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WO2024170639A1 - Nouveaux inhibiteurs de cytomegalovirus - Google Patents

Nouveaux inhibiteurs de cytomegalovirus Download PDF

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Publication number
WO2024170639A1
WO2024170639A1 PCT/EP2024/053757 EP2024053757W WO2024170639A1 WO 2024170639 A1 WO2024170639 A1 WO 2024170639A1 EP 2024053757 W EP2024053757 W EP 2024053757W WO 2024170639 A1 WO2024170639 A1 WO 2024170639A1
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Prior art keywords
group
mmol
diazepane
compound according
amino
Prior art date
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Ceased
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PCT/EP2024/053757
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English (en)
Inventor
Mark BRÖNSTRUP
Martin Messerle
Nanaji Arisetti
Simon KALVERKAMP
Vadim KOROTKOV
Shahab NAHREVANIAN
Till ORTH
Jessica RÜCKERT
Thomas F. SCHULTZ
Steffi STEPHEN
Karen Wagner
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Medizinische Hochschule Hannover
Original Assignee
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Medizinische Hochschule Hannover
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Priority to AU2024221841A priority Critical patent/AU2024221841A1/en
Priority to CN202480012826.1A priority patent/CN120693334A/zh
Publication of WO2024170639A1 publication Critical patent/WO2024170639A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel inhibitors of Cytomegalovirus (CMV).
  • CMV Cytomegalovirus
  • Cytomegalovirus is a virus from the family Herpesviridae. Infection with CMV is very common since it is present worldwide and can affect anyone. On the whole, it is an infection which does not usually cause any serious health issues. Once the virus has infected a person, it will remain in that person’s body for the remainder of his or her life. In fact, it is latent for a long time and it does not tend to recurrent infection unless the person’s immune system is affected. Most people who are infected by the virus and who do not have serious health issues do not, on the whole, have any symptoms which might cause them to believe that they are infected with CMV. People who do develop some symptoms may suffer from a high temperature, swollen lymph glands, muscle pain or tiredness.
  • the virus is often transmitted from person to person through direct contact with body fluids such as saliva, sperm, blood, urine and other secretions. It may also be passed on through breast milk, in transplanted organs or cells (e.g., blood stem cells), during blood transfusions and from mother to child during pregnancy or childbirth.
  • body fluids such as saliva, sperm, blood, urine and other secretions.
  • body fluids such as saliva, sperm, blood, urine and other secretions. It may also be passed on through breast milk, in transplanted organs or cells (e.g., blood stem cells), during blood transfusions and from mother to child during pregnancy or childbirth.
  • the present invention provides compounds of formula (I): wherein
  • Cy is an optionally substituted 1 ,4 diazepane group
  • Ar 1 is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; and
  • Ar 2 is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; or a salt thereof.
  • Cy is unsubstituted or substituted by one or two substituents that are independently selected from -F, -CH3, and -CH(CH3)2. Further preferably, Cy is selected from the following groups:
  • Ar 1 is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S.
  • Ar 1 is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S.
  • Ar 1 is an optionally substituted phenyl group. Further preferably, Ar 1 is an optionally substituted pyridyl group.
  • Ar 1 is an optionally substituted heteroaryl group containing 9 ring atoms selected from C, N, O and S.
  • Ar 1 is unsubstituted.
  • Ar 1 is substituted by a halogen atom, a CN group, an OH group, a N3 group, a SFs group, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, O and S (wherein the optional substituents are preferably selected from halogen or a C1-6 alkyl group or a C1-6 heteroalkyl group), a heteroaralkyl group (e.g., a benzyloxy group), or a heteroalkylcycloalkyl group.
  • a halogen atom e.g., a benzyloxy group
  • Ar 1 is substituted by a halogen atom, a CN group, a SFs group, a C1- 6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, or a heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, O and S.
  • Ar 1 is selected from the following groups:
  • Ar 1 is selected from the following groups: Further preferably, Ar 2 is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S.
  • Ar 2 is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, O and S.
  • Ar 2 is substituted by one or two substituents which are independently selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc -OH, -OCH3 and -CN.
