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WO2025058977A1 - Modulateurs de protéase de type 3c de coronavirus et leurs utilisations - Google Patents

Modulateurs de protéase de type 3c de coronavirus et leurs utilisations Download PDF

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WO2025058977A1
WO2025058977A1 PCT/US2024/045797 US2024045797W WO2025058977A1 WO 2025058977 A1 WO2025058977 A1 WO 2025058977A1 US 2024045797 W US2024045797 W US 2024045797W WO 2025058977 A1 WO2025058977 A1 WO 2025058977A1
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mmol
alkylene
methyl
compound
salt
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Inventor
Rajan Anand
Brett C. Bookser
Nathan Shapiro
Peijun LI
Sungjoon HUH
Carl ESTRADA
Delphine KARILA
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Vir Biotechnology Inc
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Vir Biotechnology 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
    • C07D487/22—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 four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • COVID-19 coronavirus disease 2019
  • 3C-like protease is present in the SARS-CoV-2 virus.
  • Very few drugs are known to effectively inhibit (e.g., inhibit the replication of) SARS ⁇ CoV ⁇ 2, such as by modulating (e.g., inhibiting) the activity of 3C-like protease.
  • R 1a and R 1b are each independently selected from: hydrogen; and C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -C(O)OR 11 , -OC(O)R 11 , - N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 ,
  • the compound or salt is represented by the structure of Formula (II): or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L 1 , L 2 , R 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • the compound or salt is represented by the structure of Formula (IV): or a pharmaceutically acceptable salt thereof; wherein Ring B, L 1 , L 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • the compound or salt is represented by the structure of Formula (V): , or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • the compound or salt is represented by the structure of Formula (VI): or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), and at least one pharmaceutically acceptable excipient.
  • a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof comprising administering to the subject an effective amount of a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).
  • the disease or disorder associated with a coronavirus 3CL protease is a coronavirus infection.
  • the disease or disorder associated with a coronavirus 3CL protease is a SARS-CoV-2 infection.
  • a method of inhibiting the replication of a coronavirus comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).
  • the coronavirus is SARS-CoV-2.
  • Alkyl refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond.
  • an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C 1 - C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C 1 -C 3 alkyl).
  • an alkyl comprises one to two carbon atoms (i.e., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C 3 -C 5 alkyl).
  • the alkyl group may be attached to the rest of the molecule by a single bind, such as, 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), and the like.
  • a single bind such as, 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), and the like.
  • 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 preferably having from two to twelve carbon atoms (i.e., C 2 -C 12 alkenyl).
  • an alkenyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenyl).
  • an alkenyl comprises two to six carbon atoms (i.e., C 2 -C 6 alkenyl).
  • an alkenyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkenyl).
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • but-1-enyl but-1-enyl
  • pent-1-enyl penta-1,4-dienyl
  • 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.
  • Alkynyl refers to a straight or branched hydrocarbon chain
  • an alkynyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C 2 -C 6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the radical group can be attached to the alkylene group and simultaneously be attached to the rest of the molecule. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene).
  • an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene).
  • an alkylene comprises one to five carbon atoms (i.e., C 1 -C 5 alkylene).
  • an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene).
  • an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene).
  • an alkylene comprises one to two carbon atoms (i.e., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkylene).
  • Alkenylene refers to a straight 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 preferably 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.
  • the radical group can be attached to the alkenylene group and simultaneously be attached to the rest of the molecule.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkenylene comprises two to ten carbon atoms (i.e., C 2 -C 10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene).
  • an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).
  • Alkynylene refers to a straight 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 preferably 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.
  • the radical group can be attached to the alkynylene group and simultaneously be attached to the rest of the molecule.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkynylene comprises two to ten carbon atoms (i.e., C 2 -C 10 alkynylene).
  • an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkynylene).
  • an alkynylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkynylene).
  • Cx-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C 1-6 alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • -Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • -C 1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • C x-y alkenyl and “C x-y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • -Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • - C 2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain.
  • -C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • the term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • Bicyclic carbocycles may be fused, bridged or spiro- ring systems.
  • the carbocycle is an aryl.
  • the carbocycle is a cycloalkyl.
  • the carbocycle is a cycloalkenyl.
  • an aromatic ring e.g., phenyl
  • carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “carbocyclene” as used herein refers to a divalent saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A carbocyclene may be optionally substituted by one or more substituents such as those substituents described herein.
  • Carbocyclene includes divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the carbocyclene to the rest of the molecule and the single bond connecting the carbocyclene to the radical group may be located on the same ring or different rings of a polycyclic carbocyclene.
  • the carbocyclene is an arylene, for example, a phenylene.
  • a “phenylene” as used herein refers to a divalent benzene group. The phenylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A phenylene may be optionally substituted by one or more substituents such as those substituents described herein.
  • Cycloalkyl refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl).
  • a cycloalkyl comprises three to ten carbon atoms (i.e., C 3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl).
  • the cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl 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. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • Cycloalkenyl refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C 3-12 cycloalkenyl).
  • a cycloalkenyl comprises three to ten carbon atoms (i.e., C 3-10 cycloalkenyl).
  • a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl).
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, 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 may be optionally substituted by one or more substituents such as those substituents described herein.
  • C x-y carbocycle is meant to include groups that contain from x to y carbons in a ring.
  • C3-6 carbocycle can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms ⁇ any of which is optionally substituted as provided herein.
  • heterocycle refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings.
  • Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
  • the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
  • the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • the heterocycle is a heteroaryl.
  • the heterocycle is a heterocycloalkyl.
  • exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl.
  • Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • Bicyclic heterocycles may be fused, bridged or spiro-ring systems.
  • a heterocycle e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “heterocyclene” as used herein refers to a divalent saturated, unsaturated, non- aromatic or aromatic ring comprising one or more heteroatoms.
  • Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • the heterocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the single bond attaching the heterocyclene group to the rest of the molecule and the single bond attaching the heterocyclene group to the radical group may be each independently connected through any atom of the heterocyclene as valency permits, including a carbon atom in the heterocyclene ring or a heteroatom in the heterocyclene ring.
  • a heterocyclene may be optionally substituted by one or more substituents such as those substituents described herein.
  • Heterocyclenes include 3- to 10- membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings).
  • Each ring of a polycyclic heterocyclene may be selected from saturated, unsaturated, and aromatic rings.
  • Polycyclic heterocyclenes may be fused, bridged or spiro-ring systems.
  • the single bond connecting the heterocyclene to the rest of the molecule and the single bond connecting the heterocyclene to the radical group may be located on the same ring or different rings of a polycyclic heterocyclene and may be attached to the rest of the molecule or the radical group through any atom of the heterocyclene, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclene is a heteroarylene. In some embodiments, the heterocyclene is a heterocycloalkylene. [0032] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms.
  • the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • the heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl 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
  • Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ring radical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • the heteroaryl ring may be selected from monocyclic or polycyclic (bicyclic and fused or bridged) systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.
  • Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic.
  • An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring.
  • a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Halo or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • haloalkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I).
  • halomethane e.g., chloromethane, bromomethane, fluoromethane, iodomethane
  • each halogen may be independently selected for example, 1-chloro,2-fluoroethane.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH 2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • salts or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • administer are defined as providing a composition to a subject via a route, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • administered should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit.
  • treatment or treating involves administering a compound or composition disclosed herein to a subject.
  • a therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • a “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • R 1a and R 1b are each independently hydrogen or C 1-4 alkyl. In some embodiments, R 1a and R 1b are each independently C 1-4 alkyl. In some embodiments, R 1a is C1-4 alkyl. In some embodiments, R 1b is C1-4 alkyl. In some embodiments, R 1a and R 1b are each independently hydrogen, methyl, or ethyl.
  • the compound or salt is represented by the structure of Formula (II): or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L 1 , L 2 , R 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • R 3 is absent; or selected from C6-10 carbocyclene and 5- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)N(R 13 ) 2 , -C(O)OR 13 , -OC(O)R 13 , -N(R 13 )C(O)R 13 , - N(R 13 )C(O)OR 13 , -N(R 13 )S(O) 2 R 13 , -S(O) 2 N(R 13 ) 2 , -S(O)R 13 , -S(O) 2 R 13 , -NO2, and -CN; and C 1-6 alkyl optionally substituted with one or more
  • R 3 is absent.
  • R 3 is selected from C 6 -C 10 arylene and 5- to 10-membered heteroarylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , - C(O)N(R 13 ) 2 , -C(O)OR 13 , -OC(O)R 13 , -N(R 13 )C(O)R 13 , -N(R 13 )C(O)OR 13 , -N(R 13 )S(O) 2 R 13 , - S(O) 2 N(R 13 ) 2 , -S(O)R 13 , -S(O) 2 R 13 , -NO 2 , and -CN; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -
  • R 3 is selected from C 6 -C 10 arylene. In some embodiments, R 3 is selected from 5- to 10-membered heteroarylene. In some embodiments, R 3 is selected from C6 arylene and 9-membered heteroarylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 13 , and C 1-6 alkyl optionally substituted with one or two substituents independently selected from halogen and -OR 13 . In some embodiments, is selected from C6 arylene. In some embodiments, R 3 is selected from 9-membered heteroarylene.
