WO2022240541A1 - Nouveaux agents antiviraux dérivés de spiropyrrolidine macrocycliques - Google Patents

Nouveaux agents antiviraux dérivés de spiropyrrolidine macrocycliques Download PDF

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WO2022240541A1
WO2022240541A1 PCT/US2022/024629 US2022024629W WO2022240541A1 WO 2022240541 A1 WO2022240541 A1 WO 2022240541A1 US 2022024629 W US2022024629 W US 2022024629W WO 2022240541 A1 WO2022240541 A1 WO 2022240541A1
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optionally substituted
mmol
compound
group
cycloalkyl
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PCT/US2022/024629
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English (en)
Inventor
Jiajun Zhang
Xiaowen Peng
Byung-Chul Suh
Jorden Kass
Xuri Gao
Hui Cao
Wei Li
Joseph D. PANARESE
Guoqiang Wang
Yat Sun Or
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Enanta Pharmaceuticals, Inc.
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Priority claimed from US17/479,669 external-priority patent/US11319325B1/en
Application filed by Enanta Pharmaceuticals, Inc. filed Critical Enanta Pharmaceuticals, Inc.
Publication of WO2022240541A1 publication Critical patent/WO2022240541A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the invention relates to compounds and methods of inhibiting coronavirus replication activity by contacting the 3C-Like protease (sometimes referred to as "3CLpro", “Main protease”, or “Mpro ”) with a therapeutically effective amount of a 3C-Like protease inhibitor.
  • the invention further relates to pharmaceutical compositions containing the coronavirus 3C- Like protease inhibitor in a mammal by administering effective amounts of such coronavirus 3C-Like protease inhibitor.
  • Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses.
  • the genomic RNA of CoVs has a 5'-cap structure and 3'-poly-A tail and contains at least 6 open reading frames (ORFs).
  • ORF 1a/b directly translates two polyproteins: pp1a and pp1ab.
  • These polyproteins are processed by a 3C-Like protease (3CLpro), also known as the main protease (Mpro), into 16 non-structural proteins.
  • 3CLpro also known as the main protease (Mpro)
  • Mpro main protease
  • These non-structural proteins engage in the production of subgenomic RNAs that encode four structural proteins, namely envelope, membrane, spike, and nucleocapsid proteins, among other accessory proteins.
  • 3C-Like protease has a critical role in the coronavirus life cycle.
  • 3CLpro is a cysteine protease involved in most cleavage events within the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and features a Cys-His dyad located in between domains I and II.3CLpro is conserved among coronaviruses and several common features are shared among the substrates of 3CLpro in different coronaviruses. As there is no human homolog of 3CLpro, it is an ideal antiviral target. Although compounds have been reported to inhibit 3CLpro activity, they have not been approved as coronavirus therapies. (Refer to WO2018/042343, W02018/023054,
  • This invention describes the methods to prepare and methods for use of compounds that are believed to inhibit the coronavirus lifecycle. Compounds of this type might be used to treat coronavirus infections and decrease occurrence of disease complications such as organ failure or death.
  • the present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, as well as methods to treat or prevent viral (particularly coronavirus) infection in a subject in need of such therapy with said compounds.
  • Compounds of the present invention inhibit the protein(s) encoded by a coronavirus or interfere with the life cycle of a coronavirus and are also useful as antiviral agents.
  • the present invention provides processes for the preparation of said compounds.
  • the present invention provides compounds represented by Formula (I), and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted -C 1 -C 8 alkyl, optionally substituted -C 2 -C 8 alkenyl, optionally substituted -C 2 -C 8 alkynyl, optionally substituted -C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted -C 1 -C 6 alkyl, and optionally substituted -C 3 -C 6 cycloalkyl; preferably, R 2 is hydrogen.
  • R 3 is hydrogen, optionally substituted -C 1 -C 4 alkyl, optionally substituted C 2 -C 4 - alkenyl, or optionally substituted -C 3 -C 6 cycloalkyl; preferably, R 3 is hydrogen.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6- membered cycloalkyl ring or heterocyclic ring;
  • A is selected from the group consisting of -R 11 , -OR 12 , -NR 13 R 14 , -C(O)R 15 , - C(O)NR 13 R 14 ,-C(R 18 R 19 )NR 15 C(O)R 11 , -C(R 18 R 19 )NR 15 C(O)0R 12 , - C(R 18 R 19 )NR 15 C(O)NR 13 R 14 , and -C(R 18 R 19 )NR 15 C(O)C(O)NR 13 R 14 ;
  • R 11 and R 12 are each independently selected from the group consisting of optionally substituted -C 1 -C 8 alkyl, optionally substituted -C 2 -C 8 alkenyl, optionally substituted -C 2 -C 8 alkynyl, optionally substituted -C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optional
  • B is an optionally substituted aryl or optionally substituted heteroaryl
  • L is -R a -Q-R b -, wherein when R a is not absent, R a is connected to B and when R a is absent, Q is connected to B;
  • R a is selected from the group consisting of absent, optionally substituted -C 1 -C 8 alkyl, optionally substituted -C 2 -C 8 alkenyl, optionally substituted -C 2 -C 8 alkynyl, optionally substituted -C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; in certain embodiments, R a is absent;
  • R b is selected from the group consisting of optionally substituted -C 1 -C 8 alkyl, optionally substituted -C 2 -C 8 alkenyl, optionally substituted -C
  • A is selected from the group consisting of -R 11 , -OR 12 , -NR 13 R 14 , -C(O)NR 13 R 14 , -C(R 18 R 19 )NR 15 C(O)R 11 , - C(R 18 R 19 )NR 15 C(O)0R 12 , -C(R 18 R 19 )NR 15 C(O)NR 13 R 14 , and -
  • R 1 is optionally substituted -C 1 -C 4 alkyl, optionally substituted -C 3 -C 6 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl.
  • R 1 is selected from the following groups:
  • R 1 is selected from the following groups:
  • R 2 is hydrogen or F.
  • R 3 is hydrogen
  • X is -CN.
  • X is -C(O)H.
  • X is -C ⁇ CR 13 , wherein R 13 are previously defined.
  • X is -C(O)CH 2 0H, - C(O)CH 2 Cl or -C(O)CH 2 F.
  • X is -C(O)CHFC1.
  • X is -C(O)C(O)NR 13 R 14 , wherein R 13 and R 14 are previously defined.
  • X is selected from the following:
  • X is selected from the following:
  • A is optionally substituted -C 1 -C 8 alkyl, optionally substituted aryl or optionally substituted heteroaryl.
  • A is derived from one of the following by removal of a hydrogen atom and is optionally substituted:
  • A is selected from the following groups, and A is optionally substituted:
  • A is selected from the following groups, and A is optionally substituted: wherein R 11 and R 12 are as previously defined.
  • A is selected from the following groups, and A is optionally substituted:
  • A is selected from the following groups, and A is optionally substituted:
  • p is 1, 2, 3 or 4
  • p is 2, 3 or 4.
  • the olefinic carbon atom is connected to B.
  • B is optionally substitiued phenyl or optionally substitiued pyridinyl.
  • the compound of Formula (I) is represented by Formula (I-a) or Formula wherein A, B, R 1 , R 2 , R 3 , L and X are as previously defined.