  • Ar 2 is selected from the following groups:
  • Ar 2 is selected from the following groups: Further preferred are compounds of formula (III): wherein R 2 is selected from the following groups: -NH2, -OH, NHMe, -NMe2, -NHAc - OCH3 and -CN; or a salt thereof.
  • R 2 is NH2.
  • the most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.
  • a herpesvirus infection especially in the treatment or prevention of a beta- herpesvirus infection; e.g., a Human Cytomegalovirus (HCMV) infection
  • HCMV Human Cytomegalovirus
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 15 carbon atoms, especially from 1 to 10 (e.g.
  • carbon atoms for example a methyl (Me, CHs), ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
  • C1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms.
  • C1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl (Me), CF3, CD3, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • alkenyl groups have one or two (especially preferably one) double bond(s)
  • alkynyl groups have one or two (especially preferably one) triple bond(s).
  • a halogen atom preferably F or Cl
  • heteroalkyl refers to an alkyl, alkenyl or alkynyl group as defined above in which one or more (preferably 1 to 8; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO2 group.
  • the expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.
  • heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).
  • a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen).
  • a heteroalkyl group contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen).
  • the term C1-C6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and/or N (especially O and/or N).
  • C2-C6 heteroalkyl refers to a heteroalkyl group containing from 2 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from O, S and/or N (especially O and/or N).
  • C1-C4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and/or N (especially O and/or N).
  • heteroalkyl refers to an alkyl group as defined above (straight-chain or branched) in which one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, sulfur or nitrogen atom or a CO group; this group preferably contains from 1 to 6 (e.g.
  • heteroalkyl groups are groups of formulae: R a -0-Y a -, R a -S-Y a -, R a -S0-Y a -, R a -S0 2 -Y a -, R a -N(R b )-S0 2 -Y a -, R a -SO 2 -N(R b )-Y a -, R a -N(R b )-Y a -, R a -C0-Y a -,
  • heteroalkyl groups are methoxy, trifluoromethoxy, -OCD3, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, -SCteMe, -NHAc, -CONH2, methoxyethyl, 1- methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, eno
  • cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
  • cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.
  • heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group.
  • a heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S).
  • Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g. -N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.
  • alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups.
  • An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.
  • heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group.
  • a heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from 1 or 2 to 6 carbon atoms.
  • alkylheterocycloalkyl alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri- unsaturated.
  • aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms.
  • aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • the expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2- imidazolyl), phenylpyrrolyl (e.g.
  • aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups.
  • aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 H-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane.
  • An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms.
  • the expression heteroaralkyl refers to groups containing both aryl and/or heteroaryl groups and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or hetero- cycloalkyl groups in accordance with the above definitions.
  • a heteroaralkyl group contains at least one heteroatom which is preferably selected from N, O and S.
  • a heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, O and S) and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and N and/or one or two cycloalkyl groups each containing 5 or 6 ring carbon atoms and/or one or two heterocycloalkyl groups, each containing 5 or 6 ring atoms comprising 1 , 2, 3 or 4 oxygen, sulfur or nitrogen atoms.
  • Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl- heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl- alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkyl- cycloalkenyl and heteroarylheteroalkylheterocyclo
  • halogen refers to F, Cl, Br or I.
  • optionally substituted refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two; especially preferably by one) substituents. If a group comprises more than one substituent, these substituents are independently selected, i.e. , they may be the same or different.
  • a group is substituted by a cyclic group, such as e.g., a cycloalkyl group or a heterocycloalkyl group, this cyclic group may be bonded to said group via a single or double bond or this cyclic group may be annulated or fused to said group.
  • a cyclic group such as e.g., a cycloalkyl group or a heterocycloalkyl group
  • substituents are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C1-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C1-C19 heteroalkylcycloalkyl, Ce-Cis aryl, C1-C17 heteroaryl, C7-C20 aralkyl and C1-C19 heteroaralkyl groups; especially C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 a
  • aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated.
  • rings of any cycloalkyl aryl group, heterocycloalkyl aryl group, cycloalkyl heteroaryl group and heterocycloalkyl heteroaryl group may be bonded to each other via a single or double bond or these rings may be annulated.
