2-(2-aminospiro[3.3]heptan-2-yl)pyrimidin-5-yl)-1-ethynyl- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • WSGR Ref 53699-720.601
  • Preparation 18A 2-methyl-N- ⁇ spiro[3.3]heptan-2-ylidene ⁇ propane-2-sulfinamide
  • THF 10 mL
  • Example 19 (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 19A tert-butyl (1-(5-((7R,14R)-1-hydroxy-6-(methyl-d3)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f] benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl) pyrimidin-2- yl)cyclobutyl)carbamate
  • the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 20 (7R,14R)-11-(6-(1-aminocyclobutyl)-5-fluoropyridin-3-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one
  • Preparation 20A N-cyclobutylidene-2-methylpropane-2-sulfinamide
  • cyclobutanone (10.00 g, 142.672 mmol) and tert-butanesulfinamide (14.41 g, 118.893 mmol) in THF (100 mL) was added Ti(Oi-Pr) 4 (67.58 g, 237.787 mmol) dropwise at room temperature.
  • the resulting mixture was stirred at room temperature for 1 h.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (4 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred at room temperature for 2 h.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (4 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere.
  • the resulting mixture was diluted with EtOAc (100 mL).
  • the resulting mixture was washed with 3 x 20 mL of water.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Example 22 (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • tert-butyl (1-(5-((7R,14R)-6-methyl-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)cyclobutyl)carbamate (150 mg, 0.209 mmol) in DCM (2 mL) was added TFA (0.4 mL) at room temperature.
  • Example 23 (7R,14R)-11-(2-(1-amino-3,3-dimethylcyclobutyl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • WSGR Ref 53699-720.601
  • Preparation 23A N-(3,3-dimethylcyclobutylidene)-2-methylpropane-2-sulfinamide
  • Ti(Oi-Pr)4 5.86 g, 20.627 mmol
  • Example 24 (7R,14R)-11-(2-((1s,3S)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 24A 2-methyl-N-(3-methylcyclobutylidene)propane-2-sulfinamide
  • THF 30 mL
  • Example 25 (7R,14R)-11-(2-((1r,3R)-1-amino-3-methylcyclobutyl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • WSGR Ref 53699-720.601
  • Preparation 25A 2-methyl-N-((1r,3R)-3-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)cycl
  • Example 26 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 26A (7R,14R)-6-(methyl-d3)-11-(1-methyl-1H-imidazol-4-yl)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Example 27 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(piperazin-1-yl)pyrimidin-5-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 27A tert-butyl 4-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)piperazine-1-carboxylate To a stirred mixture of (7R,14R)-11-chloro-6-(methyl-d3)-1-((trimethy
  • Example 27 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(piperazin-1-yl)pyrimidin-5-yl)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 28 and 29 (1S,3s)-3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile and (1R,3r)-3-amino-3-(5-((7R,14R)-1- WSGR Ref: 53699-720.601 ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-
  • N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2- sulfinamide (1.60 g, 7.536 mmol) in DCM (20 mL) dropwise at -76 °C.
  • the resulting mixture was stirred for additional 2 h at -76 °C under nitrogen atmosphere.
  • the reaction was quenched WSGR Ref: 53699-720.601 with water at 0 °C.
  • the resulting mixture was extracted with CH2Cl2 (3 x 100 mL).
  • the combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Example 28 and 29 (1S,3s)-3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)- 1-methylcyclobutane-1-carbonitrile and (1R,3r)-3-amino-3-(5-((7R,14R)-1-ethynyl-6-(methyl- d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile 3-amino-3-(5-((7R,
  • Example 30 (7R,14R)-11-(6-(2-aminospiro[3.3]heptan-2-yl)pyridin-3-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one
  • Preparation 30A N-[2-(5-bromopyridin-2-yl)spiro[3.3]heptan-2-yl]-2-methylpropane-2- sulfinamide
  • 5-bromo-2-iodopyridine 527 mg, 1.856 mmol
  • Toluene (7 mL) was added 2.5M n-BuLi (0.74 mL, 1.856 mmol) at -78 °C under nitrogen atmosphere.
