EP4370111A1 - Dhodh inhibitors and their use as antiviral agents - Google Patents

Dhodh inhibitors and their use as antiviral agents

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Publication number
EP4370111A1
EP4370111A1 EP22747687.6A EP22747687A EP4370111A1 EP 4370111 A1 EP4370111 A1 EP 4370111A1 EP 22747687 A EP22747687 A EP 22747687A EP 4370111 A1 EP4370111 A1 EP 4370111A1
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European Patent Office
Prior art keywords
alkyl
aryl
substituted
cycloalkyl
group
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Pending
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EP22747687.6A
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German (de)
French (fr)
Inventor
Chris Meier
Nora Constanze LAUBACH
Desiree RIJONO
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Universitaet Hamburg
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Universitaet Hamburg
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Publication of EP4370111A1 publication Critical patent/EP4370111A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to anthranilic acid compounds useful as DHODH inhibitors, pharmaceutical compositions con- taining the compounds, and the use of the compounds and compo- sitions in methods of treatment of a disease, disorder or con- dition caused by an RNA virus.
  • DHODH Dihydroorotate dehydrogenase
  • UMP uridine monophosphate
  • An inhibition of DHODH and thus a suppression of de novo synthesis of UMP leads to a downregulation of the intracel- lular number of pyrimidine nucleotides. This can lead to limi- tations in cell growth and proliferation.
  • DHODH inhibitors One of the most potent DHODH inhibitors is brequinar with an IC50 of about 10 nM. It has been investigated for cancer treat- ment and as an immunosuppressive drug in clinical trials. How- ever, due to a narrow therapeutic window and inconsistent pharmacokinetics the further development was cancelled.
  • DHODH inhibitor is teriflunomide that derives from the prodrug leflunomide. It is the first approved DHODH inhibitor for the treatment of rheumatoid arthritis and is also used against multiple sclerosis. Disadvantages of this drug are a long plasma half-life and liver toxicity.
  • ABR-222417 is reported to result in a marked increase in graft survival time when screened in a low-responder heart allograft transplantation model in rats.
  • WO 2005/075410 discloses the use of certain DHODH inhibitor compounds for the treatment of autoimmune diseases, inflamma- tory diseases, organ transplant rejection and malignant neoplasia.
  • virology is a rather novel field of application of DHODH inhibitors.
  • US 2014/0080768 Al and WO 2009/153043 Al generally mention the potential use of DHODH inhibitors for various diseases and disorders including some viral diseases, besides autoimmune diseases, immune and inflammatory diseases, cancer, destruc- tive bone disorders and others.
  • RNA viruses RNA viruses
  • the compounds are characterized by acceptable pharmacokinetic parameters, like ADME (Absorption, Distribution, Metabolism, and Excretion) properties.
  • ADME Absorption, Distribution, Metabolism, and Excretion
  • the present invention relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula I: wherein:
  • W is C or N, and preferably is C
  • R 1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C (0)-0-R 1 -group is joined to the -NH-group or -X-group shown in Formula (I) to form together with the W- containing aromatic ring shown in Formula (I) a hetero ring system;
  • R 2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said al- kyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably independently selected from the group consisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl
  • R 3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moi- ety is preferably independently selected from the group con- sisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with halo
  • X is 0 or NH, and preferably is NH;
  • Y is CR 4 or N, and preferably is CR 4 ;
  • Z is 0, S, NH or CR 5 2, and preferably is 0;
  • R 4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and preferably is H;
  • R 5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy and acetyl, and preferably is H.
  • the above-defined compounds have a high antiviral efficacy.
  • the compounds have been found to have a high antiviral activity against a wide spec- trum of viruses, especially a wide spectrum of RNA viruses.
  • the compounds have been found to be promising candi- dates for in vivo applications as broad-spectrum antiviral drug.