  • R 3 is optionally substituted with one or more substituents independently selected from halogen, -OR 13 , and C 1-6 alkyl optionally substituted with one or two substituents independently selected from halogen and -OR 13 . In some embodiments, R 3 is optionally substituted with one or two or three substituents independently selected from halogen, -OR 13 , and C 1-6 alkyl optionally substituted with one or two substituents independently selected from halogen and -OR 13 . In some embodiments, R 3 is selected from phenylene, benzoxazolene, and the point of connection between R 3 and L 2 .
  • the compound or salt is represented by the structure of Formula (IV): or a pharmaceutically acceptable salt thereof; wherein Ring B, L 1 , L 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • n is selected from 0, 1, 2, 3, and 4. In some embodiments, n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 1, 2, 3, and 4. In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 2 and 3. In some embodiments, n is 2. In some embodiments, n is 3.
  • L 1 is absent or C1-2 alkylene. In some embodiments, L 1 is absent or methylene. In some embodiments, L 1 is absent. In some embodiments, L 1 is methylene. [0062] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (V):
  • the compound or salt is represented by the structure of Formula (VI): or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • Ring B is 5- to 10-membered heterocyclene. In some embodiments, Ring B is 5- to 10-membered heteroarylene. In some embodiments, Ring B is selected from triazolylene, pyridylene, quinolinylene, and pyrrolopyridylene. In some embodiments, Ring B is selected from triazolylene. In some embodiments, Ring B is selected from pyridylene. In some embodiments, Ring B is selected from quinolinylene. In some embodiments, Ring B is selected from pyrrolopyridylene.
  • R 5 is independently selected at each occurrence from halogen, -OR 14 , -CN, and C 1-6 alkyl. In some embodiments, R 5 is independently selected at each occurrence from halogen. In some embodiments, R 5 is independently selected at each occurrence from halogen; and m is 0 or 1 or 2 or 3. In some embodiments, R 5 is independently selected at each occurrence from chloro. In some embodiments, R 5 is independently selected at each occurrence from chloro; and m is 0 or 1. [0066] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), m is selected from 0, 1, 2, 3, and 4.
  • m is selected from 0, 1, 2, and 3. In some embodiments, m is selected from 0, 1, and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1. [0067] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (IV), is selected from wherein y denotes the point of connection to L 2 .
  • L 2 is selected from: ; wherein t denotes the point of connection to Ring B.
  • R 6 is selected from: hydrogen; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , - N(R 16 )C(O)OR 16 , -N(R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 ,
  • R 6 is selected from hydrogen and C 1-6 alkyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1-6 alkyl. In some embodiments, R 6 is selected from hydrogen, methyl, and ethyl. In some embodiments, R 6 is selected from hydrogen and methyl. In some embodiments, R 6 is methyl.
  • R 3 is absent and the structure of Formula (I) is represented by the structure of Formula (VII): or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L 1 , L 2 , R 1a , R 1b , R 2 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • L 1 is absent and the structure of Formula (I) is represented by the structure of Formula (VIII):
  • Ring A, Ring B, L 2 , R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • Ring A, Ring B, L 2 , R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound or salt of Formula (I).
  • the compound or salt is ,
  • the compound or salt is ,
  • compounds or salts of Formula (I), are intended to include all Z-, E- and tautomeric forms as well.
  • “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. “Atropisomers” are different compounds displaying different conformations due to hindered rotation at a single bond.
  • the compounds or salts for Formula (I), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • Stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • compounds or salts for Formula (I) may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers.
  • Methods of producing substantially pure enantiomers exist.
  • a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302).
  • Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds or salts for Formula (I) exist as tautomers.
  • a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • Some non–limiting examples of tautomeric equilibrium include: [0081]
  • the compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds 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.
  • deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • compounds described 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.
  • salts particularly pharmaceutically acceptable salts, of the compounds of Formula (I).
  • the compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • the methods and compositions of Formula (I) include the use of amorphous forms as well as crystalline forms (e.g., polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • Compounds of Formula (I) also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • compounds or salts of Formula (I) may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • Prodrugs may help enhance the cell permeability of a compound relative to the parent drug.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell.
  • the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell.
  • the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell.
  • the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
  • the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
  • the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (III) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (IV) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (V) and at least one pharmaceutically acceptable excipient.
  • the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (VI) and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
  • the pharmaceutical compositions can also include the compounds, salts or conjugates in a free- base form or pharmaceutically-acceptable salt form.
  • Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate).
  • the active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated.
  • the active compounds can have complementary activities that do not adversely affect each other.
  • the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant.
  • chemotherapeutic agent cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant.
  • Such molecules can be present in combination in amounts that are effective for the purpose intended.
  • the compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.
  • the compositions can be formulated for administration as an injection.
  • Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles.
  • Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension can also contain suitable stabilizers.
  • Injections can be formulated for bolus injection or continuous infusion.
  • the compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds, salts or conjugates can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle.
  • Vehicles can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin.
  • Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used.
  • Liposomes can be used as carriers.
  • the vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
  • Sustained-release preparations can also be prepared.
  • sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules).
  • sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides, copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly- D-( –)-3-hydroxybutyric acid.
  • LUPRON DEPO TM i.e., injectable microspheres composed of
  • compositions can be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer.
  • This formulation can be a lyophilized formulation or an aqueous solution.
  • Acceptable carriers, excipients, and/or stabilizers can be nontoxic to recipients at the dosages and concentrations used.
  • Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non- ionic surfactants or polyethylene glycol.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid and methionine
  • preservatives polypeptides
  • proteins such as serum albumin or gelatin
  • hydrophilic polymers amino acids
  • a compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be formulated in any suitable pharmaceutical formulation.
  • a pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.
  • a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).
  • EDTA ethylene diamine tetra acetic acid
  • Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration.
  • the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject.
  • the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration.
  • the dosage form is formulated for oral administration.
  • the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder.
  • the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form.
  • the disclosure provides a pharmaceutical composition for oral administration containing at least one compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) and a pharmaceutical excipient suitable for oral administration.
  • compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs.
  • Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier.
  • the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) moistened with an inert liquid diluent.
  • an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (
  • the disclosure provides a pharmaceutical composition for injection containing a compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) disclosed herein and a pharmaceutical excipient suitable for injection.
  • a pharmaceutical excipient suitable for injection a pharmaceutical excipient suitable for injection.
  • Components and amounts of agents in the composition are as described herein.
  • the compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • compositions may also be prepared from a compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration.
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the present disclosure provides a method for treatment, comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I).
  • a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof the method comprising administering to the subject an effective amount of a compound or salt of Formula (I).
  • a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof the method comprising administering to the subject an effective amount of a compound or salt of Formula (II).
  • provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (III). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (IV). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (V).
  • a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof comprising administering to the subject an effective amount of a compound or salt of Formula (VI).
  • the disease or disorder associated with a coronavirus 3CL protease is a coronavirus infection.
  • the disease or disorder associated with a coronavirus 3CL protease is a SARS-CoV-2 infection.
  • the disease or disorder associated with a coronavirus 3CL protease is a MERS (e.g., MERS-CoV) infection, a SARS (e.g., SARS-CoV, SARS-CoV-1) infection, a 229E (e.g., HCoV-229E) infection, a NL63 (e.g., HCoV-NL63) infection, a OC43 (e.g., HCoV-OC43) infection, or a HKU1 (e.g., HCoV-HKU1) infection.
  • MERS e.g., MERS-CoV
  • SARS e.g., SARS-CoV, SARS-CoV-1
  • 229E e.g., HCoV-229E
  • NL63 e.g., HCoV-NL63
  • OC43 e.g., HCoV-OC43
  • HKU1 e.g., HCoV-
  • provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (I). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (II). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (III).
  • provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (IV). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (V). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (VI).
  • the coronavirus is SARS-CoV-2. In some embodiments, the coronavirus is MERS-CoV, SARS-CoV-1, HCoV-229E, HCoV-NL63, HCoV-OC43, or HCoV-HKU1.
  • EXAMPLES [0121] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to limit the disclosure in any way. [0122] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein.
  • Step 1 A mixture of (3-methoxycarbonylphenyl)boronic acid (709 mg, 3.94 mmol, 1.5 eq), N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (900 mg, 2.63 mmol, 1 eq), Pd2(dba)3 (120 mg, 131 ⁇ mol, 0.05 eq), PCy3 (88 mg, 315 ⁇ mol, 102 ⁇ L, 0.12 eq) and K3PO4 (947.34 mg, 4.46 mmol, 1.7 eq) in dioxane (9 mL) and Water (4.5 m
  • Step 2 To a solution of methyl 3-(4-((diphenylmethylene)amino)isoquinolin-5- yl)benzoate (650 mg, 1.47 mmol, 1 eq) in THF (19 mL) and EtOH (19 mL) was added HCl (2 M, 3.08 mL, 4.19 eq). The mixture was stirred at 20°C for 12 h. LCMS analysis showed the reaction was completed. The resulting mixture was concentrated under reduced pressure to give a residue.