  • the compound of Formula (I) has the stereochemistry shown in Formula (I-a).
  • the compound of Formula (I) is represented by Formula (II): wherein A, B, R 1 , L and X are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (III-l) ⁇ (IP-3): wherein A, R 1 , R 2 , R 3 , L and X are as previously defined.
  • R 9 is independently selected from the group consisting of: halogen, -CN, -OR 12 , -0C(O)R 11 , -0C(O)NR 13 R 14 , -C(O)NR 13 R 14 , - SR 12 , -S(O)R 11 , -S(O) 2 -R 11 , -S(O)(NH)R 11 , -S(O) 2 -NR 13 R 14 , -NR 13 R 17 , optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 3 -C 8 cycloalkyl, optionally substituted 3- to 8- membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl,
  • the compound of Formula (I) is represented by Formula (I).
  • the compound of Formula (I) is represented by Formula (IV- a) or Formula (IV-b): wherein A, R 1 , R 9 , nl, L and X are as previously defined.
  • the compound of Formula (I) has the stereochemistry shown in Formula (IV-a).
  • the compound of Formula (I) is represented by the Formula
  • the compound of Formula (I) is represented by Formula (VI- 1) or Formula (VI-2): wherein A, R 1 , R 2 , R 9 , R 21 , R 22 , R 23 , R 24 , nl, and X are as previously defined.
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C 1 -C 6 alkyl, and optionally substituted -C 3 -C 6 cycloalkyl; and m is 1, 2, 3, 4, 5, or 6.
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen, fluorine, methyl, -CF 3 and cyclopropyl, and R 2 is hydrogen.
  • the compound of Formula (I) is represented by one of
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen, fluorine, methyl, -CF 3 and cyclopropyl, and R 2 is hydrogen.
  • the compound of Formula (I) is represented by Formula (I).
  • Wi and W 2 are independently selected from the group consisting of absent, -0-, - NR 13 -, and -CR 21 R 23 -; wherein A, R 1 , R 2 , R 9 , R 13 , R 21 , R 23 , R 31 , R 32 , nl, m, and X are as previously defined.
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen, fluorine, methyl, -CF 3 and cyclopropyl, and R 2 is hydrogen.
  • the present invention provides compounds of Formula (IX): wherein is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C 3 -C 8 cycloalkyl, and optionally substituted 3- to 8-membered heterocycloalkyl; and A, R 1 , R 2 , R 9 , R 31 , R 32 , W 1 , W 2 , nl, m and X are as previously defined.
  • W 2 is absent.
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen, fluorine, methyl, -CF 3 , and cyclopropyl, and R 2 is hydrogen.
  • A, R 1 , R 9 , R 13 , R 31 , R 32 , m, nl and X are as previously defined.
  • X is -CN.
  • the compound of Formula (I) is represented by one of
  • X is - CN.
  • the compound of Formula (I) is represented by one of
  • the compound of Formula (I) is represented by one of Formulae (XI-la) and (XI-2a): wherein T, A, R 1 , R 31 , R 32 , and m are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (XII-1) ⁇ (XII-6): wherein nl, A, R 1 , R 9 , R 31 , R 32 , m and X are as previously defined.
  • X is -CN.
  • the compound of Formula (I) is represented by one of
  • X is -CN.
  • the compound of Formula (I) is represented by one of Formulae (XIII-1) ⁇ (XIII-6):
  • the compound of Formula (I) is represented by one of Formulae (XIII-la) ⁇ (XIII-6a): wherein A, R 1 , R 31 , R 32 , and m are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (XIII-1) ⁇ (XIII-6) and (XIII-la) ⁇ (XIII-6a), wherein R 1 is selected from the following groups: and A is selected from the following groups: or A is selected from the following groups: wherein R 11 and R 12 are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (IX-la) ⁇ (IX-4a): wherein A, R 1 , R 21 , and R 23 are as previously defined.
  • A is selected from the following groups, wherein R 11 and R 12 are as previously defined:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a biologically active compound of the invention for the treatment of coronavirus in a mammal containing an amount of a coronavirus 3 CL pro inhibitor that is effective in treating coronavirus and a pharmaceutically acceptable carrier or expedient.
  • the present invention provides a method of inhibiting the activity of a coronavirus 3CLpro, comprising contacting the coronavirus 3CLpro with an effective amount of a coronavirus 3CLpro inhibitor compound or agent.
  • the present invention also provides a method of targeting coronavirus inhibition as a means of treating indications caused by coronavirus related viral infections.
  • the present invention provides a method of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds.
  • the present invention provides a method of treating or preventing a coronavirus infection in a subject in need thereof, further comprising administering to the subject an additional therapeutic agent selected from the group consisting of a coronavirus protease inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, inducer of cellular viral RNA sensor, therapeutic vaccine, and agents of distinct or unknown mechanism, and a combination thereof.
  • an additional therapeutic agent selected from the group consisting of a coronavirus protease inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, inducer of cellular viral RNA sensor, therapeutic vaccine, and agents of distinct or unknown mechanism, and a combination thereof.
  • the present invention provides a method of reducing viral load in the subject to a greater extent compared to the administering of a compound selected from the group consisting of a coronavirus protease inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • a compound selected from the group consisting of a coronavirus protease inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • the present invention provides a method resulting in a lower incidence of viral mutation and/or viral resistance than the treatment with a compound selected from the group consisting of a coronavirus protease inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, inducer of cellular viral RNA sensor, therapeutic vaccine, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • aryl refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • aromatic groups can be substituted or unsubstituted.
  • bicyclic aryl or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
  • C 1 -C 4 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
  • C 1 -C 4 alkyl refers to alkyl groups containing from one to four, one to six, one to eight, one to twelve, 2 to 4 and 3 to 6 carbon atoms respectively.
  • C 1 -C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, «-butyl, tert- butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
  • alkenyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • C 2 -C 8 alkenyl refers to alkenyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.
  • alkynyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • C 2 -C 8 alkynyl refers to alkynyl groups containing from two to eight, two to twelve, two to four, three to four or three to six carbon atoms respectively.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.
  • cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefmic double bond.
  • Preferred cycloalkyl groups include C 3 -C 12 cycloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 8 cycloalkyl and C 4 -C 7 cycloalkyl.
  • C 3 -C 12 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene- cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro [2.5] octyl, 3- methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.
  • cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefmic double bond.
  • Preferred cycloalkenyl groups include C 3 -C 12 cycloalkenyl, C 3 -C 8 cycloalkenyl or C 5 -C 7 cycloalkenyl groups.
  • C 3 -C 12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2- enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3-en-12-yl, and the like.
  • arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl.
  • substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
  • heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
  • substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
  • arylalkyl is aryl-C 1 -C 6 alkyl
  • heteroarylalkyl is heteroaryl-C 1 -C 6 alkyl.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • Preferred alkoxy are (C 2 -C 3 ) alkoxy.
  • any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)0, C(O)NH, 0C(O)0, OC(O)NH, OC(O)NH 2 , S(O) 2 NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2, C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
  • groups comprising one or more functional groups, non-ar
  • Carbon atoms of an aliphatic group can be optionally oxo-substituted.
  • An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefenic double bond.
  • heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2- oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
  • One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C 1 -C 12 -alkyl; C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, -C 3 -C 12 -cycloalkyl, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C 2 -C 12 -alkyl, -NH-C 2 -C 8 - alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- heterocycloalkyl
  • the substituents are independently selected from halo, preferably Cl and F; C 1 -C 4 -alkyl, preferably methyl and ethyl; halo-C 1 -C 4 -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C 2 -C 4 -alkenyl; halo-C 2 -C 4 -alkenyl; C 3 -C 6 - cycloalkyl, such as cyclopropyl; C 1 -C 4 -alkoxy, such as methoxy and ethoxy; halo-C 1 -C 4 - alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; acetyl, trifluoroacetyl, -CN; -OH; NH 2 ; C 1 -C 4 -alkylamino; di(C 1 -C 4 -alkyl)a
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from C 1 -C 4 -alkyl; -CF 3 , -OCH 3 , - OCF 3 , -F, -Cl, -Br, -I, -OH, -NO 2 , -CN, and -NH 2 .
  • a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.
  • halo or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
  • the term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
  • hydrox includes hydrogen and deuterium.
  • recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but not limited to, mesylate, tosylate, trill ate. p- nitrobenzoate, phosphonate and the like.
  • activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxy carbonyl, tert-butoxy- carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxy carbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl- methyl (trityl), methoxy methyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)- ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxy carbonyl, t-butoxy carbonyl, 12-fluorenyl- methoxy carbonyl, benzyloxy carbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al. , Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. 2 nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M.
  • subject refers to an animal.
  • the animal is a mammal. More preferably, the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • the term "pharmaceutically acceptable salt,” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable carrier or excipient means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectable.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, 1) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay,
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs.
  • Delivery of aerosolized therapeutics, particularly aerosolized antibiotics is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No. 5,508,269 to Smith et al, and WO 98/43650 by Montgomery, all of which are incorporated herein by reference).
  • the compounds of the present invention may be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents useful in the prevention or treatment of viral diseases or associated pathophysiology.
  • antiviral therapeutic agents or anti-inflammatory agents useful in the prevention or treatment of viral diseases or associated pathophysiology.
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other antiviral or anti-inflammatory therapeutic agents.
  • the compounds herein and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of respiratory disease, inflammatory disease, autoimmune disease, for example; anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, Ieukotriene modulators (e.g., montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate
  • LP immunophosphatidic
  • FLAP 5-lipoxygenase activating protein
  • LP immunophosphatidic
  • FLAP 5-lipoxygenase activating protein
  • bronchodilators e.g., muscarinic antagonists, beta-2 agonists
  • methotrexate and similar agents
  • monoclonal antibody therapy such as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents
  • cytokine receptor therapies e.g.
  • antigen non-specific immunotherapies e.g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents
  • suitable anti-infective agents including antibiotic agents, antifungal agents, antheimintic agents, antimalarial agents, antiprotozoal agents, antitubercuiosis agents, and antiviral agents, including those listed at https://www.drugs.com/drug-class/anti-infectives.html.
  • combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
  • An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • viral infections are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a “therapeutically effective amount” of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations may contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the “additional therapeutic or prophylactic agents” include but are not limited to, immune therapies (e.g. interferon), therapeutic vaccines, antifibrotic agents, anti- inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (e.g. N- acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (e.g. ribavirin and amantidine).
  • the compositions according to the invention may also be used in combination with gene replacement therapy.
  • Scheme 1 illustrates a general method to prepare the nitrile compound (X-16) of formula I from the amino ester compound (X-1), wherein B is as previously defined and PG 1 is C1-C4 alkyl or Bn.
  • Treatment of amine (X-1) with formaldehyde affords the cyclized amine (X-2), which was converted to (X-3) by using appropriate protecting group PG 2 (e.g. Boc).
  • Treatment of (X-3) with NBS in solvents containing AcOH at low temperature provides the rearranged spiro-proline derivative (X-4). Examples of this sequence of transformation has been reported in literature (Pellegrini C. et al.
  • Scheme 2 illustrates a general method to synthesize the aldehyde compound (XI-9) of formula (I), wherein A, R 1 , R 2 , R 3 , L and B are as previously defined.
  • the ester compound of formula (X-7), wherein R 3 , B, L 1 , PG 1 and PG 2 are as previously defined, is reduced to the alcohol compound (XI-1) by employing reducing reagents such as, but not limited to, LiBH 4 , NaBH 4 , or DIBAL-H.
  • the primary alcohol (XI-1) is protected by the protecting group PG 4 (e.g. TBS, Bn, etc.) to yield the compound (XI-2).
  • the protecting group PG 2 e.g.
  • Boc of (XI-1) is removed under acidic conditions (e.g. TFA, HC1, formic acid, TMSOTf/lutidine, etc).
  • acidic conditions e.g. TFA, HC1, formic acid, TMSOTf/lutidine, etc.
  • Coupling of the amine compound (XI-3) with the acid compound (X-8) wherein PG 3 , L 2 , R 1 , and R 2 are as previously defined, under amide coupling conditions (e.g. HATU, EDC, DCC, or T 3 P) provides compound (XI -4).
  • amide coupling conditions e.g. HATU, EDC, DCC, or T 3 P
  • macrocyclization of (XI-4) e.g.
  • PG 3 is cleaved under the appropiate conditions (e.g. hydrogenation or HC1) to afford amine compound (XI-6), which is further coupled with acid chloride (X-12) to form the compound (XI-7), where A is as previously defined.
  • PG4 was removed (e.g.
  • Scheme 3 illustrates a general method to synthesize the alkyne compound (XII-1) of formula (I), wherein A, R 1 , R 2 , R 3 , L and B are as previously defined.
  • the alkyne compound (XII-1) is prepared by Seyferth-Gilbert homologation or Corey-Fuchs reaction from the aldehyde compound (XI-9), wherein A, R 1 , R 2 , R 3 , L and B are as previously defined.
  • Scheme 4 illustrates a general method to synthesize the a-ketoamide compound (XIII- 3) of formula (I), wherein A, R 1 , R 2 , R 3 , R 13 , L and B are as previously defined.
  • Scheme 5 illustrates a general method to synthesize the hydroxyketone compound (XIV-5) of formula (I).
  • Dihydroxylation of the alkene (XIV-1) using Upjohn Dihydroxylation (0sO 4 , NMO) affords the diol (XIV-2), whose primary alcohol is selectively protected with an appropriate protecting group PG 5 (e.g. TBS) to form the alchol (XIV-3).
  • Oxidation of the alcohol (XIV-3) with appropriate oxidants e.g.
  • Step 1-1 To a clear colorless solution of 2-(tert-butyl) 3-methyl (S)-l,3,4,9-tetrahydro-2H- pyrido[3,4-b]indole-2,3-dicarboxylate (45.00 g, 136 mmol) in THF (720 ml) in a three neck 2000 mL flask at 0 °C (internal temperature) was added water (90 ml) in one portion. Acetic acid (54.6 ml, 953 mmol) was added at 0 °C. The cloudy mixture was cooled to -30 °C
  • the cloudy yellow solution was allowed to warm up to -20 °C and poured portionwise into a mixture of potassium carbonate (65.9 g, 477 mmol) in cold water ( ⁇ 300 ml), saturated NaHCO 3 solution ( ⁇ 400 ml) and EtOAc (300 ml) with stirring. The mixture was further diluted with EtOAc (500 ml). The aqueous layer was extracted with EtOAc (*1). The combined organic layers were washed with brine (*1), dried over Na 2 SO 4 (s), filtered and concentrated to afford crude product as a light yellow sticky oil (56.0 g).