  • the above-defined compounds have been found to act by inhibition of a host enzyme. This brings several advan- tages compared to inhibitors targeting viral enzymes, such as (i) a higher barrier to resistance, (ii) a broad coverage of different viruses that goes along with a preventative prepara- tion for new emerging virus infections, and (iii) allowing an- tiviral therapy of virus infections without druggable viral targets.
  • the above-defined compounds have been found to act by inhibition of the host enzyme DHODH.
  • the DHODH sets itself apart from other cellular targets by the fact that the host cell is able to overcome its temporary inhibition by the steady supply of pyrimidine nucleotides for resting cells via salvage pathway.
  • the above-defined compounds show a high meta- bolic stability with no cleavage at the amide group and very reduced or even no hydroxylation.
  • a good membrane permeability and good plasma stability are shown by the compounds of the invention as well. This underscores their position as promis- ing candidates for further in vivo pharmacokinetic studies.
  • the compound to be used according to the invention is represented by formula (I) and W is C.
  • the monoaromatic ring shown in Formula I is pref- erably a phenyl ring and the compounds to be used according to the invention are anthranilic acid derivatives.
  • the compound to be used according to the invention is represented by formula (I) and R 1 is H.
  • the compound is preferably present as a free anthranilic acid.
  • the free acid is deprotonated resulting in a negatively charged carboxylate.
  • prodrug moieties can be installed at the R 1 position to enable penetration through the cell membrane and allow the re- lease of the active carboxylic acid inside the cell.
  • R 1 can be a pharmaceutically acceptable cation or alkyl, cycloalkyl, heterocyclyl or -C(0)-alkyl, wherein the alkyl or -C(0)-alkyl can be unsubstituted or op- tionally substituted with one or more moieties which can be the same or different, each moiety being independently select- ed from the group consisting of -0C(0)-alkyl, -OC(0)0-alkyl, heterocyclyl, aryl and heteroaryl.
  • R 1 can be - C (0)-alkyl to form an anhydride prodrug moiety.
  • R 1 can be alkyl substituted with -OC (0)0-alkyl to form an alkoxycarbonyloxyalkyl (POC) moiety.
  • R 1 can be al- kyl substituted with aryl which in turn is substituted with an -0-C (0)-alkyl group to form an acyloxybenzyl moiety.
  • R 1 is selected from the group consisting of
  • R 1 is selected from the group consist- ing
  • the -C (O)-0-R 1 -group can be joined to the -NH-group or -X-group shown in Formula (I) to form togeth- er with the monoaromatic ring shown in Formula (I) a hetero ring system.
  • a hetero ring system is a quinazolinedione, such as
  • the compounds to be used according to the inven- tion are characterized in that the aromatic ring of the anthranilic core is substituted by one or more R 2 substituents.
  • R 2 is a substituent, in particular one substituent, as defined above.
  • R 2 is H.
  • R 2 is aryl, preferably phenyl, which can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of alkyl, ar- yl, halogen, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl .
  • R 2 is wherein
  • R 6 is H; halogen, preferably F; or aryl, preferably phenyl;
  • R 7 is H; halogen, preferably F; alkyl, preferably methyl; or aryl, preferably phenyl; and
  • R 8 is H; cycloalkyl, preferably cyclohexyl; aryl, preferably phenyl; haloaryl, preferably 4-F-phenyl; arylalkyl, preferably 4-ethyl-phenyl, 4-pentyl-phenyl; alkylaryl, preferably benzyl; aryloxy, preferably phenyloxy; arylalkoxy, preferably benzyloxy; or heterocyclylalkyl, preferably morpholinomethyl.
  • R 2 is , wherein R6 b , R 7 and R 8 are selected as shown in the following table:
  • R 2 is alkynyl, preferably ethynyl, which can be unsubstituted or optionally substituted with a moiety selected from the group consisting of aryl, aryl substituted with alkyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substituted with arylalkyl, aryl substi- tuted with alkoxy, aryl substituted with aryloxy, aryl substi- tuted with -O-arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl.