  • Step 1 A mixture of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (4.2 g, 12.25 mmol, 1 eq), LiCl (1.56 g, 36.75 mmol, 3 eq), allyltributylstannane (8.11 g, 36.75 mmol, 7.52 mL, 2 eq) and Pd(PPh3) 2 Cl2 in DMF (40 mL) were degassed and purged with N2 for 3 times, then the resulting mixture was heated to 90°C and stirred at 90 °C for 12 h under N2 atmosphere.
  • Step 2 To a solution of N-(5-allylisoquinolin-4-yl)-1,1-diphenylmethanimine in MeCN (20 mL) was added TFA (4 mL) and H2O (4 mL) at 20°C. The mixture was stirred at 20°C for 4 h. The resulting mixture was diluted with H 2 O (30 mL) and extracted with petroleum ether (3 ⁇ 30 mL). The water layer was lyophilization to give 5-allylisoquinolin-4-amine (1922 mg, 34.68 mmol, 74% yield).
  • Step 2.2-(But-3-en-1-yloxy)-4-methoxyaniline A mixture of 2-(but-3-en-1-yloxy)-4- methoxy-1-nitrobenzene (950 mg, 0.18 mmol), SnCl2 (4.00 g, 21.3 mmol), and 1.07 mL of conc. HCl in 43 mL of EtOH was heated at 100 C for 90 min, then cooled to rt and 5.3 mL of 10 M NaOH was added with ice bath cooling and the mixture stirred 5 min. The mixture was diluted with EtOAc, water and then filtered. The filtrate was washed with water, brine, dried (MgSO4) and evaporated.
  • 2-(but-3-en-1-yloxy)-4- methoxy-1-nitrobenzene 950 mg, 0.18 mmol
  • SnCl2 (4.00 g, 21.3 mmol)
  • 1.07 mL of conc. HCl in 43 mL of EtOH was heated at 100
  • Step 2 To a solution of 1-(allyloxy)-3-chloro-5-methoxy-2-nitrobenzene (900.00 mg, 3.69 mmol, 1 eq) in EtOH (10 mL) and H 2 O (2 mL) was added NH 4 Cl (1.98 g, 36.94 mmol, 10 eq) at 20°C. The resulting mixture was heated to 80°C and stirred at 80°C for 5 min. Then Fe (1.24 g, 22.16 mmol, 6 eq) was added, and then mixture was stirred at 80°C for 12 h. LCMS analysis showed the starting material was consumed completely and desired product was formed. Another vial was set up as described above.
  • the reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (500 mL ⁇ 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure.
  • Step 3 tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)(methyl)carbamate.
  • Step 1 To a solution of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (1.8 g, 5.25 mmol, 1 eq) in dioxane (18 mL) and H2O (3.6 mL) was added (4- (methoxycarbonyl)phenyl)boronic acid (1.89 g, 10.50 mmol, 2 eq), K3PO4 (1.89 g, 8.93 mmol, 1.7 eq), Pd 2 (dba) 3 (240.40 mg, 262.53 ⁇ mol, 0.05 eq), PCy 3 (176.69 mg, 630.07 ⁇ mol, 204.26 ⁇ L, 0.12 eq) under N2.
  • Step 2 To a solution of methyl methyl 4-(4-((diphenylmethylene)amino)isoquinolin-5- yl)benzoate (1.25 g, 2.82 mmol, 1 eq) in THF (32.5 mL) and MeOH (32.5 mL) was added HCl (2 M, 5.65 mL, 4 eq). Then the mixture was stirred at 20°C for 12 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was added into MTBE (5 mL).
  • Step 1 A mixture of tert-butyl (5-bromoisoquinolin-4-yl)carbamate (8 g, 24.75 mmol, 1 eq), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (9.77 g, 37.13 mmol, 1.5 eq), Pd(dppf)Cl 2 (3.62 g, 4.95 mmol, 0.2 eq), K 3 PO 4 (7.88 g, 37.13 mmol, 1.5 eq) in dioxane (80 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 6 h under N2 atmosphere.
  • Step 2 To a solution of methyl 4-(4-((tert-butoxycarbonyl)amino)isoquinolin-5- yl)picolinate (9.55 g, 25.17 mmol, 1 eq) in DCM (40 mL) was added HCl/dioxane (4 M, 95 mL, 15.10 eq). The mixture was stirred at 25°C for 3 h.
  • Step 1 A mixture of tert-butyl (5-bromoisoquinolin-4-yl)carbamate (0.5 g, 1.55 mmol, 1 eq), trimethyl(prop-2-ynoxy)silane (496.02 mg, 3.87 mmol, 594.03 ⁇ L, 2.5 eq), Pd(PPh 3 ) 2 Cl 2 (217.18 mg, 309.42 ⁇ mol, 0.2 eq), CuI (370.36 mg, 437.55 ⁇ mol, 0.1 eq), TEA (3.71 g, 11.38 mmol, 2.6 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the resulting mixture was heated to 90°C and stirred at 90°C for 12 h under N2 atmosphere.
  • Step 2 To a solution of Pd/C (1.61 g, 1.51 mmol, 10% purity, 0.3 eq), Pd(OH) 2 (423.66 mg, 301.67 ⁇ mol, 10% purity, 0.06 eq) in EtOH (5 mL) was added tert-butyl (5-(3-hydroxyprop- 1-yn-1-yl)isoquinolin-4-yl)carbamate (1.5 g, 5.03 mmol, 1 eq) and the mixture was purged with H 2 for 3 times, the resulting mixture was stirred at 25°C for 2 h under H 2 atmosphere.
  • Step 1 A mixture of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (5 g, 14.58 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.04 g, 26.25 mmol, 4.45 mL, 1.8 eq), K 3 PO 4 (4.64 g, 21.88 mmol, 1.5 eq), Pd(OAc) 2 (163.72 mg, 729.25 ⁇ mol, 0.05 eq) and XPhos (695.29 mg, 1.46 mmol, 0.1 eq) in dioxane (30 mL) and H2O (3 mL) was degassed and purged with N 2 for 3 times, and then The
  • Step 2 A mixture of 1,1-diphenyl-N-(5-vinylisoquinolin-4-yl)methanimine (2 g, 5.98 mmol, 1 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then added 9- BBN (0.5 M, 40 mL, 3.34 eq) at 0°C, the mixture was stirred at 35°C for 12 h under N 2 atmosphere.
  • Step 1 A mixture of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (16 g, 46.67 mmol, 1eq), tert-butyl acrylate (6.58 g, 51.34 mmol, 7.45 mL, 1.1 eq), palladium bis(tri-tert- butylphosphine) (715.55 mg, 1.40 mmol, 0.03 eq) and N-cyclohexyl-N-methyl-cyclohexanamine (10.03 g, 51.34 mmol, 10.89 mL, 1.1 eq) in Tol.
  • Step 2 To a solution of Pd/C (19.00 g, 17.85 mmol, 10% purity) in EtOH (200 mL) was added tert-butyl (E)-3-(4-((diphenylmethylene)amino)isoquinolin-5-yl)acrylate (19 g, 43.73 mmol, 1eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25°C for 2 h. LCMS showed the reaction mixture was completed.
  • Step 3 To a solution of tert-butyl 3-(4-((diphenylmethylene)amino)isoquinolin-5- yl)propanoate (1.2 g, 2.75 mmol, 1eq) in MeOH (10 mL) was added NaOAc (1.98 g, 24.19 mmol, 8.8 eq) and hydroxylamine;hydrochloride (2.29 g, 32.99 mmol, 12 eq). The mixture was stirred at 20°C for 12 h. LCMS showed the reaction mixture was completed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 1 A mixture of 3-bromo-5-nitropyridin-4-amine (20 g, 91.74 mmol, 1 eq), ethynyl(trimethyl)silane (27.03 g, 275.22 mmol, 38.13 mL, 3 eq) and Et 3 N (58.48 g, 577.96 mmol, 80.44 mL, 6.3 eq) in dioxane (300 mL) was degassed and purged with N2 for 3 times, then PdCl2(PPh3) 2 (3.22 g, 4.59 mmol, 0.05 eq) and CuI (873.59 mg, 4.59 mmol, 0.05 eq) was added to above mixture.
  • the resulting mixture was degassed and purged with N 2 for 3 times, then it was heated to 70°C and stirred at 70°C for 12 h under N2 atmosphere.
  • the resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic layers were washed with water (2 ⁇ 100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of 3-nitro-5-((trimethylsilyl)ethynyl)pyridin-4-amine (30 g, 127.49 mmol, 1 eq) in MeOH (400 mL) was added K2CO3 (52.86 g, 382.47 mmol, 3 eq) at 25°C. The resulting mixture was stirred at 25°C for 2 h. The resulting mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 ⁇ 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • K2CO3 52.86 g, 382.47 mmol, 3 eq
  • Step 3 A mixture of 3-ethynyl-5-nitropyridin-4-amine (9.5 g, 58.23 mmol, 1 eq) and pyrrolidine (8.28 g, 116.47 mmol, 9.72 mL, 2 eq) in H2O (500 mL) was heated 150°C and stirred at 150°C for 1 h. Three vial was set up as described above. All four reaction mixtures were combined for work up and purification. LCMS analysis showed 10% starting material remained and 84% of desired compound was detected. The resulting mixture was filtered and concentrated under reduced pressure to give a residue.
  • the resulting mixture was heated to 60°C and stirred at 60°C for 12 h.