  • the compounds of formula (I), (II) or (Illi) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
  • the present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.
  • one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium.
  • Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology.
  • Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and/or increases the formation of desired active metabolites.
  • the present invention also encompasses the partially and fully deuterated compounds of formula (I), (II) or (Illi).
  • the term hydrogen also encompasses deuterium.
  • the present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a salt (especially a pharmaceutically acceptable salt), solvate or hydrate thereof, optionally in combination with one or more carrier substances and/or one or more adjuvants.
  • the present invention further provides a compound or a pharmaceutical composition as described herein for use in the treatment or prevention of a herpesvirus infection.
  • the present invention moreover provides the use of a compound or a pharmaceutical composition as described herein for the preparation of a medicament for use in the treatment or prevention of a herpesvirus infection.
  • the present invention provides a method for the treatment or prevention of a herpesvirus infection in a subject which comprises administering to the subject an effective amount of a compound of formula (I), (II) or (Illi), or a salt thereof.
  • the present invention provides a method for the treatment or prevention of a herpesvirus infection in a subject which comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula (I), (II) or (Illi), or a salt thereof.
  • herpesvirus are beta-herpesviruses.
  • Further preferred examples of the herpesvirus are human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and human cytomegalovirus (HCMV).
  • the compounds of the present invention may especially preferably be used in the treatment or prevention of a Cytomegalovirus (CMV) infection; e.g., a Human Cytomegalovirus (HCMV) infection.
  • CMV Cytomegalovirus
  • HCMV Human Cytomegalovirus
  • the present invention also relates to pro-drugs which are composed of a compound of formula (I), (II) or (Illi) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy- , acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl- oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g.
  • the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of formula (I), (II) or (Illi).
  • salts (especially pharmacologically acceptable salts) of sufficiently basic compounds are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid.
  • a sufficiently acidic compound may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein.
  • alkali or earth alkali metal salts for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts;
  • the compounds described herein may be solvated, especially hydrated.
  • the hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water-free compounds.
  • the solvates and/or hydrates may e.g. be present in solid or liquid form.
  • such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g.
  • transdermal delivery system such as a plaster containing the active ingredient or intranasal.
  • TDS transdermal delivery system
  • the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • excipients e.g.
  • lipids e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils.
  • excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils.
  • lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH 7 to 8, preferred 7.4).
  • excipients as are e.g.
  • the pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • stabilization e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.
  • the compounds of the invention can be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to conventional chemical methods.
  • the particular processes to be utilised in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the type of substitution at various locations of the molecule and the commercial availability of the starting materials play a role in the path to be followed and in the chosen reaction conditions for the preparation of the specific compounds of this invention. Those factors are readily recognised by one of ordinary skill in the art.
  • HPLC - electrospray mass spectra were obtained using an Agilent 6130 Single Quadrupole LC/MS System equipped with 1260 Infinity II LC System.
  • Flash chromatography was performed using Pure C-850 FlashPrep system in a flash mode.
  • Reversed phase (RP) separations were performed using FlashPure EcoFlex C18 cartridges from Buchi with H2O - MeCN eluent. Normal phase separations were performed using FlashPure silica cartridges from Buchi.
  • reaction mixture was washed with saturated NH4CI (2 x 100 mL), 1M NaOH (2 x 100 mL) and brine (100 mL).
  • the organic phase was dried over Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by HPLC (C18, MeCN/water 0.1 % HCOOH). The product containing fractions were lyophilized to dryness yielding the desired product.
  • N -(4-(pentafluoro-A 6 -sulfaneyl)phenyl)-1 ,4-diazepane-1 -carboxamide (8) was prepared according to GP3 starting from crude 7 (0.91 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step.
  • 4-Cyclopropylphenyl isocyanate (9) was prepared according to GP1 starting from 4-cyclopropylaniline hydrochloride (100 mg, 0.59 mmol), triphosgene (87 mg, 0.3 mmol) and EtsN (1.23 mL, 8.84 mmol) in DCM (3 mL). The product was directly used for the next step.