  • Example 31 and 32 (7R,14R)-11-(2-((1S,2R)-1-amino-2-methylcyclobutyl)pyrimidin-5- yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(2-((1R,2S)-1-amino-2- methylcyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 31A 2-methyl-N-(2-methylcyclobutylidene)propane-2-sulfinamide
  • the resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere.
  • the reaction was quenched by the addition of sat. NaHCO3 aq. (10 mL).
  • the mixture was diluted with ethyl acetate (10 mL), stirred for 10 min. and filtered, the filter cake was washed with ethyl acetate (20 mL).
  • the aqueous layer was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 33 (7R,14R)-11-(2-(6-amino-2-oxaspiro[3.3]heptan-6-yl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 33A 6-(5-bromopyrimidin-2-yl)-2-oxaspiro[3.3]heptan-6-ol
  • To a stirred solution of 5-bromo-2-iodopyrimidine (1.40 g, 4.905 mmol) in DCM (10 mL) was added 2.5 M n-BuLi in hexane (1.96 mL, 4.905 mmol) at -78 °C under nitrogen atmosphere.
  • the resulting mixture was stirred at 60 °C for 16 h.
  • the resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH 3 CN in Water (10 mmol/L NH 4 HCO 3 ), 20% to 55% gradient in 25 min; detector, 254 nm.
  • Example 34 (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(but-1-yn-1-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one WSGR Ref: 53699-720.601
  • Preparation 34A tert-butyl (1-(5-((7R,14R)-1-(but-1-yn-1-yl)-6-(methyl-d3)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate To a stirred mixture of (7R,14R)-11-
  • Example 35 (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 35A N-cyclopentylidene-2-methylpropane-2-sulfinamide
  • cyclopentanone 3.00 g, 35.664 mmol
  • tert-butanesulfinamide 5.19 g, 42.797 mmol
  • Ti(Oi-Pr) 4 21.3 mL, 71.328 mmol
  • Example 36 and 37 (7R,14R)-11-(6-((1S,2R)-1-amino-2-methylcyclobutyl)pyridin-3- yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(6-((1R,2S)-1-amino-2-methylcyclobutyl)pyridin- 3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one WSGR Ref: 53699-720.601
  • Preparation 36A 2-methyl-N-(2-methylcyclobutylidobuty
  • the resulting mixture was stirred at room temperature for 12 h. The reaction was quenched with water at room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (5 x 20 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH 3 CN in Water (10 mmol/L NH 4 HCO 3 ), 20% to 50% gradient in 30 min; detector, 254 nm to (7R,14R)-11-(6-(1-amino-2-methylcyclobutyl)pyridin-3-yl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one (54 mg, 95%) as a yellow solid.
  • Example 38 (7R,14R)-11-(2-(1-amino-3,3-difluorocyclobutyl)pyrimidin-5-yl)-1- ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 38A 1-(5-bromopyrimidin-2-yl)-3,3-difluorocyclobutan-1-ol
  • To a stirred solution of 5-bromo-2-iodopyrimidine (1477 mg, 5.185 mmol) in DCM (15 mL) was added 2.5 M n-BuLi in hexane (2.07 mL, 5.185 mmol) at -78 °C under nitrogen atmosphere.
  • the resulting mixture was stirred at 60 °C for 6 h.
  • the resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10 mmol/L NH 4 HCO 3 ), 25% to 55% gradient in 30 min; detector, 254 nm.
  • the resulting mixture was concentrated under vacuum.
  • Example 40 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(pyrrolidin-2-yl)pyrimidin-5-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one formate
  • Preparation 40A 3-(dimethylamino)-2-iodoprop-2-enal To a solution of 3-(dimethylamino)prop-2-enal (5.00 g, 50.437 mmol) in DCM (200 mL) was added NIS (11.35 g, 50.437 mmol) at room temperature.
  • the reaction was stirred for 1 h at room temperature.