  • the reaction mixture was poured into ice water (2000 mL) and extracted with ethyl acetate (3 ⁇ 1000 mL). The combined organic layers were washed with water (2 ⁇ 800 mL) and brine (1000 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-nitro-1H-pyrrolo[3,2- c]pyridine (46 g, 143.10 mmol, 1 eq) in EtOH (450 mL) and H 2 O (90 mL) was added NH 4 Cl (76.55 g, 1.43 mol, 10 eq) at 20°C. The resulting mixture was heated to 90°C and stirred at 90°C for 5 min. Then Fe (47.95 g, 858.62 mmol, 6 eq) was added, and the mixture was stirred at 90°C for 12 h.
  • NH 4 Cl 76.55 g, 1.43 mol, 10 eq
  • Step 1 To a solution of 7-nitro-1H-pyrrolo[3,2-c]pyridine (8 g, 49.04 mmol, 1 eq) in DMF (80 mL) was added 3-bromoprop-1-ene (11.87 g, 98.08 mmol, 2 eq) and K 2 CO 3 (13.56 g, 98.08 mmol, 2 eq). The mixture was heated to 50°C and stirred at 50°C for 8 h. LCMS analysis showed the reaction was completed.
  • Step 2 To a solution of 1-allyl-7-nitro-1H-pyrrolo[3,2-c]pyridine (2 g, 9.84 mmol, 1 eq) in EtOH (10 mL) and H2O (2 mL) was added NH4Cl (5.26 g, 98.43 mmol, 10 eq), then Fe (3.30 g, 59.06 mmol, 6 eq) was added at 80°C to the mixture, the mixture was stirred at 80°C for 12 h. LCMS analysis showed desired product was formed. The reaction mixture was filtered before cold. Then the resulting mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (2 ⁇ 20 mL).
  • Step 1 To a solution of 3-chloro-5-nitropyridin-4-ol (12 g, 68.75 mmol, 1 eq) in acetone (50 mL) was added K2CO3 (14.25 g, 103.13 mmol, 1.5 eq) and allyl bromide (12.48 g, 103.13 mmol, 1.5 eq) at 20°C. The resulting mixture was heated to 40°C and stirred at 40°C for 12 h. LCMS analysis showed the starting material was consumed completely. The resulting mixture was filtered, the filter liquor concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 6-chloro-2-methyl-2H-indazol-5-amine (10 g, 55.06 mmol, 1 eq) in ACN (100 mL) was slowly added NBS (9.8 g, 55.06 mmol, 1 eq) at 0°C. The resulting mixture was heated to 25°C and stirred at 25°C for 1 h. LCMS analysis showed starting material was consumed completely and one main peak with desired mass was detected.
  • Step 2 To a solution of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (3 g, 11.51 mmol, 1 eq) in dioxane (24 mL) and H2O (6 mL) was added potassium; trifluoro (vinyl) boranuide (3.08 g, 23.02 mmol, 2 eq), Cs 2 CO 3 (7.5 g, 23.02 mmol, 2 eq) and Pd(dppf)Cl 2. CH 2 Cl 2 (0.94 g, 1.15 mmol, 0.1 eq) at 25°C. The resulting mixture was heated to 80°C and stirred at 80°C for 12 h.
  • Step 2 To a solution of benzyl (4-bromo-6-chloro-2-methyl-2H-indazol-5-yl)carbamate (4 g, 10.14 mmol, 1 eq) and tert-butyl prop-2-yn-1-ylcarbamate (3.93 g, 25.32 mmol, 2.5 eq) in DMF (50 mL) and TEA (25 mL) was added CuI (0.27 g, 2.03 mmol, 0.2 eq) and Pd(PPh3) 2 Cl2 (0.94 g, 1.15 mmol, 0.1 eq) at 25°C.
  • Step 3 To a solution of 5% Pd/C (1 g) in EA (20 mL) was added benzyl (4-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2-methyl-2H-indazol-5-yl)carbamate (2 g, 42.65 mmol, 1 eq) under N 2 atmosphere. The suspension was degassed and purged with H 2 for 5 times. The mixture was stirred under H2 (15 Psi.) at 50°C for 12 h. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue.
  • Step 1 A mixture of (3,4,5-trifluorophenyl)methanamine (20 g, 124 mmol, 1 eq) and benzoyl isothiocyanate (22.3 g, 136 mmol, 18.4 mL, 1.1 eq) in DCM (200 mL) was degassed and purged with N 2 for 3 times, and then the resulting mixture was stirred at 25°C for 3 h under N 2 atmosphere.
  • Step 2 To a solution of N'-benzoyl-N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (40 g, 123 mmol, 99% yield). LCMS (ESI+): m/z 325.2 [M+H] + . [0189] Step 2: To a solution of N'-benzoyl-N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (40 g, 123.33 mmol, 1 eq) in EtOH (400 mL) was added NaOH (1 M, 400 mL) at 25°C. The resulting mixture was stirred at 25°C for 2 h.
  • Step 3 To a solution of N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (34 g, 154 mmol, 1 eq) in EtOH (350 mL) were added NaHCO3 (14.27 g, 169.83 mmol, 6.61 mL, 1.1 eq) and MeI (21.91 g, 154.39 mmol, 9.61 mL, 1 eq) at 25°C. The resulting mixture was heated to 50°C and stirred at 50°C for 1 h. The resulting mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 1 A mixture of (2,4,5-trifluorophenyl)methanamine (30 g, 186.19 mmol, 1 eq), benzoyl isothiocyanate (33.42 g, 204.81 mmol, 27.56 mL, 1.1 eq) in DCM (300 mL) was degassed and purged with N 2 for 3 times, and then the resulting mixture was stirred at 25°C for 2 h under N2 atmosphere. LCMS showed the desired product was formed.
  • Step 2 A mixture of N'-benzoyl-N-(2,4,5-trifluorobenzyl)carbamimidothioic acid (35 g, 107.92 mmol, 1 eq), NaOH (1 M, 175 mL, 1.62 eq) in EtOH (175 mL) was degassed and purged with N 2 for 3 times, and then the resulting mixture was heated to 80°C and stirred at 80°C for 2 h under N2 atmosphere. LCMS analysis showed the desired product was formed. The resulting mixture was concentrated under reduced pressure to remove EtOH (250 mL).
  • Step 3 A mixture of N-(2,4,5-trifluorobenzyl)carbamimidothioic acid (20 g, 91 mmol, 1 eq), CH 3 I (12.9 g, 91 mmol, 5.68 mL, 1 eq) in EtOH (200 mL) was degassed and purged with N 2 for 3 times at 20°C, and then the resulting mixture was heated to 50°C and stirred at 50°C for 0.5h under N2 atmosphere. LCMS analysis showed the desired product was formed. The resulting mixture was concentrated under reduced pressure to remove EtOH (100 mL).
  • Step 2 To a solution of methyl 1-allyl-1H-1,2,4-triazole-3-carboxylate (5 g, 29.91 mmol, 1 eq) in THF (25 mL) was added LiAlH4 (1.14 g, 29.91 mmol, 1 eq) under N2 atmosphere at 0°C. The resulting mixture was stirred at 0°C for 1 h. The resulting mixture was quenched by adding NaSO4 ⁇ 10H2O at 0°C, and then filtered and concentrated under reduced pressure to give (1-allyl-1H-1,2,4-triazol-3-yl)methanol (2 g, 14 mmol, 48% yield).
  • Step 3 To a solution of 6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine- 2,4(1H,3H)-dione (5.5 g, 18.14 mmol, 1 eq) in THF (50 mL) was added (1-allyl-1H-1,2,4- triazol-3-yl)methanol (5.05 g, 36.27 mmol, 2 eq), PPh 3 (9.61 g, 36.64 mmol, 2.02 eq) and DIAD (4.51 g, 22.31 mmol, 1.23 eq) at 0°C. The resulting mixture was stirred at 25°C for 1 h.
  • Step 1 A mixture of 4-chloro-3-methylbenzonitrile (25 g, 164.92 mmol, 1 eq), NBS (35.22 g, 197.90 mmol, 1.2 eq) and AIBN (13.54 g, 82.46 mmol, 0.5 eq) in isopropyl acetate (250 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 80°C for 3 h under N 2 atmosphere.
  • Step 2 To a solution of NH3/MeOH (7 M, 371.88 mL, 30 eq) in MeOH (2 L) was added 3-(bromomethyl)-4-chlorobenzonitrile (20 g, 86.77 mmol, 1 eq) at 25°C. The mixture was heated to 40°C and stirred at 40°C for 12 h. TLC showed the reaction mixture was completed. Another both reaction were set up as described above. All three reaction mixtures were combined for work up and purification.
  • Step 3 A mixture of 3-(aminomethyl)-4-chlorobenzonitrile (20 g, 80.80 mmol, 1 eq, HBr) and TEA (12.26 g, 121.20 mmol, 16.87 mL, 1.5 eq) in DCM (200 mL) was degassed and purged with N 2 for 3 times, Then benzoyl isothiocyanate (13.85 g, 84.84 mmol, 11.41 mL, 1.05 eq) in DCM (100 mL) was added dropwise and then the mixture was stirred at 25°C for 3 h under N2 atmosphere.