  • Step 1-2 A clear colorless solution of the mixture of compounds from Step 1-1 (3.94 g, 11.4 mmol, dr 10/1) in acetonitrile (40 mL) was treated with NBS (2.23 g, 12.5 mmol) in three portions at room temperature. The reaction was stirred at room temperature for 3 h. It became a light yellow solution. LCMS showed no SM. The reaction was quenched with aqueous Na 2 S 2 O 3 . The mixture was allowed to stir at room temperature for additional 30 min. The cloudy mixture was further diluted with EtOAc (80 mL). The aqueous layer was extracted with EtOAc twice.
  • Step 1-3 A clear colorless solution of the compound from Step 1-2 (4.2 g, 9.9 mmol) in n- PrOH (35 mL) was treated with triethylamine (1.7 mL, 11.9 mmol), potassium vinyltrifluoroborate (1.6 g, 11.9 mmol) and PdCl 2 (dppl) (290 mg, 0.4 mmol) under N 2 . The mixture was degassed and backfilled with N 2 (*3). The resulting orange suspension was bubbled with N 2 for 10 min. The reaction was warmed to 100 °C and stirred for 20 h. It became dark red/brown mixture. TLC (CH/EtOAc 2:1) showed no SM.
  • Step 1-4 A clear light yellow solution of the compound from Step 1-3 (3.3 g, 8.9 mmol) in 7 N ammonia in MeOH (80 ml, 560 mmol) was stirred at 50 °C in a sealed pressure vessel over the weekend (3 d). LCMS showed no SM. The mixture was allowed to cool down and concentrated in vacuo to give a yellow gel-like solid. The solid was redissolved in 30 mL MeOH/dioxane (1 : 10), co-evaporated in vacuo to give a light yellow solid. The crude was dried under high vacuum for 1 h, then mashed to small pieces and dried under high vacuum overnight to give a light yellow powder.
  • Step 1-5 To a clear solution of the compound from Step 1-4 (1.15 g, 3.22 mmol) in DMF (2 ml) at rt was added 4 M HC1 in 1,4-dioxane (8 ml, 32 mmol). The resulting clear yellow solution was stirred at rt for 2 h. The mixture was concentrated by rotavapor. The residual clear DMF solution was poured into DCM (150 ml) with stirring to get a white slurry. The mixture was sonicated to form a cloudy suspension. The solid was collected by filtration, washing with DCM, and then MTBE. The solid was dried under vacuum to afford the desired product as an off-white powder (862 mg, 2.93 mmol, 91%).
  • Step 1-6 A solution of tert-butyl L-leucinate hydrochloride (2.1 g, 9.39 mmol) and pent-4- enal (1 g, 11.89 mmol) in DCE (30 ml) was treated with sodium triacetoxyborohydride (2.7 g, 12.74 mmol) at room temperature. The reaction was stirred at room temperature for 2 h and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 1-7 A solution of the compound from Step 1-6 (1.96 g, 7.67 mmol) in CH 2 Cl 2 (30 ml) was treated with DIPEA (4.02 ml, 23.02 mmol) and Cbz-Cl (1.315 ml, 9.21 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with a saturated solution of sodiun bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, fitlered and concentrated in vacuo.
  • Step 1-8 A solution of the compound from Step 1-7 (650 mg, 1.669 mmol) in CH 2 Cl 2 (2 ml) was treated with TFA (2 ml, 26.0 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, then co-evaporated with toluene twice. The crude was dried under high vacuum to give the desired product (547 mg, 1.641 mmol, 98 % yield) as an off-white syrup.
  • Step 1-9 A solution of the compound from Step 1-5 (335 mg, 1.140 mmol) and the compound from Step 1-8 (375 mg, 1.125 mmol) in DMF (2 ml) and CH 2 Cl 2 (2 ml) was treated with N-methylmorpholine (500 ⁇ l, 4.55 mmol) and HATU (470 mg, 1.236 mmol).
  • the reaction was stirred at rom temperature for 1 h.
  • the reaction was quenched with a saturated solution of sodium bicarbonate and diluted with ethyl acetate.
  • the organic layer was washed with water and brine twice, dried over sodium sulfate, filered and concentrated in vacuo.
  • the crude was added to a 12 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (230 mg, 0.402 mmol, 35 % yield) as a white solid.
  • Step 1-10 A solution of the compound from Step 1-9 (163 mg, 0.285 mmol) in toluene (250 ml) was treated with Zhan IB cat. (41 mg, 0.056 mmol). The mixture was degassed by freeze-pump-thaw and refilled with N 2 over 3 times. The reaction was warmed to 90 °C and stirred overnight. The reaction was concentrated in vacuo. The crude was added to a 12 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (163 mg, 0.285 mmol, 86% yield) as a brownish foam.
  • Step 1-11 A solution of the compound from Step 1-10 (30 mg, 0.055 mmol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (60 ⁇ l, 0.430 mmol) and TFAA (30 ⁇ l, 0.212 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 2 h and quenched with a saturated solution of sodium bicarbonate. The mixture was stirred at room temperature for 30 min. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 1 (21 mg, 0.040 mmol, 72 % yield) as a white solid.
  • Step 2-1 A solution of the compound from Step 1-11 (19 mg, 0.036 mmol) in MeOH (0.3 ml) and CH 2 Cl 2 (0.3 ml) was treated with Pd-C (4 mg, 3.76 ⁇ mol) under H 2 . The mixture was bubbled with H 2 for 5 min. The reaction was stirred at room temperature for 2 h. The mixture was filtered through celite and concentrated in vacuo to give the desired product (12 mg, 0.030 mmol, 84 % yield) as an off-white solid.
  • Step 2-2 A solution of the compound from Step 2-1 (12 mg, 0.030 mmol) was treated with N-methylmorpholine (30 ⁇ l, 0.273 mmol) and Cbz-Cl (20 ⁇ l, 0.140 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 1 h and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 2 9 mg, 0.017 mmol, 56 % yield) as a white solid.
  • Example 3 was treated with paraformaldehyde (1.8 g, 59.9 mmol) and PTSOH (168 mg, 0.883 mmol). The suspension was warmed to 110 °C and refluxed under Dean-Stark conditions for 3 h. The reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 3-3 A solution of the compound from Step 1-5 (349 mg, 1.188 mmol) and the compound from Step 3-2 (435 mg, 1.362 mmol) in DMF (3 ml) and CH2C12 (3 ml) was treated wih N-methylmorpholine (550 ⁇ l, 5.00 mmol) and HATU (550 mg, 1.446 mmol). The reaction was stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate and quenched with a saturated solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 3-4 A solution of the compound from Step 3-3 (177 mg, 0.317 mmol) in Toluene (300 ml) was treated with Zhan IB cat. (47 mg, 0.064 mmol). The mixture was degassed and refilled with N2 by freeze-pump-thaw at -78 °C. The reaction was warmed to 90 °C and stirred overnight. The mixture was concentrated in vacuo. The crude was added to a 12 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (17 mg, 0.032 mmol, 10 % yield) as a brownish foam.