  • the reaction mixture was washed with sat aqueous Na2S2O3 (150 mL) and water (2 x 50 mL).
  • the organic phase was dried over Na2SO4 and concentrated to give a black solid.
  • the crude product was re-crystallized from ethyl acetate/hexane (1/4, 40mL) to afford 3- (dimethylamino)-2-iodoprop-2-enal (8.30 g, 73%) as a dark yellow solid.
  • Preparation 40C tert-butyl 2-(5-iodopyrimidin-2-yl)pyrrolidine-1-carboxylate A solution of tert-butyl 2-carbamimidoylpyrrolidine-1-carboxylate (1.30 g, 6.095 mmol) and t- BuONa (0.64 g, 6.705 mmol) in EtOH (18 mL) was stirred at room temperature for 10 min. To the above solution was added 3-(dimethylamino)-2-iodoprop-2-enal (1.65 g, 7.314 mmol) at room temperature. The resulting mixture was stirred at 80 °C for additional 16 h.
  • the resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 42 (7R,14R)-11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 42A N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide
  • 2-bromo-5-iodopyridine 5.83 g, 20.542 mmol
  • THF 40 mL
  • n- butyllithium solution 8 mL, 20.00 mmol, 2.5M in THF
  • reaction mixture was stirred at -78 °C for 30 min. Then a solution of 2-methyl- N-(oxetan-3-ylidene)propane-2-sulfinamide (3.00 g, 17.118 mmol) in 10 mL THF was added to above reaction dropwise and the mixture was stirred for another 1 h. The reaction was quenched with sat. NH4Cl (50 mL), extracted with EtOAc (3 x 50 mL).
  • the resulting mixture was stirred for 2 h at room temperature.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with water (5 x 10 mL), dried over anhydrous Na 2 SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 +0.05%NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% to 48% B in 10 min; Wave Length: 254nm/220nm) to afford (7R,14R)- 11-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (4 mg, 15%).
  • Example 43 (7R,14R)-11-(2-(1-aminocyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 43A (7R,14R)-1-chloro-6-(methyl-d 3 )-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- WSGR Ref: 53699-720.601 2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 44 and 45 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-((R)-pyrrolidin-2- yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one and (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-((S)-pyrrolidin-2-yl)pyrimidin-5-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one WSGR Ref: 53699-720.601 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-(2-(pyrrolidin-2-yl)pyrimidin-5-yl
  • Example 46 (7R,14R)-11-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Example 47 and 48 (7R,14R)-11-(2-((1s,3S)-1-amino-3-methoxycyclobutyl)pyrimidin- 5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one and (7R,14R)-11-(2-((1r,3R)-1-amino-3- methoxycyclobutyl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 47A N-(3-methoxy-1-(5-((7R,14R)-6-(methyl-
  • the resulting mixture was stirred at room temperature for 1 h.
  • the reaction was quenched by the addition of Water (5 mL) at room temperature.
  • the mixture was basified to pH 7 with saturated Na2CO3 (aq.).
  • the resulting mixture was extracted with EtOAc (3 x 15 mL).
  • the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 50 (7R,14R)-6-(methyl-d3)-11-(2-(2-methylpyrrolidin-2-yl)pyrimidin-5-yl)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 50A tert-butyl 2-methyl-2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)pyrrolidine-1-carboxylate
  • the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in EtOAc (20 mL). The resulting mixture was diluted with water (10 mL). The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred at room temperature for 2 h.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 40% B in 10 min; Wave Length: 254 nm; RT1(min): 12.06) to afford (7R,14R)-1-ethynyl-11-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- WSGR Ref: 53699-720.601 one (10 mg, 80%).