  • Step 4 A mixture of (Z)-N'-benzoyl-N-(2-chloro-5-cyanobenzyl)carbamimidothioic acid (20 g, 60.64 mmol, 1 eq) in EtOH (200 mL) was added NaOH (1 M, 200.00 mL, 3.30 eq).
  • Step 5 A mixture of N-(2-chloro-5-cyanobenzyl)carbamimidothioic acid (11 g, 48.74 mmol, 1 eq) in EtOH (150 mL) was added NaHCO3 (4.09 g, 48.74 mmol, 1.90 mL, 1 eq) and MeI (6.92 g, 48.74 mmol, 3.03 mL, 1 eq). Then the mixture was stirred at 50°C for 1 h under N2 atmosphere. LCMS showed the reaction mixture was completed. The resulting mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 6 A mixture of methyl 3-(4-aminoisoquinolin-5-yl)benzoate (5.26 g, 18.90 mmol, 1eq), methyl (2-chloro-5-cyanobenzyl)carbamimidothioate (9.73 g, 26.46 mmol, 1.4 eq, HI), TEA (14.54 g, 143.69 mmol, 20 mL, 7.60 eq) in MeCN (100 mL) was added DSC (48.42 g, 189.00 mmol, 10 eq) and DMAP (461.81 mg, 3.78 mmol, 0.2 eq).
  • reaction mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 h under N 2 atmosphere. LCMS showed the reaction mixture was completed.
  • the reaction mixture was filtered and the filter layer was concentrated.
  • the crude product was poured into water (100 mL), extracted with ethyl acetate (30 mL ⁇ 3). The organic layer was washed with brine (50 mL) and dried over Na 2 SO 4 and concentrated.
  • the final target was purified by SFC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; gradient:55%-85% B over 8.0 min) to give peak 1 (2.3 g, 3.89 mmol, 45.40% yield, 98.7% purity) and peak 2 (2.26 g, 3.85 mmol, 44.88% yield, 99.3% purity).
  • the reaction was cooled to room temperature, poured into ice water (200 mL) and stirred for 10 min. The pH value of the solution was adjusted to 9 ⁇ 10 with aqueous NaOH (30%). Then H2O2 (30%, 20 mL) was added slowly at 5 °C. The resulting mixture was stirred at 25 °C for 2 h, extracted with ethyl acetate (150 mL ⁇ 3). The combined organic layer were washed with brine (100 mL ⁇ 3), dried over Na2SO4, then filtered and concentrated under reduced pressure.
  • Step 4 methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-5-carboxylate and methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-3-carboxylate.
  • methyl 1H-1,2,4-triazole-3-carboxylate 5.4 g, 42.5 mmol
  • tert-butyl 3-(2- bromoethyl)benzoate (12.0 g, 42.3 mmol) in CH3CN (150 mL) was added K2CO3 (11.7 g, 84.8 mmol) at 25 o C under N 2 protection.
  • Methyl 1-(3-(tert- butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-5-carboxylate LC-MS m/z (ESI): [M+H] + 332.3.
  • Methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-3-carboxylate LC-MS m/z (ESI): [M+H] + 332.3.
  • Step 5 tert-butyl 3-(2-(5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate.
  • methanol 50 mL
  • water 5 mL
  • NaBH4 2.2 g, 56.7 mmoL
  • Step 6 tert-butyl 3-(2-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate.
  • Step 2 tert-butyl 3-(2-(3-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate.
  • Step 3 6-chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine: To a solution of potassium; trifluoro(methoxymethyl)boranuide (2.6 g, 17.1 mmol), K2CO3 (3.4 g, 24.6 mmol) and 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (2.1 g, 8.1 mmol) in dioxane (200 mL) and H2O (40 mL) was added Pd(dppf)Cl2 (650 mg, 0.9 mmol) at 25 °C under N2 protection. The resulting mixture was stirred at 100 °C for 16 h. After cooled to room temperature.
  • Step 2 4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine.
  • 6- chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine 950 mg, 4.05 mmol
  • allyl(bromo)magnesium 9.5 mL, 9.5 mmol, 1 M in THF
  • the resulting mixture was stirred at 25 °C for 14 h. After cooled to 0 °C.
  • the reaction mixture was quenched with 30 mL of saturated aqueous NH 4 Cl, extracted with ethyl acetate (40 mL ⁇ 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , then filtered and concentrated under reduced pressure.
  • the crude product was purified by C18 column (0.5% NH 3 •H 2 O-MeCN system) to afford 4-(but-3-en-1-yl)-6- chloro-2-methyl-2H-indazol-5-amine (452 mg 48% yield).
  • Step 2 (2-(aminomethyl)-4,5-difluorophenyl)methanol.
  • 2-carbamoyl- 4,5-difluorobenzoic acid (16.0 g, 81.5 mmol, 1.0 eq) in THF (330 mL)
  • BH 3 -THF (1M, 408 ml, 408 mmol, 5.0 eq) was added dropwise at 20 °C.
  • the resulting mixture was stirred at 60 °C for 14 h. After cooled to 0 °C.
  • the reaction mixture was quenched with 100 mL of MeOH.
  • the reaction mixture was concentrated to dryness.
  • the reaction mixture was diluted with 50 mL of water, extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na 2 SO 4 , then filtered and concentrated under reduced pressure.
  • the crude product was purified Prep-HPLC column (0.5% NH 3 •H 2 O-MeCN system) to provide tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4-yl)methyl)carbamate (520 mg, 43.6% yield).
  • Step 2 benzyl (4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2-methyl- 2H-indazol-5-yl)carbamate.
  • the reaction mixture was diluted with 50 mL of water, extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure.
  • the residue was purified by C18 column (0.5% NH3•H2O-MeCN system) to afford tert-butyl (2-(5-amino-6- chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate (1.0 g, 22.6% yield).
  • Step 2 6-chloro-2-methyl-4-(2-(methylamino)ethyl)-2H-indazol-5-amine.
  • BH3-THF tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate (1.0 g, 3.1 mmol) in BH3-THF (20 mL, 1.0 M in THF) was stirred at 50 °C for 12 h under N2 protection. After cooled to room temperature. The reaction mixture was quenched with 30 mL of MeOH and 10 mL of HCl (1.0 N). The mixture was stirred at 50 °C for 2 h. After cooled to room temperature.
  • Step 3 3-((3-(4-(allyloxy)-5-chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-4-methylbenzonitrile.
  • the resulting mixture was stirred at 50 °C for 14 h. After cooled to room temperature.
  • the reaction mixture was diluted with 80 mL of water, extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na 2 SO 4 , then filtered and concentrated under reduced pressure.
  • Step 3 methyl 3-((3-amino-5-chloropyridin-4-yl)methyl)benzoate.
  • the reaction mixture was diluted with 40 mL of water, extracted with ethyl acetate (80 mL ⁇ 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure.
  • Step 2 methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-5-carboxylate and methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-3-carboxylate.
  • Step 4 tert-butyl 3-((5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate.
  • Step 2 tert-butyl 3-((3-((4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate.
  • Step 3 tert-butyl 4-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)butanoate.
  • Step 2.5-Chloroisoquinolin-4-amine To a suspension of N-(5-chloroisoquinolin-4-yl)- 1,1-diphenylmethanimine (75.0 g, 177 mmol) in THF (885 mL) was added HCl (177 mL, 177 mmol) (1M solution in water), and the suspension was stirred at rt for 16 h, more HCl (1M solution in water, 88.5 mL, 88.5 mmol) was added and stirring was continued for another 24 h (40 h in total), The reaction mixture was concentrated down, the residue was acidified with aq.
  • Step 3 tert-Butyl ((4-aminoisoquinolin-5-yl)methyl)carbamate.
  • 5- chloroisoquinolin-4-amine (2.30 g, 12.70 mmol)
  • potassium (((tert-butoxy- carbonyl)amino)methyl)trifluoroborate 9.54 g, 38.20 mmol
  • dioxane 120 mL
  • H2O (12 mL
  • N2 was bubbled through the reaction for 5 min, Cs2CO3 (17.0 g, 51.00 mmol), Pd(OAc) 2 (286.0 mg, 1.27 mmol) and cataCXium A (962.0 mg, 2.55 mmol) were added to the mixture, N 2 was bubbled for another 5 min, the mixture was heated at 110°C for 16 h.
  • Step 4 tert-butyl (E)-((4-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isoquinolin-5-yl)methyl)carbamate.
  • tert-butyl ((4-aminoisoquinolin-5-yl)methyl)carbamate (1.44 g, 5.16 mmol) in THF (100 mL) was added TEA (2.2 mL, 15.50 mmol) and then triphosgene (625.0 mg, 2.07 mmol) solution in THF (100 mL) at 0 oC.
  • tert-Butyl 3-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)isonicotinate To a solution of tert-butyl (E)-3-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isonicotinate (1.08 g, 2.090 mmol) in dry toluene (8.4 mL), was added TEA (0.88 mL, 6.270 mmol) and the reaction mixture was stirred 15 min at rt.
  • Triphosgene (253.0 mg, 0.836 mmol) was then added portionwise and the reaction was stirred at 100 °C for 3 h.