  • R 2 is alkynyl, preferably ethynyl, which is sub- stituted with a moiety selected from the group consisting of phenyl; phenyl substituted with 4-haloalkyl like 4-CF 3 ; phenyl substituted with 4-alkyl like 4-C 4 H 9 or 4-O d Hi 3 ; phenyl substi- tuted with 4-alkoxy like 4-ethoxy or 4-pentoxy; phenyl substi- tuted with 4-aryloxy like 4-phenyloxy; phenyl substituted with arylalkoxy like 4-benzyloxy; phenyl substituted with 4-aryl like 4-phenyl; phenyl substituted with 4-cycloalkyl like 4- cyclohexyl; phenyl substituted with 4-arylalkyl like 4-benzyl; and alkyl, preferably methyl or butyl, which is substituted with aryloxy, preferably phenyloxy, which in turn is
  • R 2 is alkynyl, preferably ethynyl, which is substituted with a moiety selected from the group consist- ing of
  • R 2 is alkynyl, preferably ethynyl, which is substituted with the foilwing moiety: wherein Y is independently selected from CR 4 and N, and preferably is CR 4 ;
  • R 4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and preferably is H;
  • R 6 is heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl and heterocyclylalkyl can be unsubstituted or substituted with one or more ring system substituents which can be the same or different;
  • R 7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, alkoxy,
  • R 2 -groups of this embodiment are de- scribed in further detail below in connection with the second aspect of the invention.
  • R 2 is a rather small, i.e. a sterically undemanding, substituent, such as H; alkyl, prefer- ably 5-alkyl like 5-methyl or 5-tBu; halogen, wherein halogen is preferably selected from F, Cl and Br, and/or wherein halo- gen is preferably 5-halogen like 5-Br or 5-F or 4-halogen like 4-F; alkoxy, preferably 5-alkoxy like 5-methoxy or 4-alkoxy like 4-methoxy; haloalkyl, preferably 5-CF 3 ; NO2, preferably 5- NO2; or aryl, preferably phenyl or biphenyl like 5-phenyl or 5- biphenyl. Most preferably, all R 2 are H.
  • substituent such as H
  • alkyl prefer- ably 5-alkyl like 5-methyl or 5-tBu
  • halogen wherein halogen is preferably selected from F, Cl and Br, and/or wherein halo- gen is preferably 5-halogen like 5-
  • R 2 represents two substituents which are joined to form together with the monoaromatic ring shown in Formula (I) a ring system or a hetero ring system.
  • the ring system and the hetero ring system can be unsubstituted or op- tionally substituted, e.g. by a ring system substituent as de- fined herein.
  • the ring system can comprise an aryl, such as e.g. a phenyl, annelated to the aromatic ring of Formula (I).
  • the phenyl ring of the anthranilic core of the compounds of Formula (I) and the phe- nyl ring annelated to it form a polycylic aromatic hydrocar- bon, such as e.g. a naphthalene.
  • the hetero ring system formed by joining two R 2 substituents to- gether with the monoaromatic ring shown in Formula (I) is
  • At least one of R 2 is joined to the -NH-group or -X-group to form together with the monoaromatic ring shown in Formula (I) a hetero ring system.
  • a hetero ring system is a quinazolinedione.
  • group Y in formula (I) is CR 4 , with R 4 being H;
  • the group R 3 in formula (I) is one or more substituents independently selected from the group consisting of H, alkyl, halogen and haloalkyl.
  • the alkyl can be 2-methylbutan-2-yl
  • the halogen can be F
  • the haloalkyl can be trifluoromethyl.
  • the compound of the first as- pect of the invention can have the general structure shown in Formula la or Ib: wherein:
  • R 3a is alkyl or haloalkyl
  • R 3b is H or halogen, wherein the halogen is preferably F.
  • the alkyl is preferably 2-methylbutan-2-yl and the haloalkyl is preferably trifluoromethyl.