  • Example 52 (7R,14R)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-11-(2-(pyrrolidin-2- yl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 52A tert-butyl 2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)pyrrolidine-1-carboxylate To a stirred mixture of tert-butyl 2-(5-((7R,14R)-1-ch
  • Example 53 (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (3,3,3-trifluoroprop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 53A tert-butyl (1-(5-((7R,14R)-1-ethynyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro- 7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)cyclobutyl)carbamate
  • Example 54 (7R,14R)-11-(2-(2-aminopropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 54A 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide To a stirred solution of acetone (4.79 g, 82.510 mmol) and tert-butanesulfinamide (2.00 g, 16.502 mmol) in THF (50 mL) was added Titanium(IV) ethoxide (18.82 g, 82.510 mmol) slowly at room temperature.
  • Example 54 (7R,14R)-11-(2-(2-aminopropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn- 1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 55 (7R,14R)-11-(2-(4-aminotetrahydro-2H-pyran-4-yl)pyrimidin-5-yl)-6-(methyl-d3)- 1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Example 56 (7R,14R)-1-ethynyl-11-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 56A (7R,14R)-11-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Example 56 (7R,14R)-1-ethynyl-11-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • 7R,14R -11-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (55 mg, 0.090 mmol) in DMF (1 mL) was added CsF (136 mg, WSGR Ref: 53699-720.601 0.900 mmol).
  • Example 57 (7R,14R)-11-(2-(2-aminopropan-2-yl)thiazol-5-yl)-1-ethynyl-6-(methyl-d3)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • the resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH 3 CN in Water (10mmol/L NH 4 HCO 3 ), 5% to 45% gradient in 30 min; detector, 254 nm to afford (7R,14R)-11-(2-(1-aminocyclobutyl)thiazol-5-yl)-1-ethynyl- 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one (11 mg, 17%).
  • Example 59 (7R,14R)-10-fluoro-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 59A (7R,14R)-11-chloro-10-fluoro-1-hydroxy-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • the resulting mixture was stirred at room temperature for 2 h.
  • the resulting mixture was filtered and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in Water (10mmol/L NH4HCO3), 30% to 45% gradient in 20 min; detector, 254 nm.
  • Example 61 (7R,14R)-11-(2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • WSGR Ref 53699-720.601
  • Example 62 (7R,14R)-11-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)-6-(methyl- d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • (7R,14R)-1-chloro-11-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)- WSGR Ref: 53699-720.601 6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one 50 mg, 0.104 mmol
  • trimethyl(prop-2-yn-1-yl)silane 14 mg, 0.104 mmol
  • Example 63 (7R,14R)-11-(2-(1-hydroxyethyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1- yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 63A (7R,14R)-1-hydroxy-11-(2-(1-hydroxyethyl)pyrimidin-5-yl)-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 66 (7R,14R)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-11-(2-(pyrrolidin-3-yl)pyrimidin-5-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one formate
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5 ⁇ m, n; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% to 23% in 10 min; Wave Length: 254 nm) to afford (7R,14R)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-11-(2-(pyrrolidin-3-yl)pyrimidin- 5-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one formate (15 mg, 33%).
  • Example 68 (7R,14R)-11-(2-(azetidin-3-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn- 1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 68A tert-butyl 3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)
  • Example 68 (7R,14R)-11-(2-(azetidin-3-yl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one formate
  • Example 70 (7R,14R)-11-(2-(2-hydroxyethoxy)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop- 1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one
  • (7R,14R)-1-chloro-11-(2-(2-hydroxyethoxy)pyrimidin-5-yl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (30 mg, 0.065 mmol) and trimethyl(prop-2-yn-1-yl)silane (36 mg, 0.325 mmol
  • Example 71 (7R,14R)-11-(2-(1-aminocyclopropyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 71A tert-butyl (1-(5-bromopyrimidin-2-yl)cyclopropyl)carbamate
  • 1-(5-bromopyrimidin-2-yl)cyclopropan-1-amine hydrochloride 100 mg, 0.399 mmol
  • DCM 2-ethylamine
  • Example 72 (7R,14R)-11-(2-((2R,3S)-3-amino-2-methylazetidin-1-yl)pyrimidin-5-yl)- 6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 72A tert-butyl ((2R,3S)-2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1- yn-1-yl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)azetidin-3-yl)c