  • Step 3-5 A solution of the compound from Step 3-4 (16 mg, 0.030 mmol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (42.0 ⁇ l, 0.302 mmol) and TFAA (21.29 ⁇ l, 0.151 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min. The reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 3 (7 mg, 0.014 mmol, 45.3 % yield) as a white solid.
  • 1 H NMR 400 MHz, Chloroform-d
  • Step 4-1 A solution of the compound from Step 1-10 (66 mg, 0.121 mmol) in MeOH (1.5 ml) was treated with Pd-C (9 mg, 8.46 ⁇ mol) under 3 ⁇ 4. The mixture was bubbled with H 2 over 5 min. The reaction was stirred at room temperature for 2 h. The mixture was filtered through celite, rinsed with dichloromethane and concentrated in vacuo to give the desired product (51 mg, 0.124 mmol, 102 % yield).
  • Step 4-2 A suspension of 4,6-difluoro-lH-indole-2-carboxylic acid (102 mg, 0.517 mmol) in CH 2 Cl 2 (1.5 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (100 ⁇ l, 0.756 mmol) dropwise. The reaction was stirred at room temperature for 1.5 h to form an orange clear solution. The stock solution of 4,6-difluoro-lH-indole-2-carbonyl chloride (0.35 M) was freshly used.
  • the crude was adde to a 4 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (10 mg, 0.017 mmol, 39 % yield) as an off-white solid.
  • Step 4-3 A solution of the compound from Step 4-2 (13 mg, 0.022 mmol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (40 ⁇ l, 0.287 mmol) and TFAA (18 ⁇ l, 0.127 mmol) dropwise. The reaction was stirred at 0 °C for 1 h and quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 4 (7 mg, 0.012 mmol, 56 % yield) as a white solid.
  • 1 H NMR 400 MHz, Chloroform-d
  • ⁇ 9.12 (s, 1H), 8.07 (s, 1H), 7.01 (dd, J 8.0, 1.6 Hz,
  • Step 5-1 A suspension of 4,6,7-trifluoro-lH-indole-2-carboxylic acid (13 mg, 0.060 mmol) in CH 2 Cl 2 (0.3 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (9 ⁇ l, 0.074 mmol) at room temperature. The reaction was stirred at room temperature for 2 h to form a colorless clear solution. The stock solution of 4,6,7-trifluoro-lH-indole-2-carbonyl chloride (0.20 M) was freshly used.
  • Step 5-2 A solution of the compound from Step 5-1 (5.7 mg, 9.35 ⁇ mol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (20 ⁇ l, 0.143 mmol) and TFAA (8 ⁇ l, 0.057 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min. The mixture was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 5 (4 mg, 6.76 ⁇ mol, 72 % yield) as a white solid.
  • 1 H NMR 400 MHz, Chloroform-d
  • ⁇ 9.14 (s, 1H), 7.72 (s, 1H), 7.02 (d, J 7.9 Hz, 1H)
  • Step 5-1 A suspension of 6-(trifluoromethyl)-lH-indole-2-carboxylic acid (36 mg, 0.157 mmol) in CH 2 Cl 2 (0.7 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (25 ⁇ l, 0.189 mmol). The mixture turned to a clear yellow solution. The reaction was stirred at room temperature for 1 h. The stock solution of 6-(trifluoromethyl)-lH-indole-2-carbonyl chloride (0.22 M) was freshly used.
  • Step 6-2 A solution of the compound from Step 6-1 (8 mg, 0.013 mmol) in CH 2 Cl 2 (0.3 ml) was treated with TEA (25 ⁇ l, 0.179 mmol) and TFAA (9 ⁇ l, 0.064 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min, then quenched with aqueous ammonia. The mixture was stirred at room temperature for 30 min. The aqueous layer was extracted with dichloromethane twice. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 6 (6.5 mg, 10.73 ⁇ mol, 84 % yield) as a white solid.
  • Step 7-1 A suspension of 1 -phenyl- 1H- 1,2, 3-triazole-4-carboxylic acid (50 mg, 0.264 mmol) in CH 2 Cl 2 (0.5 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (40 ⁇ l,
  • Step 7-2 A suspension of the compound from Step 7-1 (18 mg, 0.031 mmol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (25 ⁇ l, 0.179 mmol) and TFAA (13 ⁇ l, 0.092 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min. The reaction was quenched with a saturated solution of sodium bicarbonate and stirred for 10 min. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 7 14 mg, 0.025 mmol, 80 % yield
  • 1 H NMR 400 MHz, Chloroform-d
  • 7.59 - 7.42 m, 3H
  • 6.82 dd,
  • Step 8-1 A suspension of tert-butyl L-leucinate hydrochloride (5.18 g, 23.15 mmol) and hex- 5-enal (2.5 g, 25.5 mmol) in DCE (65 ml) was treated with sodium triacetoxyhydroborate (5.91 g, 27.9 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. The mixture was quenched with a saturated solution of sodium bicarbonate. The mixture was stirred at room temperature for additional 1 h. The aqueous layer was extracted with DCM over 3 times.
  • Step 8-2 A solution the compound from Step 8-1 (4.2 g, 15.59 mmol) in CH 2 Cl 2 (60 ml) was treated with TEA (6.5 ml, 46.6 mmol) and Cbz-Cl (2.7 ml, 18.91 mmol) dropwise. The reaction was stirred at room temperature for 2 h. The reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtererd and concentrated in vacuo.
  • Step 8-3 A solution of the compound from Step 8-2 (380 mg, 0.942 mmol) in CH 2 Cl 2 (2 ml) was treated with TFA (1.5 ml, 19.47 mmol) dropwise. The reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and coevaporated with toluene twice. The crude was dried under high vacuum for 30 min to give the desired product (350 mg, 1.01 mmol, 107 % yield).
  • Step 8-4 A solution of the compound from Step 8-3 (350 mg, 1.007 mmol) and the compound from Step 1-5 (296 mg, 1.007 mmol) in DMF (4 ml) was treated with HATU (286 mg, 0.752 mmol) and N-methylmorpholine (550 ⁇ l, 5.00 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 1 h, then quenched with aqueous ammonia and diluted with ethyl acetate. The organic layer was washed with brine twice, dried over sodium sulfate, filtererd and concentrated in vacuo. The crude was added to 12 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (84 mg, 0.143 mmol, 14 % yield) as a colorless syrup.
  • Step 8-5 A solution of the compound from Step 8-4 (84 mg, 0.143 mmol) in toluene (140 ml) was treated with Zhan IB cat. (21 mg, 0.029 mmol). The mixture was degassed by freeze-pump-thaw at -78 °C and backfilled with N 2 over 3 times. The reaction was warmed to 90 °C and stirred overnight. The mixture was concentrated in vacuo. The crude was added to a 4 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (10 mg, 0.018 mmol, 13 % yield) as a brownish foam.
  • Step 8-7 A solution of 4,6-difluoro-lH-indole-2-carboxylic acid (198 mg, 1.004 mmol) in CH 2 Cl 2 (2 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (150 ⁇ L, 1.134 mmol) dropwise. The reaction was stirred at room temperature for 2 h. The stock solution of 4,6-difluoro-lH-indole-2-carbonyl chloride (0.5 M) was freshly used.