  • the compound of the first as- pect of the invention has the general structure shown in For- mula la or Ib, wherein R 3a is an unsubstituted linear or branched Ci-C 6 -alkyl, an unsubstituted C3-C6-cycloalkyl, or a linear or branched C1-C6- haloalkyl; and
  • R 3b is H or halogen.
  • the compound according to the first aspect of the invention has one of the following structures:
  • the present invention relates to a com- pound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula II or Formula Ila:
  • W is C or N, and preferably is C
  • R 1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl;
  • Y is independently selected from CR 4 and N, and preferably is CR 4 ;
  • R 4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and preferably is H;
  • R 6 is heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl and heterocyclylalkyl can be unsubstituted or substituted with one or more ring system substituents which can be the same or different and are described below;
  • R 7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, alkoxy,
  • R 8 is -C(O)-alkyl, -C(0)O-alkyl, -C(0)NH-alkyl, -C(0)- cycloalkyl, -C(0)O-cycloalkyl, -C(0)NH-cycloalkyl, -C(0)-aryl,
  • Z is - (CH 2 ) n" , -0- (CH 2 ) n - , -NH- (CH 2 ) n- , - (CH 2 ) p-L- (CH 2 ) q - ,
  • n is an integer from 1 to 6; p and q are integers independently selected from 0 to 6;
  • L is a linking group selected from the group consisting of heteroaryl, aryl, heterocyclyl and cycloalkyl;
  • X is 0, S, NH, CH 2 , S(0) or C(0), and preferably is 0, S or NH;
  • R 9 is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of H, halo- gen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl and trialkylsilyl;
  • R 10 is aryloxy or arylalkyl or optionally R 10 represents two substituents linked to each other to form together with the aryl or heteroaryl a polycyclic ring system, wherein prefera- bly the polycyclic ring system is a naphthalene or fluorene; and R 11 is alkyl, cycloalkyl or -Z-X-R 9 .
  • the compounds of the second aspect are less vulnerable for metabolism com- pared to the inhibitors described in WO 2020/225330. Without wishing to be bound by any theory, it is believed that due to the heterocyclyl or heterocyclylalkyl substituent R 6 polarity is added and the compounds are less lipophilic which makes them less vulnerable for metabolism.
  • R 6 is se- lected from the group consisting of
  • R 7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, - C(0)-alkyl, -C(0)-haloalkyl, -NH-alkyl and -N (alkyl)2.
  • the alkyl in the above R 7 groups is methyl or ethyl. More- over, if R 7 is halogen, it is preferaby F.
  • the compound according to the second aspect of the invention has one of the following structures:
  • the present invention relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula III: ( H I ) wherein: W is N;
  • R 1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C (0)-0-R 1 -group is joined to the -NH-group or -X-group shown in Formula (III) to form together with the W-containing aromatic ring shown in Formula (III) a hetero ring system;
  • R 2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said al- kyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably independently selected from the group consisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl
  • X is CH2, 0 or NH, and preferably is NH
  • R 3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl , alkoxy, aryl, arylalkyl, heteroalkyl, heteroarylalkyl, amido, carbamoyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl, arylalkyl, heteroalkyl, heteroarylalkyl, amido, and carbamoyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably inde- pendently selected from the group consisting of hydroxyl, hal- ogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, aryl
  • the compounds of the third aspect show a high metabolic stability and good membrane permeability.
  • the compound has the general structure shown in Formula Ilia: wherein R 1 , R 2 , W and X are as defined above in formula (III);
  • R 3a is H, -CH 3 , -CF 3 , or halogen
  • R 3b and R 3C are the same or different and are independently se- lected from the group consisting of H, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl, trialkylsilyl and carbonyl substituents, such as amides or ureas.
  • R 3b and R 3c are joined to each other to form - together with the ring they are attached to - a possibly substituted ring system.
  • Redoxal a known DHODH inhibitor
  • Redoxal is a compound synthesized via the coupling of two anthranilic acid compounds.