  • tert-Buty I 4-((4-cyclopropy Ipheny l)carbamoy l)-1 ,4-diazepane-1 -carboxylate (10)
  • tert-Butyl 4-((4-cyclopropylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (10) was prepared according to the general procedure GP2 starting from the solution of crude 9 (0.59 mmol) in toluene (5 mL) and a solution of tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (118 mg, 0.59 mmol) in THF (5 mL). The product was directly used for the next step.
  • N -(4-cyclopropylphenyl)-1 ,4-diazepane-1 -carboxamide (11) was prepared according to GP3 starting from crude 10 (0.59 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step without further purification.
  • fert-Butyl 4-((4-Ethynylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (13) tert- Butyl 4-((4-ethynylphenyl)carbamoyl)-1,4-diazepane-1 -carboxylate (13) was prepared according to the general procedure GP2 starting from the solution of crude 12 (0.85 mmol) in toluene (5 mL) and a solution of tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (171 mg, 0.85 mmol) in THF (5 mL). The product was directly used for the next step.
  • N -(4-((Trifluoromethyl)thio)phenyl)-1 ,4-diazepane-1 -carboxamide (17) was prepared according to GP3 starting from crude 16 (0.52 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step without further purification.
  • terf-Butyl 4-((3-Chlorophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (18) was prepared according to the general procedure GP2 starting from the solution of crude 3- chlorophenyl isocyanate (120 mg, 0.78 mmol) in dry THF (2 mL) and a solution of tertbutyl 1 ,4-diazepane-1 -carboxylate (1) (157 mg, 0.78 mmol) in THF (3 mL). The product was directly used for the next step.
  • N -(3-Chlorophenyl)-1 ,4-diazepane-1 -carboxamide (19) was prepared according to GP3 starting from crude tert-butyl 4-((3-chlorophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (18) (0.78 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step without further purification.
  • Boc terf-Butyl 4-((4-isopropylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (20) was prepared according to the general procedure GP2 starting from the solution of 4- isopropylphenyl isocyanate (684 mg, 4.2 mmol) in dry THF (15 mL) and a solution of tertbutyl 1 ,4-diazepane-1 -carboxylate (1) (850 mg, 4.2 mmol) in dry THF (15 mL). The product was directly used for the next step.
  • N -(4-lsopropylphenyl)-1 ,4-diazepane-1 -carboxamide (3TO 073) was prepared according to GP3 starting from crude 20 (4.2 mmol) in DCM (20 mL) and TFA (5 mL). The product was directly used in the next step without further purification.
  • N -([ 1 , 1 '-Biphenyl]-4-yl)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamide (SK-C25) was prepared according to GP4 starting from the solution of crude 28 (0.42 mmol) in DMF (0.5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 37 mg (9%). The compound exists as a ca. 1 : 1 mixture of two conformers.
  • N -(4-Bromophenyl)-1,4-diazepane-1 -carboxamide (30) was prepared according to GP3 starting from crude 29 (220 mg, 0.55 mmol) in DCM (2.5 mL) and TFA (2.5 mL). The product 30 was directly used in the next step without further purification.
  • N -(4-lodophenyl)-1 ,4-diazepane-1 -carboxamide (32) was prepared according to GP3 starting from crude 31 (220 mg, 0.49 mmol) in DCM (2.5 mL) and TFA (2.5 mL). The product 32 was directly used in the next step without further purification.
  • the compound 34 (89 mg, 0.29 mmol) was dissolved in DCM (2 mL). TFA (0.5 mL) was added to the solution and stirred for 3 h at room temperature. The solvent was removed under reduced pressure to give the product 35 as brownish solid, which was used for the next step without further purification.
  • 4-(2,2,2-Trifluoroethyl)phenyl isocyanate (39) was prepared according to GP1 starting from 4-(2,2,2-trifluoroethyl)aniline (50 mg, 0.28 mmol), triphosgene (42 mg, 0.14 mmol) and EtsN (40 ⁇ L, 0.28 mmol) in DCM (3 mL). The product was used for the next step without purification.
  • VK631 4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(1 H-indol-6-yl)-1 ,4-diazepane-1- carboxamide (VK631) was synthesized according to GP7 starting from 1/-/-indol-6-amine (66 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)).