  • the reaction mixture was cooled down to rt, more TEA (0.29 mL, 2.090 mmol) and triphosgene (190.0 mg, 0.627 mmol) were added (portionwise) and reaction was stirred again at 100 °C for 2 h.
  • the reaction mixture was cooled down to rt and concentrated under reduced pressure. Residue was purified by C18 column chromatography (5- 100% MeCN in 10 mM aq.
  • Example 2 Synthesis of (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclodecaphane-2 2 ,2 4 -dione (Compound 1)
  • Step 3 (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-5- oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane-2 2 ,2 4 -dione (Compound 1).
  • Example 3 Synthesis of (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacycloundecaphane-2 2 ,2 4 -dione (Compound 2) [0298] Step 1.6- ⁇ [2-Chloro-4-methoxy-6-(pent-4-en-1-yloxy)phenyl]amino ⁇ -3-[5-(prop-2- en-1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione.
  • Step 2 (2 5 Z)-4 6 -chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphan-9-ene-2 2 ,2 4 - dione.
  • Step 3 (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-5- oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphane-2 2 ,2 4 -dione (Compound 2).
  • Example 4 Synthesis of (Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclononaphane-2 2 ,2 4 -dione (Compound 3)
  • Step 2 (2 5 Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 4 2 H-3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclononaphan-7-ene-2 2 ,2 4 - dione.
  • Example 5 Synthesis of (Z)-1 5 ,4 6 -dichloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)- pyridinacyclodecaphane-2 2 ,2 4 -dione (Compound 4) [0306] Step 1.6- ⁇ [4-(But-3-en-1-yl)-6-chloro-2-methylindazol-5-yl]amino ⁇ -3-[5-chloro-4- (prop-2-en-1-yloxy)pyridin-3-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione.
  • Step 2 (2 5 Z)-1 5 ,4 6 -dichloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-4 2 H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclodecaphan- 7-ene-2 2 ,2 4 -dione.
  • Step 3 (Z)-1 5 ,4 6 -dichloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 4 2 H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclodecaphane-2 2 ,2 4 -dione (Compound 4).
  • Example 6 Synthesis of (Z)-4 6 -fluoro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclononaphane-2 2 ,2 4 -dione (Compound 5) [0310] Step 1.3-(5-allylisoquinolin-4-yl)-6-((2-(allyloxy)-6-fluoro-4-methoxyphenyl)amino)- 1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione To a mixture of 3-(5- allylisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,
  • Example 7 Synthesis of (2 5 Z,7Z)-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphan-7- ene-2 2 ,2 4 -dione (Compound 6) [0314] In a similar way as (Z)-4 6 -fluoro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphane-2 2 ,2 4 - dione, (2 5 Z,7Z)-4 4 -methoxy-2 1 -(2,4,5
  • Example 8 Synthesis of (Z)-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane- 2 2 ,2 4 -dione (Compound 7) [0316] In a similar way as (Z)-4 6 -fluoro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphane-2 2 ,2 4 - dione, (Z)-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)-2 1
  • Example 9 Synthesis of (Z)-5-((4 6 -chloro-4 2 -methyl-2 2 ,2 4 ,8-trioxo-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-4 2 H-3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclodecaphane-21-yl)methyl)-2-fluorobenzonitrile (Compound 8) [0318] Step 1.
  • Example 10 Synthesis of (Z)-5-((4 6 -chloro-4 2 ,7-dimethyl-2 2 ,2 4 ,8-trioxo-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-4 2 H-3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclodecaphane-2 1 -yl)methyl)-2-fluorobenzonitrile (Compound 9) [0322] In a similar way as (Z)-5-((4 6 -chloro-4 2 -methyl-2 2 ,2 4 ,8-trioxo-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H- 3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-2 1 -yl)methyl)-2-fluorobenz
  • Example 11 Synthesis of 5 6 -chloro-5 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 - tetrahydro-5 2 H-4,8-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)- benzenacyclononaphane-3 2 ,3 4 ,9-trione (Compound 10) [0324] Step 1.
  • Step 3.5 6 -chloro-5 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-5 2 H-4,8- diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclononaphane- 3 2 ,3 4 ,9-trione (Compound 10).
  • Example 12 Synthesis of 5 6 -chloro-5 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 - tetrahydro-5 2 H-4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)- benzenacyclooctaphane-3 2 ,3 4 ,8-trione (Compound 11) [0328] Step 1.
  • Step 3.5 6 -chloro-5 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-5 2 H-4,7- diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclooctaphane- 3 2 ,3 4 ,8-trione (Compound 11).
  • Example 13 Synthesis of 5 6 -chloro-5 2 ,7-dimethyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-5 2 H-4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina- 1(1,3)-benzenacyclooctaphane-3 2 ,3 4 ,8-trione (Compound 12) Step 3 [0332] Step 1.
  • Step 3.5 6 -chloro-5 2 ,7-dimethyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-5 2 H- 4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclooctaphane- 3 2 ,3 4 ,8-trione (Compound 12).
  • Example 14 Synthesis of 5 6 -Chloro-5 2 ,8-dimethyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-5 2 H-4,8-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina- 1(1,3)-benzenacyclononaphane-3 2 ,3 4 ,9-trione (Compound 13) [0336] Step 1.
  • Example 15 Synthesis of 5-methyl-11-(2,4,5-trifluorobenzyl)-11,12,13,14- tetrahydro-5,9-diaza-2(4,5)-isoquinolina-1(3,6)-triazina-3(1,3)-benzenacyclononaphane- 12,14,4-trione (Compound 14) [0340] Step 1.
  • Example 16 Synthesis of 4 6 -chloro-4 2 -(2-methoxyethyl)-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-1 1 H,4 2 H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclononaphane-2 2 ,2 4 -dione (Compound 15) [0344] Step 1.4-Allyl-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine.
  • Step 3.4 6 Chloro-4 2 -(2-methoxyethyl)-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-1 1 H,4 2 H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclononaphan-6-ene-2 2 ,2 4 -dione.
  • reaction mixture was purged with N 2 , evacuated and stirred under H 2 (via balloon) at rt for 30 min.
  • the mixture was filtered through a pad Celite and the residue was purified by C18 column chromatography (0- 60% MeCN in 10 mM aq.
  • Example 17 Synthesis of (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(3,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3,10-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacycloundecaphane-2 2 ,2 4 ,9-trione (Compound 16) [0349] Step 1. Methyl pent-4-ynoate.
  • Methyl 5-(2- amino-3-chloro-5-methoxyphenyl)pent-4-ynoate (66.0 mg, 0.247 mmol) was dissolved in MeOH (2.5 mL), purged with N2 and PtO2 (5.9 mg, 0.025 mmol) was added. The reaction was stirred at rt for 20 h under H 2 balloon pressure, partial conversion was observed by LC-MS. The solid residue was filtered off and the MeOH solution was degassed with N2, PtO2 (5.9 mg, 0.025 mmol) was added and the mixture was stirred for 9 h under H2 balloon pressure.
  • Step 7 (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 3,10-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphane-2 2 ,2 4 ,9- trione.
  • reaction mixture was purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO3). Desired fractions were combined and lyophilized. Residue was purified again by C18 column chromatography (0-100% MeCN in 10 mM aq.
  • Example 18 Synthesis of 4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-4 2 H-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-2 2 ,2 4 ,9-trione, atropisomer 1 (Compound 17) and atropisomer 2 (Compound 18) [0357] Step 1. Methyl 5-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)pent-4-ynoate.
  • Step 3 Methyl 5-(5-((5-(5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate.
  • Step 4 Lithium 5-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate.
  • Step 6.4 6 Chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H- 3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacycloundecaphane-2 2 ,2 4 ,9- trione, atropisomer 1 and atropisomer 2.
  • System Name Waters SFC
  • System Description Autopurification SFC-MS (Fluid Delivery Module, Pump Control Module II, 2767 Injector/Collector, Stack injector Thar, Analytical Prep 2 Oven, Heat Exchanger, 515 ACD, 515 MUP, ABPR-20, 2998 PDA, QDa Performance).
  • Example 19 Synthesis of (Z)-4 6 -chloro-4 4 -methoxy-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3,11-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclododecaphane-2 2 ,2 4 ,10-trione (Compound 19) [0366] Step 1. Methyl 6-(2-amino-3-chloro-5-methoxyphenyl)hex-5-ynoate.
  • Example 20 Synthesis of (Z)-4 6 -Chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-8-oxa-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-2 2 ,2 4 ,9-trione (Compound 20) [0372] Step 1. Ethyl (E)-3-(5-Amino-6-chloro-2-methyl-2H-indazol-4-yl)acrylate.
  • the crude product from the first step was dissolved in CH2Cl2 (2 mL), then imidazole (58.4 mg, 0.849 mmol) and tert- butyldimethylsilyl chloride (119.0 mg, 0.779 mmol) were added and the resulting mixture was stirred at room temperature for 4 h.
  • the reaction mixture was extracted with CH 2 Cl 2 (20 mL) and washed with brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • tert-Butyl ((4-(4-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-5-(3,4,5-trifluorobenzyl)-5,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate.