  • Step 8-8 A solution of a mixture of the compound from Step 8-7 (2.7 mg, 0.04 mmol) in CH 2 Cl 2 (0.3 ml) was treated with TEA (20 ⁇ l, 0.143 mmol) and TFAA (10 ⁇ l, 0.071 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min, then quenched with aqueous ammonia. The mixture was stirred at room temperature for 30 min. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purfied by reverse phase HPLC to give Example 8 (0.61 mg, 1.038 ⁇ mol, 8 % yield) as a white solid.
  • Step 9-1 A suspension of tert-butyl L-phenylalaninate hydrochloride (16 g, 62.1 mmol) and pent-4-enal (7.3 ml, 73.9 mmol) in DCE (200 ml) was treated with sodium triacetoxyborohydride (19 g, 90 mmol) portionwise over 10 min at room temperature. The reaction was stirred at room temperature overnight to form a light pink solution. The reaction was quenched with a saturated solution of sodium bicarbonate at 0 °C. The mixture was stirred at room temperature for 1 h. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 9-2 A solution of the compound from Step 9-1 (5.34 g, 12.61 mmol, 98 % yield) in CH 2 Cl 2 (50 ml) was treated with DIPEA (9 ml, 51.5 mmol) and Cbz-Cl (2.2 ml, 15.41 mmol) dropwise. The reaction was stirred at room temperature for 2 h and quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude was added to an 80 g silica gel column and eluted by MTBE/cyclohexane from 0% to 20% to give the desired product (5.34 g, 12.61 mmol, 98 % yield) as a colorless oil.
  • Step 9-3 A solution of the compound from Step 9-2 (739 mg, 1.745 mmol) in CH 2 Cl 2 (3.5 ml) was treated with TFA (2.5 ml, 32.4 mmol) dropwise. The reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, then co-evaporated with toluene twice. The crude was dried under high vacuum overnight to give the desired product (681 mg, 1.853 mmol, 106 % yield) as a colorless syrup.
  • Step 9-4 A suspension of the compound from Step 9-3 (670 mg, 1.823 mmol) and the compound from Step 1-5 (529 mg, 1.801 mmol) in DMF (3 ml) and CH 2 Cl 2 (6 ml) was treated with N-methylmorpholine (792 ⁇ l, 7.20 mmol). The reaction was stirred at room temperature for 5 min to form a cloudy suspension. The mixture was treated with HATU (698 mg, 1.836 mmol) in one portion. The reaction was stirred at room temperature for 1 h, then quenched with a saturated solution of sodium bicarbonate and diluted with ethyl acetate.
  • Step 9-5 A solution of the compound from Step 9-4 (100 mg, 0.165 mmol) in toluene (160 ml) was treated with Zhan IB cat. (24 mg, 0.033 mmol). The mixture was freezed to -78 °C, degassed and backfilled with N 2 by freeze-pump-thaw over 3 times. The reaction was warmed to 90 °C and stirred overnight. The mixture was concentrated in vacuo. The crude was added to a 12 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (27 mg, 0.047 mmol, 28 % yield) as a brownish foam.
  • Step 9-6 A solution of the compound from Step 9-5 (26 mg, 0.045 mmol) in MeOH (0.3 ml) was treated with Pd-C (3.8 mg, 3.57 ⁇ mol) under 1 atm H 2 . The mixture was bubbled with H 2 over 5 min. The reaction was stirred at room temperature for 2 h. The mixture was filtered through celite and rinsed with MeOH. The resulting filtrate was concentrated in vacuo to give the desired product (19 mg, 0.043 mmol, 95 % yield) as a brownish foam.
  • Step 9-7 A suspension of 4,6-difluoro-lH-indole-2-carboxylic acid (102 mg, 0.517 mmol) in CH 2 Cl 2 (1 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (80 ⁇ l, 0.605 mmol) dropwise. The reaction was stirred at room temperature for 2 h to form a brownish solution. The stock solution of 4,6-difluoro-lH-indole-2-carbonyl chloride (0.50 M) was freshly used.
  • Step 9-8 A solution of the compound from Step 9-7 (17 mg, 0.027 mmol) in CH 2 Cl 2 (0.5 ml) was treated with TEA (25 ⁇ l, 0.179 mmol) and TFAA (13 ⁇ l, 0.092 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane over 3 times.
  • Example 9 (12 mg, 0.020 mmol, 73 % yield) as a white solid.
  • Step 10-1 A suspension of l-(4-fluorophenyl)-lH-l,2,3-triazole-4-carboxylic acid (38 mg, 0.183 mmol) in CH 2 Cl 2 (0.6 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l- amine (26 ⁇ l, 0.197 mmol) dropwise. The reaction was stirred at room temperature for 1 h. The stock solution of l-(4-fluorophenyl)-lH-l,2,3-triazole-4-carbonyl chloride (0.30 M) was freshly used.
  • Step 10-2 A solution of the compound from Step 10-1 (15 mg, 0.024 mmol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (25 ⁇ l, 0.179 mmol) and TFAA (10 ⁇ l, 0.071 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min. The reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 10 (11 mg, 0.018 mmol, 75 % yield) as a white solid.
  • 1 H NMR 400 MHz, Chloroform-d
  • Step 26-1 A solution of the compound from Step 1-10 (65 mg, 0.119 mmol) in THF (0.6 ml) was treated with Co(acac) 2 (14 mg, 0.054 mmol) and phenylsilane (50 ⁇ l, 0.405 mmol) under O 2 (1 atm). The reaction was stirred at room temperature for 3 d. The mixture was concentrated in vacuo to give a crude product that was redissolved in MeOH (1 mL). The solution was treated with NaBH4 (30 mg, 0.793 mmol) at 0 °C and the reaction was stirred for 1 h. The reaction was quenched with a saturated solution of ammonium chloride.
  • Step 26-2 A solution of the compound from Step 26-1 (76 mg, 0.135 mmol) in THF (2 ml) was treated with TEA (100 ⁇ L, 0.717 mmol) and triethylsilyl trifluoromethanesulfonate (100 ⁇ L, 0.442 mmol) dropwise at 0 °C. The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 26-3 A solution of the compound from Step 26-2 (55 mg, 0.081 mmol) in MeOH (0.4 ml) was treated with Pd-C (10 mg, 9.40 ⁇ mol) under 3 ⁇ 4 (0.164 mg, 0.081 mmol) (1 atm).
  • Step 26-4 A suspension of 4,6-difluoro-lH-indole-2-carboxylic acid (79 mg, 0.401 mmol) in CH 2 Cl 2 (0.8 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (60 ⁇ l, 0.454 mmol) dropwise. The reaction was stirred at room temperature for 1 h to give a orange solution (0.501 molar) of 4,6-difluoro-lH-indole-2-carbonyl chloride in DCM that was freshly used.
  • Step 26-5 A solution of the compound from Step 26-4 (18 mg, 0.025 mmol) in THF (0.4 ml) was treated with hydrogen fluoride-pyridine (20 ⁇ l, 0.155 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. The mixture was concentrated, added to a 4 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (14 mg, 0.023 mmol, 92 % yield) as a white solid.
  • ESI MS m/z 606.41 [M-H]-.