  • Example 72 (7R,14R)-11-(2-((2R,3S)-3-amino-2-methylazetidin-1-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one To a stirred solution of tert-butyl ((2R,3S)-2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- (prop-1-yn-1-yl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4
  • Example 75 (7R,14R)-11-(2-((S)-2-(aminomethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 75A tert-butyl (((S)-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- WSGR Ref: 53699-720.601 yl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl
  • Example 76 (7R,14R)-11-(2-(1-hydroxycyclopropyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • WSGR Ref 53699-720.601
  • Preparation 76A (7R,14R)-11-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyrimidin-5-yl)- 1-hydroxy-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Example 79 (7R,14R)-11-(2-(1-aminopropyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1- yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 79A tert-butyl (1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)propyl)carbamate
  • tert-butyl (1-(5-((7R,14R)-1-
  • Example 82 (7R,14R)-11-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 82A (7R,14R)-1-hydroxy-11-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 82 (7R,14R)-11-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop-1- yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • (7R,14R)-11-(2-(1-hydroxycyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-5- oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-1-yl trifluoromethanesulfonate 50 mg, 0.085 mmol
  • KF 14 mg, 0.255 mmol
  • Pd(PPh3)2Cl2 11 mg, 0.017 m
  • Example 83 (7R,14R)-11-(2-(1-hydroxycyclopentyl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one WSGR Ref: 53699-720.601
  • Preparation 83A (7R,14R)-1-hydroxy-11-(2-(1-hydroxycyclopentyl)pyrimidin-5-yl)-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 85 (7R,14R)-11-(2-(3-aminoazetidin-1-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 85A tert-butyl (1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2- yl)azetidin-3-yl)carbamate
  • tert-butyl (1-(5-(5-(5-(5
  • Example 87 (7R,14R)-11-(2-((2S,3R)-3-amino-2-methylazetidin-1-yl)pyrimidin-5-yl)- 6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 87A tert-butyl ((2S,3R)-2-methyl-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1- WSGR Ref: 53699-720.601 yn-1-yl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2
  • Example 88 (7R,14R)-11-(2-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)pyrimidin-5- yl)-6-(methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Preparation 88A tert-butyl ((3R,4R)-4-hydroxy-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1- yn-1-yl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2
  • Example 88 (7R,14R)-11-(2-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)pyrimidin-5-yl)-6- (methyl-d3)-1-(prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • tert-butyl ((3R,4R)-4-hydroxy-1-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- WSGR Ref: 53699-720.601 (prop-1-yn-1-yl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)pyrrol
  • Example 90 (7R,14R)-6-(methyl-d3)-11-(2-(3-methylazetidin-3-yl)pyrimidin-5-yl)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 90A tert-butyl 3-methyl-3-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-(prop-1-yn-1-yl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)azetidine-1-carboxylate To a stirred mixture of tert-butyl 3-(5-((7R,
  • Example 91 (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(ethyl-d5)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • a mixture of (7R,14R)-1-chloro-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-6-(ethyl-d5)-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one 50 mg, 0.097 mmol), trimethyl(prop-2-yn-1-yl)silane (21 mg, 0.194 mmol), K 2 CO 3 (67 mg, 0.485 mmol), SP
  • Example 92 (7R,14R)-11-(2-(3-aminopentan-3-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • Preparation 92A 2-methyl-N-(3-(5-((7R,14R)-6-(methyl-d 3 )-5-oxo-1-(prop-1-yn-1-yl)-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin
  • Example 93 (7R,14R)-11-(2-(2-aminopropan-2-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 93A tert-butyl (2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1-((triisopropylsilyl)ethynyl)- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11- yl)pyrimidin-2-yl)propan-2-yl)carbamate A mixture of (7R,14R)-6-(methyl-d3)-11-(4,4,5,
  • Example 93 (7R,14R)-11-(2-(2-aminopropan-2-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 94 (7R,14R)-11-(2-(3-aminopentan-3-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • WSGR Ref 53699-720.601
  • Preparation 94A (7R,14R)-1-chloro-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • the resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere.