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • VK667 4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-(trifluoromethoxy)phenyl)-1 ,4-diazepane- 1 -carboxamide (VK667) was prepared according to GP4 starting from the solution of crude 43 (0.24 mmol) in DMF (5 mL), 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (45 mg, 0.35 mmol), HATU (133 mg, 0.35 mmol) and DIPEA (0.3 mL, 226 mg, 1.75 mmol).
  • the product was purified by flash chromatography (cyclohexane : EtOAc 80 : 20 to 0 : 100) and after that by HPLC (C18; H 2 O : MeCN + 0.1% HCOOH).Yield: 44 mg (44%).
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • N -(4-lsopropylphenyl)-7-methyl-1 ,4-diazepane-1 -carboxamide was prepared according to GP3 starting from the crude 52 (0.58 mmol) in CH2CI2 (8 mL) and TFA (0.8 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.
  • the product was purified by flash chromatography (RP; C18; MeCN : H2O) and then additionally by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 106.6 mg (48%).
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • N -(4-lsopropylphenyl)-7-methyl-1 ,4-diazepane-1 -carboxamide was prepared according to GP3 starting from 54 (151 mg, 0.46 mmol) in CH2CI2 (5 mL) and TFA (1 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.
  • the product was purified by flash chromatography (RP; C18; MeCN : H 2 O) and then additionally by HPLC (018; H2O : MeCN + 0.1% HCOOH) yielding 87 mg (49%) of the desired product.
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • N -(4-(1 ,4-diazepane-1-carbonyl)-1 ,2,5-oxadiazol-3-yl)acetamide (57) was prepared according to GP3 starting from 56 (300 mg, 0.85 mmol) in CH2CI2 (10 mL) and TFA (1 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.
  • the product was purified flash chromatography (RP; C18; MeCN : H2O) and then additionally by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 28 mg (10%).
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • N -(4-(Benzyloxy)phenyl)-1 ,4-diazepane-1 -carboxamide (61) was prepared according to GP3 starting from 60 (109 mg, 0.26 mmol) in CH2CI2 (4 mL) and TFA (0.4 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.
  • the product was purified by column chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 64.3 mg (31%).
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • the product was purified by column chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 66.6 mg (32%).
  • the compound exists as a ca. 1 : 1 mixture of two conformers.
  • the compound 64 (30 mg, 0.08 mmol) was added to the solution of HBr in HOAc (32%) (1 mL). The reaction mixture was stirred for 18 h at r. t. It was concentrated under reduced pressure and purified by flash chromatography (C18; MeCN : H2O) yielding 15.6 mg (87%) of the desired product that was directly used for the next step.
  • the compound 63 (216 mg, 0.59 mmol) was added to the solution of HBr in HOAc (32%) (1 mL). The reaction mixture was stirred for 18 h at r. t. It was concentrated under reduced pressure and purified by flash chromatography (C18; MeCN : H2O) yielding the desired product that was directly used for the next step.
  • Absolute MeOH (6.2 ⁇ L, 4.9 mg, 0.15 mmol) was added to the mixture of NaH (12 mg, 0.3 mmol, 60% dispersion in mineral oil) and absolute THF (0.35 ml_). The mixture was stirred for 5 min at r. t. and a solution of 67 (19.9 mg, 0.05 mmol) in absolute MeOH (20 pL) was added. The reaction mixture was stirred for 75 min at 50 °C, cooled down to r. t., filtered and purified by HPLC (C18; H 2 O : MeCN + 0.1% HCOOH). Yield: 1.9 mg (10%). The compound exists as a ca. 1 : 1 mixture of two conformers.
  • Inhibitors were initially dissolved in DMSO at a concentration of 10 mM (stock solutions) and then further diluted in DMEM medium. 3 h after virus inoculation the cell culture medium was replaced with DMEM containing the inhibitor at appropriate concentrations (3 wells per concentration [triplicates]). Depending on the activity of individual inhibitors, the examined concentrations ranged from 10 pM to low nanomolar values, applying 2- fold dilution steps. After incubation for 7 days the GFP signals of infected cell cultures in individual wells were measured with a plate reader (Cytation 3 Cell Imaging Multi-Mode Reader; Biotek, VT, USA).