  • Step 26-6 A solution of the compound from Step 26-5 (14 mg, 0.023 mmol) in DCM (0.4 ml) was treated with TEA (30 ⁇ l, 0.215 mmol) and TFAA (13 ⁇ l, 0.092 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 30 min, and then quenched with ammonium hydroxide. The mixture was stirred for additional 30 min. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 26 (7 mg, 0.012 mmol, 52 % yield) as a white solid.
  • ESI MS m/z 588.43 [M-H]-.
  • Step 27-1 A solution of Example 26 (5 mg, 8.48 ⁇ mol) in CH 2 Cl 2 (0.3 ml) was treated with Dess-Martin periodinane (9 mg, 0.021 mmol). The reaction was stirred at room temperature for 1 h. The mixture was added to a 4 g silica gel column and eluted by ethyl acetate/cyclohexane from 0% to 100% to give Example 27 (5 mg, 8.51 ⁇ mol, 100 % yield) as a white solid.
  • ESI MS m/z 586.38 [M-H]-.
  • Step 28-1 A solution of ((benzyloxy)carbonyl)-L-leucine (6.1 g, 22.99 mmol) in THF (60 ml) was treated with NaH (2.86 g, 71.5 mmol) portionwise over 45 min at 0 °C, then treated with 3-iodoprop-l-ene (6.2 ml, 67.8 mmol) dropwise over 5 min at 0 °C. The reaction was allowed to warm to room temperature and stirred overweekend. The reaction was quenched with an aqueous solution of sodium bisulfate dropwise at 0 °C until pH was 2. The mixture was stirred at room temperature for 30 min.
  • Step 28-2 A solution of the compound from Step 1-2 (5.09 g, 11.97 mmol) in 1,4-Dioxane (50 ml) was treated with K 2 CO 3 (2.53 g, 18.31 mmol), bis(pinacolato)diboron (3.67 g, 14.45 mmol) and PdCl 2 (dppl) (880 mg, 1.203 mmol) under N 2 . The mixture was bubbled with N2 over 10 min. The reaction was warmed to 85 °C and stirred overnight. The mixture was filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo.
  • Step 28-3 A solution of the compound from Step 28-2 (4.5 g, 9.53 mmol) in THF (20 ml) and Water (5 ml) was treated with m-CPBA (2.8 g, 11.36 mmol). The reaction was stirred at room temperature for 3 h. The reaction was quenched with a saturated solution of sodium thiosulfate. The mixture was stirred for additional 30 min. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 28-4 A solution of the compound from Step 28-3 (2.19 g, 6.04 mmol) in Acetone (25 ml) was treated with K 2 CO 3 (1.78 g, 12.88 mmol) and allyl bromide (0.55 ml, 6.36 mmol). The reaction was stirred at room temperature overnight. The mixture was filtered and concentrated in vacuo. The crude was added to a 40 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (1.7 g, 4.22 mmol, 70 % yield) as a white solid.
  • ESI MS m/z 401.29 [M-H]-.
  • Step 28-6 A suspension of the compound from Step 28-5 (1.8 g, 4.65 mmol) in 1,4-Dioxane (12 ml) was treated with 4N HC1 in dioxane (15 ml, 60.0 mmol). The reaction was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and dried under high vacuum to give the desired product (1.7 g, 5.25 mmol, 113 % yield) as a white solid.
  • ESI MS m/z 288.33 [M+H] + .
  • Step 28-7 A solution of the compound from Step 28-1 (543 mg, 1.778 mmol) and the compound from Step 28-6 (500 mg, 1.544 mmol) in DMF (1.5 ml) and CH 2 Cl 2 (4.5 ml) was treated with N-methylmorpholine (700 ⁇ l, 6.37 mmol) and HATU (704 mg, 1.851 mmol).
  • Step 28-8 A solution of the compound from Step 28-7 (680 mg, 1.183 mmol) in Toluene (1200 ml) was treated with Zhan IB cat. (178 mg, 0.243 mmol) under N 2 . The mixture was degassed and backfilled with N 2 through freeze-pump-thaw at -78 °C over 5 times. The reaction was warmed to 90 °C and stirred overnight. The mixture was concentrated in vacuo. The crude was added to a 40 g silica gel column and eluted by acetone/cyclohexane from 0% to 100% to give the desired product (600 mg, 1.098 mmol, 93 % yield) as a brownish solid.
  • Step 28-10 A suspension of 4,6-difluoro-lH-indole-2-carboxylic acid (63 mg, 0.320 mmol) in DCM (0.6 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l -amine (51 ⁇ l, 0.385 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 2 h to give the resulting solution (0.533 molar) of 4,6-difluoro-lH-indole-2-carbonyl chloride that was freshly used.
  • Step 28-11 A solution of the compound from Step 28-10 (8 mg, 0.013 mmol) in CH 2 Cl 2 (0.3 ml) was treated with TEA (14 ⁇ l, 0.100 mmol) and TFAA (7 ⁇ l, 0.050 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min, and then quenched with ammonium hydroxide. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was added to a 4 g sillica gel column and eluted by ethyl acetate/cyclohexane from 0% to 100% to give
  • Example 28 (6 mg, 10.42 ⁇ mol, 77 % yield) as a white solid.
  • ESI MS m/z 574.38 [M-H]-.
  • 1H NMR (400 MHz, Chloroform-d) ⁇ 8.98 (s, 1H), 7.75 (s, 1H), 6.87 (d, J 8.6 Hz, 1H),
  • Step 29-1 A solution of 2-((l-(2,4-difluorophenyl)cyclopropyl)amino)-2-oxoacetic acid (39 mg, 0.162 mmol) in CH 2 Cl 2 (0.4 ml) was treated with l-chloro-N,N,2-trimethylprop-l-en-l- amine (25 ⁇ l, 0.189 mmol) dropwise. The reaction was stirred at room temperature for 1.5 h to give a clear solution (0.404 molar) of 2-((l-(2,4-difluorophenyl)cyclopropyl)amino)-2- oxoacetyl chloride in DCM that was freshly used.
  • Step 29-2 A solution of the compound from Step 29-1 (19 mg, 0.030 mmol) in CH 2 Cl 2 (0.4 ml) was treated with TEA (40 ⁇ l, 0.287 mmol) and TFAA (17 ⁇ l, 0.120 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 2 h, and then quenched with ammonium hydroxide. The mixture was stirred for additional 30 min. The aqueous layer was extracted with dichloromethane over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • SARS-CoV-23C-like (3CL) protease fluorescence assay FRET: Recombinant SARS- CoV-23CL-protease was expressed and purified.
  • TAMRA-SITSAVLQSGFRKMK-Dabcyl- OH peptide 3CLpro substrate was synthesized. Black, low volume, round-bottom, 384 well microplates were used.
  • test compound 0.85 ⁇ L of test compound was dissolved in DMSO then incubated with SARS-CoV-23CL-protease (10 nM) in 10 ⁇ L assay buffer (50 mM HEPES [pH 7.5], 1 mM DTT, 0.01% BSA, 0.01% Triton-X 100) for 30 min at RT.
  • 10 ⁇ L of 3CL-protease substrate (40 ⁇ M) in assay buffer was added and the assays were monitored continuously for 1 h in an Envision multimode plate reader operating in fluorescence kinetics mode with excitation at 540 nm and emission at 580 nm at RT. No compound (DMSO only) and no enzyme controls were routinely included in each plate. All experiments were run in duplicate.