  • the resulting mixture was diluted with water (10 mL) followed by extraction with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure.
  • Example 95 (7R,14R)-11-(2-(1-hydroxypropyl)pyrimidin-5-yl)-6-(methyl-d3)-1-(prop- 1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one WSGR Ref: 53699-720.601
  • Preparation 95A (7R,14R)-1-hydroxy-11-(2-(1-hydroxypropyl)pyrimidin-5-yl)-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Example 96 (7R,14R)-11-(2-(2-aminobutan-2-yl)pyrimidin-5-yl)-1-ethynyl-6-(methyl- d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • Preparation 96A 2-methyl-N-(2-(5-((7R,14R)-6-(methyl-d3)-5-oxo-1- ((triisopropylsilyl)ethynyl)-5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-11-yl)pyrimidin-2-yl)butan-2-yl)propane-2-sulfinamide
  • the resulting mixture was concentrated under vacuum.
  • the mixture was basified to pH 8 with saturated Na2CO3 (aq.).
  • the precipitated solids was filtered, the filter cake was washed with EtOAc (4 x 100 mL).
  • the resulting mixture was extracted with EtOAc (3 x 400 mL).
  • the combined organic layers were concentrated under reduced pressure.
  • Example 97 (7R,14R)-2-fluoro-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6-(methyl-d3)-1- (prop-1-yn-1-yl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one
  • (7R,14R)-1-chloro-2-fluoro-11-(2-(2-hydroxypropan-2-yl)pyrimidin-5- yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 5(14H)-one 60 mg, 0.125 mmol
  • trimethyl(prop-2-yn-1-yl)silane 70 mg, 0.625 mmol
  • Example 98 (7R,14R)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-1-ethynyl-6- (methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one WSGR Ref: 53699-720.601
  • Preparation 98A (7R,14R)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one
  • Example 99 (7R,14R)-11-(difluoromethoxy)-1-ethynyl-6-(methyl-d3)-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one
  • 7R,14R -11-(difluoromethoxy)-6-(methyl-d3)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one (50 mg, 0.093 mmol) in THF (1 mL) was added TBAF (0.11 mL, 0.112 mmol, 1M in THF) at room temperature.
  • Example 100 (7R,14R)-1-ethynyl-6-(methyl-d3)-11-((1-methyl-1H-pyrazol-4- yl)methoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)- one
  • Preparation 100A (7R,14R)-6-(methyl-d3)-11-((1-methyl-1H-pyrazol-4-yl)methoxy)-1- ((triisopropylsilyl)ethynyl)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-5(14H)-one

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Abstract

L'invention concerne des inhibiteurs de TNF-alpha, des compositions pharmaceutiques comprenant les composés inhibiteurs, et des procédés d'utilisation des composés inhibiteurs de TNF-alpha pour le traitement de maladies ou de troubles.
PCT/US2024/061017 2023-12-21 2024-12-19 Modulateurs de l'activité de tnf-alpha Pending WO2025137267A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016050975A1 (fr) * 2014-10-03 2016-04-07 Ucb Biopharma Sprl Dérivés d'imidazole pentacycliques fusionnés
WO2020084008A1 (fr) * 2018-10-24 2020-04-30 UCB Biopharma SRL Dérivés d'imidazole pentacycliques fusionnés utilisés en tant que modulateurs de l'activité du tnf
WO2024251282A1 (fr) * 2023-06-09 2024-12-12 上海翰森生物医药科技有限公司 Inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016050975A1 (fr) * 2014-10-03 2016-04-07 Ucb Biopharma Sprl Dérivés d'imidazole pentacycliques fusionnés
WO2020084008A1 (fr) * 2018-10-24 2020-04-30 UCB Biopharma SRL Dérivés d'imidazole pentacycliques fusionnés utilisés en tant que modulateurs de l'activité du tnf
WO2024251282A1 (fr) * 2023-06-09 2024-12-12 上海翰森生物医药科技有限公司 Inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation

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