  • the GFP-expressing virus Underwent two rounds of infection during the 7-day incubation period, resulting in spread of the viral infection to the majority of the cells and strong GFP expression (corresponding to 100% infection).
  • GFP signals of inhibitor-treated cultures were calculated in relation to the untreated cultures (in %). Dose response curves are exemplarily shown for some of the inhibitors ( Figure 1). The maximal inhibition is determined by the GFP signal resulting from cells that were infected in the first round, i.e. following inoculation of cultures with the HCMV-GFP variant (approx. 1 of 20 cells) [i.e. in the absence of further virus production and viral spread].
  • Figure 1 shows the activity of some of the HCMV inhibitors.
  • the indicated substances were tested for inhibition of HCMV infection using the assay described in the text. Untreated cultures served as controls (black, dotted lines). Means +/- SD are depicted using GraphPad Prism software version 5.0. Concentrations of the inhibitors are indicated on the X-axis. Results are representative of 3 experiments performed.

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Abstract

La présente invention concerne de nouveaux inhibiteurs du cytomégalovirus (CMV) de formule (I), dans laquelle Cy est un groupe 1,4 diazépane éventuellement substitué ; Ar1 est un groupe phényle éventuellement substitué ; un groupe naphtyle éventuellement substitué ; ou un groupe hétéroaryle éventuellement substitué contenant de 5 à 10 atomes cycliques choisis parmi C, N, O et S ; et Ar2 est un groupe hétéroaryle éventuellement substitué contenant 5 ou 6 atomes cycliques choisis parmi C, N, O et S ; ou un sel de celui-ci.
PCT/EP2024/053757 2023-02-16 2024-02-14 Nouveaux inhibiteurs de cytomegalovirus Ceased WO2024170639A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2008064054A2 (fr) * 2006-11-21 2008-05-29 Boehringer Ingelheim International Gmbh Composés qui modulent le récepteur cb2

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064054A2 (fr) * 2006-11-21 2008-05-29 Boehringer Ingelheim International Gmbh Composés qui modulent le récepteur cb2

Non-Patent Citations (6)

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Title
CAROL SHOSHKES REISS: "Cannabinoids and Viral Infections", PHARMACEUTICALS, vol. 3, no. 6, 9 June 2010 (2010-06-09), pages 1873 - 1886, XP055765009, DOI: 10.3390/ph3061873 *
COCKCROFT X L ET AL: "Phthalazinones 2: Optimisation and synthesis of novel potent inhibitors of poly(ADP-ribose)polymerase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 16, no. 4, 15 February 2006 (2006-02-15), pages 1040 - 1044, XP027965805, ISSN: 0960-894X, [retrieved on 20060215] *
DORIS RIETHER ET AL: "1,4-Diazepane compounds as potent and selective CB2 agonists: Optimization of metabolic stability", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 21, no. 7, 4 February 2011 (2011-02-04), pages 2011 - 2016, XP028162326, ISSN: 0960-894X, [retrieved on 20110209], DOI: 10.1016/J.BMCL.2011.02.017 *
HICKEY EUGENE R ET AL: "Selective CB2 receptor agonists. Part 1: The identification of novel ligands through computer-aided drug design (CADD) approaches", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 25, no. 3, 17 December 2014 (2014-12-17), pages 575 - 580, XP029131252, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2014.12.033 *
MATHILDE MALGRAS: "The Antiviral Activities of Poly-ADP-Ribose Polymerases", VIRUSES, vol. 13, no. 4, 30 March 2021 (2021-03-30), CH, pages 582, XP093153458, ISSN: 1999-4915, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066025/pdf/viruses-13-00582.pdf> DOI: 10.3390/v13040582 *
MAZZOTTA SARAH ET AL: "Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 185, 3 November 2019 (2019-11-03), XP085936059, ISSN: 0223-5234, [retrieved on 20191103], DOI: 10.1016/J.EJMECH.2019.111840 *

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