  • the compounds to be used according to the present invention can be present in the form of a dimer, i.e. two molecules hav- ing the structure of formula (I), (II) or (III) can be coupled to form a dimer.
  • two molecules of formula (I) or two molecules of formula (III) are coupled via substituents R 2 and/or R 3 .
  • the phe- nyl ring of the first anthranilic acid core is coupled via R 2 to R 2 of the phenyl ring of the second anthranilic acid core or to R 3 of the benzodioxole-type or naphthyl ring system of the second anthranilic acid core.
  • two molecules of formula (II) are coupled via sub- stituents R 6 /R 7 and/or R 8 .
  • the Y-containing monoaromatic ring of the first anthranilic acid core is coupled via R 6 or R 7 to R 6 or R 7 of the Y-containing monoaromatic ring of the second anthranilic acid core or to R 8 of the second anthranilic acid core.
  • Suitable routes of synthesis to provide dimers according to the invention are known and are described below.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as me- thyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • substituted alkyl means that the alkyl group may be substi- tuted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH (cycloalkyl), -N (alkyl)2, carboxy and -C(0)O-alkyl.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • suitable alkenyl groups include ethenyl and propenyl.
  • substituted alkenyl means that the alkenyl group may be sub- stituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • substituted alkynyl means that the alkynyl group may be substituted by one or more substitu- ents which may be the same or different, each substituent be- ing independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitro- gen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxy- gen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothieny
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable arylalkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl . The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls com- prise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substitu- ents" which may be the same or different, and are as defined herein.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Pre- ferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, re- places an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being inde- pendently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio
  • Ring system substitu- ent may also mean a single moiety which simultaneously re- places two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • moi- ety are methylene dioxy, ethylenedioxy, -C(CH 3)2 - and the like which form moieties such as, for example:
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur at- oms present in the ring system.
  • Preferred heterocyclyls con- tain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N (Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non- limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl , 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting exam- ples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl . The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower al- kyl. Non-limiting examples of suitable hydroxyalkyl groups in- clude hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C (0)- or cycloalkyl-C(0)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl.
  • Pre- ferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(0)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-0- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2- naphthalenemethoxy .
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • a suitable aralkylthio group is benzylthio.
  • the bond to the par- ent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting ex- amples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(0)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C (0)- group.
  • Non- limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl .
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the par- ent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicat- ed group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious thera-Guic agent.
  • prodrug denotes a compound that is a drug precursor which, up- on administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of For- mula I, II or III or a salt and/or solvate thereof.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution- phase and isolatable solvates. Non-limiting examples of suita- ble solvates include ethanolates, methanolates, and the like. "Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • the compounds of Formula I, II, Ila or III can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I, II, Ila or III herein is under- stood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic ba- ses.
  • zwitterions when a compound of Formula I, II or III con- tains both a basic moiety, such as, but not limited to a pyri- dine or imidazole, and an acidic moiety, such as, but not lim- ited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physio- logically acceptable) salts are preferred, although other salts can also be useful.
  • Salts of the compounds of the Formu- la I, II or III may be formed, for example, by reacting a com- pound of Formula I, II or III with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization .
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates , fumarates, hydro- chlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen- containing groups may be quarternized with agents such as low- er alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, dieth- yl, and dibutyl sulfates dimethyl, dieth- yl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substitu- ents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated with- in the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • Individual stereoisomers of the compounds of the invention may, for exam- ple, be substantially free of other isomers, or may be ad- mixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the compounds of Formula I, II, Ila and III have pharmacologi- cal properties.
  • the compounds of Formula I, II and III have found to be inhibitors of DHODH.
  • it has been found that the compounds of Formula I, II and III have a very high antiviral efficacy against various RNA viruses in an up to one-digit nanomolar range.