  • Example 21 Synthesis of (2 5 Z,5 4 Z)-4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H,5 1 H-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazina-5(4,1)-pyrazolacycloundecaphane-2 2 ,2 4 ,9-trione (Compound 21) Compound 21 [0379] Step 1.
  • Step 4 Methyl 4-(4-(5-((5-(5-(aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol- 4-yl)-1H-pyrazol-1-yl)butanoate.
  • Step 6 (2 5 Z,5 4 Z)-4 6 -Chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-4 2 H,5 1 H-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazina-5(4,1)- pyrazolacycloundecaphane-2 2 ,2 4 ,9-trione.
  • Example 22 Synthesis of (Z)-4 6 -chloro-4 2 -(2-methoxyethyl)-2 1 -(3,4,5- trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola- 2(3,6)-triazinacycloundecaphane-2 2 ,2 4 ,9-trione (Compound 22) [0386] Step 1. Methyl 5-(5-amino-6-chloro-2-(2-methoxyethyl)-2H-indazol-4-yl)pent-4- ynoate.
  • Example 23 Synthesis of (Z)-4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,9-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclodecaphane-2 2 ,2 4 ,8-trione (Compound 23). [0393] Step 1. tert-Butyl (E)-4-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)but-3-enoate.
  • the filtrate was diluted with H2O (10 mL) and was extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL ⁇ 3), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-100% EtOAc in heptanes). Further purification was performed by C18 column chromatography (0-100% MeCN 10 mM aq.
  • Step 2 tert-Butyl 4-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)butanoate.
  • tert-butyl (E)-4-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)but-3-enoate and tert- butyl (E)-4-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)but-2-enoate mixture of 3:1, 184.0 mg, 0.572 mmol
  • MeOH 5.7 mL
  • Step 3 tert-Butyl 4-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)butanoate.
  • Example 24 Synthesis of 4 5 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-3,10-diaza-4(6,7)-benzo[d]oxazola-1(4,5)-isoquinolina-2(3,6)- triazinacycloundecaphane-2 2 ,2 4 ,9-trione (Compound 24) [0399] Step 1.7-Bromo-5-chloro-2-methylbenzo[d]oxazol-6-amine.
  • Step 5 Methyl 5-(6-((5-(5-(aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-5-chloro-2- methylbenzo[d]oxazol-7-yl)pentanoate.
  • Step 7.4 5 -Chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3,10- diaza-4(6,7)-benzo[d]oxazola-1(4,5)-isoquinolina-2(3,6)-triazinacycloundecaphane-2 2 ,2 4 ,9- trione.
  • Step 1 tert-Butyl (6-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)hex-5-yn-1-yl)car- bamate.
  • 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (4-bromo-6-chloro-2- methyl-2H-indazol-5-amine (750.0 mg, 2.790 mmol)
  • tert-butyl hex-5-yn-1-ylcarbamate (770.0 mg, 3.830 mmol)
  • CuI (27.1 mg, 0.140 mmol
  • PdCl2(PPh3) 2 100 mg, 0.140 mmol
  • PPh3 PPh3
  • reaction mixture was purged with N 2 for 2 min then stirred at 65 °C for 92 h.
  • the reaction mixture was cooled down to rt, filtered and washed with DCM. Filtrate was concentrated under reduced pressure and residue was purified by silica gel column chromatography (0 to 100% EtOAc in heptanes). The desired fractions were combined and concentrated under reduced pressure. Residue was purified again by C18 column chromatography (5-60% MeCN in 10 mM aq.
  • Step 5 (Z)-4 6 -Chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H- 3,11-diaza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclododecaphane-2 2 ,2 4 ,12-trione.
  • Example 26 Synthesis of (Z)-4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,10-diaza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)- pyridinacycloundecaphane-2 2 ,2 4 ,11-trione (Compound 26)
  • Step 1 tert-Butyl (5-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)pent-4-yn-1-yl)- carbamate.
  • 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (4-bromo-6- chloro-2-methyl-2H-indazol-5-amine (1.75 g, 6.520 mmol)
  • tert-butyl pent-4-yn-1-ylcarbamate (1.63 g, 8.470 mmol)
  • CuI (63.3 mg, 0.326 mmol
  • PdCl2(PPh3) 2 233.0 mg, 0.326 mmol
  • PPh 3 17.0 mg, 0.652 mmol
  • reaction mixture was purged with N2 for 2 min then stirred at 65 °C for 89 h.
  • the reaction mixture was cooled down to rt, concentrated under reduced pressure and diluted in EtOAc (125 mL). Organic phase was washed with water (3 x 25 mL) and brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 5 (Z)-4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H- 3,10-diaza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacycloundecaphane-2 2 ,2 4 ,11-trione.
  • Example 27 Synthesis of 4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3, 2 4 - tetrahydro-4 2 H-3,6-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-2 2 ,2 4 ,7-trione: mixture of atropisomers (Compound 27), atropisomer 1 (Compound 28), and atropisomer 2 (Compound 29) [0419] Step 1. Methyl (E)-5-(4-aminoisoquinolin-5-yl)pent-4-enoate.
  • Step 7.4 6 -chloro-4 2 -methyl-2 1 -(3,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3, 2 4 -tetrahydro-4 2 H-3,6- diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacycloundecaphane-2 2 ,2 4 ,7-trione.
  • Example 28 Synthesis of (Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)- triazolacyclotridecaphane-3 2 ,3 4 ,9-trione (Compound 30) [0427] Step 1.
  • reaction was stirred at -78 °C for 1 h then at 0 °C for 30 min.
  • the reaction mixture was quenched with few drops of sat. aq. NH4Cl and purified by C18 column chromatography (0- 100% MeCN in 10 mM aq.
  • Step 3 (Z)-1 6 -Chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro- 1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazolacyclotridecaphane-3 2 ,3 4 ,9- trione.
  • Example 29 Synthesis of (Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,8-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-2 2 ,2 4 ,9-trione (Compound 31) [0431] Step 1.
  • reaction was stirred at -78 °C for 1.5 h then at 0 °C for 1 h.
  • the reaction mixture was quenched with few drops of sat. aq. NH4Cl and purified by C18 column chromatography (5%- 80% MeCN in 10 mM aq.
  • Step 3 (Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H- 3,8-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacycloundecaphane-2 2 ,2 4 ,9- trione.
  • Example 30 Synthesis of (Z)-5 6 -chloro-5 2 -methyl-3 1 -(3,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-5 2 H-4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina- 1(1,4)-benzenacyclooctaphane-3 2 ,3 4 ,8-trione: mixture of atropisomers (Compound 32), atropisomer 1 (Compound 33), and atropisomer 2 (Compound 34)
  • Step 1 Methyl (E)-4-(4-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isoquinolin-5-yl)benzoate.
  • methyl 4-(4-aminoisoquinolin-5-yl)benzoate 400.0 mg, 1.440 mmol
  • TEA 0.6 mL, 4.300 mmol
  • triphosgene 17.0 mg, 0.575 mmol
  • reaction mixture was degassed with N 2 for 5 mins and stirred at 0°C for 1 h under N2.
  • a solution of methyl (3,4,5- trifluorobenzyl)carbamimidothioate 382.0 mg, 1.470 mmol
  • dry THF 4.7 mL
  • the reaction mixture was quenched with H 2 O (15 mL) and was extracted with EtOAc (10 mL).
  • Step 3 Methyl 4-(4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-2-methyl- 2H-indazol-5-yl)amino)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)benzoate.
  • Example 31 Synthesis of (Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 2 H,5 1 H-2,9-diaza-1(5,4)-indazola-3(6,3)-triazina-5(3,1)-triazola- 7(1,3)-benzenacycloundecaphane-3 2 ,3 4 ,8-trione (Compound 35) [0442] Step 1.
  • Example 32 Synthesis of 1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 - tetrahydro-1 2 H,5 1 H-2,9-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazola-7(1,3)- benzenacycloundecaphane-3 2 ,3 4 ,8-trione (Compound 36) [0446] Step 1.
  • Step 3.1 6 Chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro- 1 2 H,5 1 H-2,9-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazola-7(1,3)- benzenacycloundecaphane-3 2 ,3 4 ,8-trione.
  • Example 33 Synthesis of (3 1 S,3 4 S,3 5 R)-3 6 ,3 6 -dimethyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3 3 ,5-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-3(3,4)- bicyclo[3.1.0]hexanacyclodecaphan-8-ene-2 2 ,2 4 ,4-trione, atropisomer 1 (Compound 37) [0450] Step 1.
  • Reaction mixture was purified by C18 column chromatography (5-50% MeCN in 10 mM aq. NH 4 HCO 3 ) to provide (1R,2S,5S)-3-(5-(5- allylisoquinolin-4-yl)-4,6-dioxo-1-(2,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, atropisomer 1 (155.0 mg, 47 %) and atropisomer 2 (144.0 mg, 44 %)s.
  • Example 34 Synthesis of (3 1 S,3 4 S,3 5 R)-3 6 ,3 6 -dimethyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3 3 ,5-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-3(3,4)- bicyclo[3.1.0]hexanacyclodecaphane-2 2 ,2 4 ,4-trione, atropisomer 1 (Compound 38) [0454] To a degassed solution of (3 1 S,3 4 S,3 5 R)-3 6 ,3 6 -dimethyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3 3 ,5-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-3(3,4)- bicyclo[3.1.0
  • the reaction mixture was filtered through a syringe filter (0.45 ⁇ m) and the filtrate was concentrated under reduced pressure.