  • SARS-CoV-23CL-protease enzyme activity was measured as initial velocity of the linear phase (RFU/s) and normalized to controlled samples DMSO (100% activity) and no enzyme (0% activity) to determine percent residual activity at various concentrations of test compounds (0 - 10 ⁇ M). Data were fitted to normalized activity (variable slope) versus concentration fit in GraphPad Prism 7 to determine IC 50 . All experiments were run in duplicate, and IC 50 ranges are reported as follows: A ⁇ 0.1 ⁇ M; B 0.1-1 ⁇ M; C > 1 ⁇ M.
  • SARS-CoV-2 Cellular Assay (Vero 76): Test compounds are serially diluted using eight half-log dilutions in test medium (MEM supplemented with 2% FBS and 50 pg/mL gentamicin). Each dilution is added to 5 wells of a 96-well plate with 80-100% confluent Vero 76 cells. Three wells of each dilution are infected with virus (SARS-CoV-2 USA- WA1/2020), and two wells remain uninfected as toxicity controls. Six wells are infected and untreated as virus controls, and six wells are uninfected and untreated as cell controls.
  • Viruses are prepared to achieve the lowest possible multiplicity of infection (MOI ⁇ 0.002) that would yield >80% cytopathic effect (CPE) at 6 days. Plates are incubated at 37 ⁇ 2°C, 5% CO 2 . For neutral red assay, on day 6 post-infection, once untreated virus control wells reach maximum CPE, plates are stained with neutral red dye for approximately 2 hours ( ⁇ 15 minutes). Supernatant dye is removed, and wells are rinsed with PBS, and the incorporated dye is extracted in 50:50 Sorensen citrate buffer/ethanol for >30 minutes and the optical density is read on a spectrophotometer at 540 nm.
  • MOI ⁇ 0.002 multiplicity of infection
  • CPE cytopathic effect
  • EC 50 concentration of test compound required to inhibit CPE by 50%
  • concentration of compound that would cause 50% cell death in the absence of virus was similarly calculated (CC 50 ).
  • EC 50 ranges are reported as follows: A ⁇ 1 ⁇ M; B 1-10 ⁇ M; C > 10 ⁇ M.
  • CC 50 ranges are reported as follows: A ⁇ 1 ⁇ M; B 1-50 ⁇ M; C > 50 ⁇ M.
  • Viral stock preparation MRC-5 cells, (a diploid cell culture line composed of fibroblasts, originally developed from the lung tissue of a 14-week-old aborted Caucasian male fetus), were used for the culturing of 229E human corona virus (hCoV). Flasks were inoculated with hCoV- 229E and viral stocks were collected once cytopathic effect (CPE) was greater than 70%. Viral stocks in Growth Media (EMEM, 1% Penn/Strep, 1% nonessential amino acids, 10% heat- inactivated FBS) plus 5% glycerol were snap frozen using liquid nitrogen and stored at -80°C. Viral stock titers were quantified by a TCID 50 (50% median tissue culture infectious dose) assay, as described elsewhere.
  • TCID 50 50% median tissue culture infectious dose
  • 229E live virus assay 384-well black cell-culture-treated plastic clear-bottom plates are used in this assay. See Figure 1 below for plate layout.
  • ECHO liquid dispenser 3-fold serial dilutions of control and test compounds suspended in DMSO are added to the plate wells in duplicate in a total volume of 125nL per well.
  • MRC-5 cells below passage 17 are seeded into the inner 240 wells of the 384-well plate at 1,500 cells per well in a volume of 12.5 ⁇ L using Growth Media.
  • Viral stock is then added to the wells at a multiplicity of infection (MOI) of 0.05 in a volume of 12.5 ⁇ L per well, bringing the total volume of each well to ⁇ 25 ⁇ L.
  • MOI multiplicity of infection
  • Each plate has a control row of 20 wells with cells plus DMSO and virus but no compound (positive control, max CPE, minimum ATPlite signal), and a row with cells plus DMSO but no compound or virus (negative control, minimum CPE, maximum ATPlite signal), and a row with no cells or virus or compound (background plate/reagent control).
  • the control wells with cells but no virus are given an additional 12.5 ⁇ L of growth media containing an equal quantity of glycerol as those wells receiving the viral stock in order to keep consistent in media and volume conditions.
  • the outer 2 rows/columns of wells are filled with 30 ⁇ L of moat media (DMEM, 1% Penn/Strep) to act as a thermal and evaporative barrier around the test wells.
  • DMEM moat media

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Abstract

La présente invention concerne des composés représentés par la formule (I), et des sels pharmaceutiquement acceptables de ceux-ci : (Formule (I)), qui inhibent l'activité de réplication du coronavirus. L'invention concerne en outre des compositions pharmaceutiques comprenant un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, et des méthodes de traitement ou de prévention d'une infection à coronavirus chez un sujet qui le nécessite, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2022/024629 2021-05-11 2022-04-13 Nouveaux agents antiviraux dérivés de spiropyrrolidine macrocycliques WO2022240541A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023125825A1 (fr) * 2021-12-29 2023-07-06 Shanghai Curegene Pharmaceutical Co., Ltd. Composés anti-coronavirus et compositions et utilisations de ceux-ci

Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2000059929A1 (fr) * 1999-04-06 2000-10-12 Boehringer Ingelheim (Canada) Ltd. Peptides macrocycliques actifs contre le virus de l'hepatite c
US8372802B2 (en) * 2008-03-20 2013-02-12 Enanta Pharmaceuticals, Inc. Fluorinated macrocyclic compounds as hepatitis C virus inhibitors
US9309284B2 (en) * 2012-05-02 2016-04-12 Kansas State University Reasearch Foundation Macrocyclic and peptidomimetic compounds as broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, caliciviruses and coronaviruses
US20200230198A1 (en) * 2016-06-20 2020-07-23 Kansas State University Research Foundation Small molecule therapeutic inhibitors against picornaviruses, caliciviruses, and coronaviruses
US11319325B1 (en) * 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059929A1 (fr) * 1999-04-06 2000-10-12 Boehringer Ingelheim (Canada) Ltd. Peptides macrocycliques actifs contre le virus de l'hepatite c
US8372802B2 (en) * 2008-03-20 2013-02-12 Enanta Pharmaceuticals, Inc. Fluorinated macrocyclic compounds as hepatitis C virus inhibitors
US9309284B2 (en) * 2012-05-02 2016-04-12 Kansas State University Reasearch Foundation Macrocyclic and peptidomimetic compounds as broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, caliciviruses and coronaviruses
US20200230198A1 (en) * 2016-06-20 2020-07-23 Kansas State University Research Foundation Small molecule therapeutic inhibitors against picornaviruses, caliciviruses, and coronaviruses
US11319325B1 (en) * 2021-05-11 2022-05-03 Enanta Pharmaceuticals, Inc. Macrocyclic spiropyrrolidine derived antiviral agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023125825A1 (fr) * 2021-12-29 2023-07-06 Shanghai Curegene Pharmaceutical Co., Ltd. Composés anti-coronavirus et compositions et utilisations de ceux-ci

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