  • the compounds to be used according to the invention are char- acterized by an IC 50 of less than 1.0 mM or 0.7 mM, preferably less than 0.3 mM, more preferably less than 0.1 mM, like less than 0.08 mM or less than 0.05 mM or less than 0.04 mM or less than 0.02 mM, wherein the IC 50 values are generated in an assay using LASV, EBOV or CCHFV using the assay described in the ex- amples herein.
  • the compounds are characterized by a low cytotoxicity, such as a CC 50 of more than 1 mM, preferably more than 8 mM, more preferably more than 15 mM, like more than 30 mM or more than 50 mM or more than 70 mM or more than 100 mM.
  • a low cytotoxicity such as a CC 50 of more than 1 mM, preferably more than 8 mM, more preferably more than 15 mM, like more than 30 mM or more than 50 mM or more than 70 mM or more than 100 mM.
  • the compounds of Formula I, II, Ila or III are expected to be useful in the therapy of viral diseases, in particular in the treatment of treatment of a disease, disor- der or condition caused by an RNA virus.
  • RNA virus refers to a virus that has RNA (ribonucleic acid) as its genetic material.
  • This nu- cleic acid is usually single-stranded RNA (ssRNA) but may be double-stranded RNA (dsRNA).
  • ssRNA single-stranded RNA
  • dsRNA double-stranded RNA
  • the RNA virus is a virus that belongs to Group III, Group IV or Group V of the Baltimore classification system of classifying viruses.
  • the RNA virus which can be affected by the com- pounds of Formula I, II, Ila or III is selected from the group consisting of bunya viruses including Toscana virus (TOSV), hazara virus (HAZV), tahyna virus (TAHV), rift valley fever virus (RVFV), Lassa virus (LSAV), Punta Toro phlebovirus (PTV) and Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV); flavi viruses including yellow fever virus (YFV), dengue virus (DENV), tick-borne encephalitis virus (TBEV), zika virus (ZIKV) and Hepatitis C virus (HCV); toga viruses including Venezuelan equine encephalitis virus (VEEV), Sindbis virus (SINV) and Chikungunya virus (CHIKV); mononegaviruses includ- ing Ebola virus (EBOV), Marburg virus (MARV), Human parainfluenza virus 3 (
  • a method of treating a mammal e.g., human having a disease or condition associated with a virus, in particular RNA virus, by administering a therapeutically effective amount of at least one compound of Formula I, II, Ila or III, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
  • the compounds according to the invention are suita- ble to be used for the treatment of autoimmune diseases, e.g. rheumatoid arthritis or multiple sclerosis, the prophylaxis of transplant rejection, the treatment of cancer, e.g. leukemia or malignant melanoma, the treatment of viral and parasite in- fections, e.g. malaria, as well as in crop science.
  • autoimmune diseases e.g. rheumatoid arthritis or multiple sclerosis
  • the prophylaxis of transplant rejection the treatment of cancer, e.g. leukemia or malignant melanoma
  • cancer e.g. leukemia or malignant melanoma
  • viral and parasite in- fections e.g. malaria
  • compositions comprising a compound of Formula I, II, Ila or III are also disclosed herein.
  • the phar- maceutical composition comprises at least one compound of For- mula I, II, Ila or III, or a pharmaceutically acceptable salt or solvate of said compound, and at least one pharmaceutically acceptable carrier.
  • inert, pharma- ceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sug- ar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water- propylene glycol solutions for parenteral injection or addi- tion of sweeteners and opacifiers for oral solutions, suspen- sions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceuti- cally acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administra- tion. Such liquid forms include solutions, suspensions and emulsions. Preferably the compound to be used according to the invention is administered orally.
  • a pharmaceuti- cally acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administra- tion.
  • Such liquid forms include solutions, suspensions and emulsions.
  • the compound to be used according to the invention is administered orally.
  • the present invention also relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, having the general struc- ture shown in Formula I, II, Ila or III, as defined above.
  • the compounds of formula I, II and III described above i.e. the compounds to be used in accordance with the first, second or third aspect of the invention, can be prepared in high yields using short routes of synthesis.