  • the crude was purified by C18 column chromatography (5-100% MeCN in 10 mM aq. NH 4 HCO 2 ) to provide dimethyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3 3 ,5-diaza-1(4,5)-isoquinolina-2(3,6)- triazina-3(3,4)-bicyclo[3.1.0]hexanacyclodecaphane-2 2 ,2 4 ,4-trione, atropisomer 1 (7.0 mg, 58 %).
  • Example 35 Synthesis of (3 1 S,3 4 S,3 5 R)-3 6 ,3 6 -dimethyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3 3 ,5-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-3(3,4)- bicyclo[3.1.0]hexanacyclodecaphan-8-ene-2 2 ,2 4 ,4-trione, atropisomer 2 (Compound 39) and (3 1 S,3 4 S,3 5 R)-3 6 ,3 6 -dimethyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-3 3 ,5-diaza- 1(4,5)-isoquinolina-2(3,6)-triazina-3(3,4)-bicyclo[3.1.0]hexanecyclode
  • Step 3 (3 1 S,3 4 S,3 5 R)-3 6 ,3 6 -dimethyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 3 3 ,5-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-3(3,4)-bicyclo[3.1.0]hexanacyclodecaphane- 2 2 ,2 4 ,4-trione, atropisomer 2.
  • Example 36 Synthesis of (Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 2 H,5 1 H-2,9-diaza-1(5,4)-indazola-3(6,3)-triazina-5(3,1)-triazola- 7(1,3)-benzenacyclodecaphane-3 2 ,3 4 ,8-trione (Compound 41) [0460] Step 1.
  • Example 37 Synthesis of 1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 - tetrahydro-1 2 H,5 1 H-2,9-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazola-7(1,3)- benzenacyclodecaphane-3 2 ,3 4 ,8-trione (Compound 42) [0464] Step 1.
  • Example 38 Synthesis of (Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)- triazolacyclododecaphane-3 2 ,3 4 ,9-trione (Compound 43) [0468] Step 1.
  • Step 3 (Z)-1 6 -Chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro- 1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazolacyclododecaphane-3 2 ,3 4 ,9- trione.
  • Example 39 Synthesis of (Z)-4 6 -chloro-4 2 -(2-methoxyethyl)-2 1 -(3,4,5- trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,9-diaza-1(4,5)-isoquinolina-4(5,4)-indazola- 2(3,6)-triazinacyclodecaphane-2 2 ,2 4 ,8-trione (Compound 44) [0472] Step 1.
  • Step 2 tert-Butyl 4-(5-amino-6-chloro-2-(2-methoxyethyl)-2H-indazol-4- yl)butanoate.
  • tert-butyl (E)-4-(5-amino-6-chloro-2-(2-methoxyethyl)-2H- indazol-4-yl)but-3-enoate and tert-butyl (E)-4-(5-amino-6-chloro-2-(2-methoxyethyl)-2H- indazol-4-yl)but-2-enoate mixture of 3:1, 185.0 mg, 0.507 mmol) in MeOH (5.1 mL) was added PtO2 (12.1 mg, 0.051 mmol) and the solution was purged with N2 for 5 min.
  • Step 3 tert-Butyl 4-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- (2-methoxyethyl)-2H-indazol-4-yl)butanoate.
  • Step 3 (Z)-4 6 -Chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H- 3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-2 2 ,2 4 ,8-trione.
  • Example 41 Synthesis of (Z)-4 6 -Chloro-4 2 -(2-methoxyethyl)-2 1 -(2,4,5- trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola- 2(3,6)-triazinacyclodecaphane-22,24,8-trione (Compound 46) [0482] Step 1. tert-Butyl (2-(5-amino-6-chloro-2-(2-methoxyethyl)-2H-indazol-4- yl)ethyl)carbamate.
  • Step 2 tert-Butyl 3-(4-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2-(2- methoxyethyl)-2H-indazol-5-yl)amino)-2,6-dioxo-5-(2,4,5-trifluorobenzyl)-5,6-dihydro- 1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)propanoate.
  • Step 4 (Z)-4 6 -Chloro-4 2 -(2-methoxyethyl)-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 - tetrahydro-4 2 H-3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclodecaphane-22,24,8-trione.
  • Example 42 Synthesis of (Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-1 1 H,4 2 H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclodecaphane-2 2 ,2 4 -dione (Compound 47) [0487] Step 1.3-(1-(But-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-((4-(but-3-en-1-yl)-6- chloro-2-methyl-2H-indazol-5-yl)amino)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine- 2,4(1H,3H)-dione.
  • Step 2 (2 5 Z,7Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 1 1 H,4 2 H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)-triazinacyclodecaphan-7-ene- 2 2 ,2 4 -dione.3-(1-(But-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-((4-(but-3-en-1-yl)-6-chloro- 2-methyl-2H-indazol-5-yl)amino)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H ione (65.0 mg, 0.098 mmol) was dissolved in DCE (39.
  • Step 3 (Z)-4 6 -Chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)-2 1 ,2 2 ,2 3 ,2 4 -tetrahydro- 1 1 H,4 2 H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)-triazinacyclodecaphane-2 2 ,2 4 - dione.
  • Example 43 Synthesis of (Z)-4 6 -chloro-4 2 -methyl-2 1 -(2,4,5-trifluorobenzyl)- 2 1 ,2 2 ,2 3 ,2 4 -tetrahydro-4 2 H-3,6-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclononaphane-2 2 ,2 4 ,7-trione (Compound 48) [0491] Step 1.
  • the mixture was concentrated down and purified by C18 column chromatography (0-60% MeCN in 10 mM aq. NH4HCO3).
  • the product obtained was re-purified by C18 column chromatography (0-60% MeCN in 10 mM aq.
  • Example 44 Synthesis of 5 5 -chloro-5 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 - tetrahydro-4,7-diaza-5(6,7)-benzo[d]oxazola-2(5,4)-isoquinolina-3(3,6)-triazina-1(1,3)- benzenacyclooctaphane-3 2 ,3 4 ,8-trione, mixture of atropisomers (Compound 49) [0495] Step 1. tert-Butyl ((6-amino-5-chloro-2-methylbenzo[d]oxazol-7- yl)methyl)carbamate.
  • Step 2 Methyl 3-(4-(4-((7-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-2-methyl- benzo[d]oxazol-6-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin- 1(2H)-yl)isoquinolin-5-yl)benzoate.
  • Step 4.5 5 -chloro-5 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-4,7- diaza-5(6,7)-benzo[d]oxazola-2(5,4)-isoquinolina-3(3,6)-triazina-1(1,3)-benzenacycloocta- phane-3 2 ,3 4 ,8-trione.
  • Example 45 Synthesis of (Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazola- 8(1,3)-benzenacyclododecaphane-3 2 ,3 4 ,9-trione (Compound 50) [0500] Step 1: tert-butyl 3-(2-(5-((4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(
  • Step 2 3-(2-(5-((4-((4-((4-(2-aminoethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol- 1-yl)ethyl)benzoic acid.
  • Step 3 (Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)-3 1 ,3 2 ,3 3 ,3 4 -tetrahydro- 1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(5,1)-triazola-8(1,3)- benzenacyclododecaphane-3 2 ,3 4 ,9-trione.
  • Example 46 Synthesis of N-(3-(5-((5-((1,2l2,4-triazol-3-yl)methyl)-4,6-dioxo-1- (2,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H- indazol-4-yl)propyl)-3-propylbenzamide (Compound 51) [0504] Step 1: tert-butyl 3-(2-(5-((4-((4-(3-((tert-butoxycarbonyl)amino)propyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)methyl)-1H-1H-1H-1
  • Step 2 3-(2-(5-((4-((4-((4-(3-aminopropyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)- 2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4- triazol-1-yl)ethyl)benzoic acid.
  • Step 3 N-(3-(5-((5-((1,2l2,4-triazol-3-yl)methyl)-4,6-dioxo-1-(2,4,5-trifluorobenzyl)- 1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol-4-yl)propyl)-3- propylbenzamide.
  • Example 47 Synthesis of (3 5 Z,5 2 Z)-1 6 -chloro-1 2 -methyl-3 1 -(2,4,5-trifluorobenzyl)- 3 1 ,3 2 ,3 3 ,3 4 -tetrahydro-1 2 H,5 1 H-2,10-diaza-1(5,4)-indazola-3(6,3)-triazina-5(3,1)-triazola- 8(1,3)-benzenacyclododecaphane-3 2 ,3 4 ,9-trione (Compound 52) [0508] Step 1: tert-butyl 3-(2-(3-((4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-

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Abstract

La présente divulgation concerne des modulateurs, tels que des inhibiteurs, de la protéase de type 3C (3CL) et des formulations de ceux-ci, lesdits modulateurs et leurs formulations étant utiles pour traiter des maladies et des troubles associés à une protéase 3CL de coronavirus et inhiber la réplication de coronavirus.
PCT/US2024/045797 2023-09-11 2024-09-09 Modulateurs de protéase de type 3c de coronavirus et leurs utilisations Pending WO2025058977A1 (fr)

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