  • compounds of Formula I can be synthesized in ac- cordance with Scheme 1 (synthesis of benzofuran-2- ylmethanamine building block) and Scheme 2 (synthesis of ureidobenzoic acid building block).
  • Example 1 The compound of Example 1 was synthesized in accordance with Schemes 1 and 2. Under nitrogen atmosphere, a 0 °C cooled solution of 2-(2- methylbutan-2-yl)phenol (3.50 mL, 3.43 g, 20.9 mmol, 1 eq.) and 4-(dimethylamino)pyridine (255 mg, 2.09 mmol, 0.1 eq) in abs. tetrahydrofurane (10 mL) was treated with cyclopentyl isocyanate (4.65 mL, 4.58 g, 41.3 mmol, 2 eq.).
  • the thawing reaction mixture was treated with methanol (2.0 mL) and aqueous hydrogen chloride solution (2M, 125 mL, 0.25 mmol, 11 eq.) and stirred until room temper- ature was reached.
  • the phases were separated, the aqueous phase was extracted with diethyl ether three times and the combined organic extracts were washed with sat. sodium bicar- bonate solution. After reextraction of the separated aqueous phase the combined organic phases were dried over sodium sul- fate, concentrated in vacuo and purified by column chromatog- raphy (silica gel, petroleum ether/dichloromethane 3:1 v/v).
  • Dest. thionyl chloride 70 ⁇ L, 0.11 g, 0.96 mmol, 1.6 eq.
  • 7-(2-Methylbutan-2- yl)benzofuran-2-ylmethanol 134 mg, 615 pmol
  • the reaction mixture was stirred for 90 min at 50 °C and mixed with dichloromethane, water and brine afterwards.
  • the separated aqueous phase was extracted with dichloromethane three times and all combined organic phases were dehydrated over sodium sulfate. Evaporation of the volatile components and subsequent column chromatography (sil- ica gel, petroleum ether/CH 2 Cl25:1 v/v) afforded the product.
  • reaction mixture was cooled to -78 °C and treated with TMEDA (0.40 mL, 0.31 g, 2.6 mmol, 2 eq.) and n-butyl lithium solution (1.4 M in cyclohexane; 1.85 mL, 2.6 mmol, 2 eq.) successively.
  • TMEDA 0.40 mL, 0.31 g, 2.6 mmol, 2 eq.
  • n-butyl lithium solution 1.85 mL, 2.6 mmol, 2 eq.
  • the thawing reaction mixture was treated with methanol (0.2 mL) and aqueous hydrogen chloride solution (2M, 8 mL, 16 mmol, 12 eq.) and stirred until room temperature was reached.
  • the phases were separated, the aqueous phase was extracted with diethyl ether three times and the combined or- ganic extracts were washed with sat. sodium bicarbonate solu- tion. After reextraction of the separated aqueous phase the combined organic phases were dried over sodium sulfate, con- centrated in vacuo and puri_ed by column chromatography (sili- ca gel, petroleum ether/ethyl acetate gradient 50:1 to 10:1 v/v).
  • 4-Fluoro-2- (trifluoromethyl)phenol was synthesized by treating a solution of 1.80 g (10.0 mmol, 1.0 equiv.) 4-fluoro-2- (trifluoromethyl)phenol in 5 mL methanol and with a suspension of 1.50 g (15.0 mmol, 1.5 equiv.) calcium carbonate in 6 mL water and a solution of 1.62 g (10.0 mmol, 1.0 equiv.) iodine monochloride in 4 mL methanol, successively. The reaction mix- ture was stirred at room temperature for 5 h before it was di- luted with water and dichloromethane.
  • Methyl 5- ((4-cyclohexylphenyl)ethynyl)-2-propionamidobenzoate (149 mg, 0.378 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL) and sodium hydroxide solution (1 M, 2 mL) was added. After stirring for 18 h tetrahydrofuran was removed under re- Jerusalem pressure and the product was precipitated by the addi- tion of hydrogen chloride solution (1 M, 3 mL). The solid was filtered and washed with water.
  • Example 17 The compound of Example 17 was synthesized in accordance with Scheme 2. Under nitrogen atmosphere, benzyl anthranilate (341 mg, 1.50 mmol) was solved in abs. tetrahydrofurane (10 mL) and added slowly to a solution of triphosgene (156 mg, 525 pmol) in abs. tetrahydrofurane (1 mL). After careful, dropwise addition of abs. triethylamine (0.42 mL, 0.30 g, 3.0 mmol), the milky re- action mixture was stirred for 90 min at room temperature. Subsequently, excess phosgene was removed by degassing and volatile reaction components were evaporated. The solid resi- due was suspended in abs.
  • Benzyl 2-(3-(naphthalen-l-yl)ureido)benzoate (371 mg, 937 pmol) was mixed with abs. tetrahydrofurane (10 mL) and palla- dium on carbon (37 mg) and stirred under hydrogen atmosphere for 19 h. After dilution with dichloromethane, the catalyst was removed by filtration and the solution was concentrated under reduced pressure. The obtained crude product was puri- fied via multiple purification steps using column chromatog- raphy (silica gel, CH 2 CI 2 /CH 3 OH gradient 30:1 to 10:1 v/v).
  • 3-Aminoisonicotinic acid (553 mg, 4.00 mmol, 1 eq.) was sus- pended in abs. tetrahydrofurane (2 mL) and 1-naphthyl isocyanate (1.2 mL, 0.85 g, 5.0 mmol, 1.25 eq.) was added dropwise.
  • the reaction mixture was stirred under reflux for 16 hours and treated with a small amount of methanol, subsequent- ly. After evaporating the solvent, the crude product was puri- fied by column chromatography (silica gel, CH 2 CI 2 /CH 3 OH/CH 3 COOH 100:10:3 v/v).
  • CCHFV strain Afg-09 2990 (Olschlager et al., Complete sequence and phylogenetic characterisation of Crimean-Congo hemorrhagic fever virus from Afghanistan. J. Clin. Virol. 2011, 50, 90-92) had been isolated at BNITM laboratory and passaged £ times before it has been used in this study.
  • LASV strain Ba366 (Lecompte et al., J. Mastomys natalensis and Lassa fever, West Africa. Emerg. Infect. Dis. 2006, 12, 1971-1974) has beenproduced recombinantly and has been passaged at BNITM la- boratory £ times.
  • EBOV strain Mayinga 1976 has been provided around 1980 by the Center for Disease Control, Atlanta, Geor- gia. The passage history since 1976 is not documented. All vi- rus stocks have been grown on Vero 81 cells, quantified by immunofocus assay (see below) and stored at -80°C until use.
  • test compounds were dissolved in DMSO at a concentration of 100 mM and stored at 20 °C.
  • Vero 81 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 3 % fetal calf serum (FCS) and streptomycin/penicillin and seed- ed at a density of 1 x 104 cells per well of a 96-well plate one day before infection.
  • Cells were inoculated with LASV Ba366, CCHFV Afg 09-2990 or EBOV Mayinga at a multiplicity of infection (MOI) of 0.01 in the BSL-4 laboratory. The inoculum was removed after 1 h and replaced by fresh medium complement- ed with different concentrations of compound.
  • Concentration of infectious virus particles in cell culture supernatant was measured three days (LASV and CCHFV) or four days (EBOV) post infection (p.i.) by immunofocus assay.
  • Cell growth and viabil- ity under compound treatment was determined by the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide (MTT) method as described previously (Gunther et el., Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro. Antiviral Res. 2004, 63, 209-215).
  • a sigmoidal dose-response curve was fitted to the data using Prism GraphPad 6.0 (GraphPad Soft- ware).
  • the inhibitory concentrations that reduced the virus titer by 50 % (IC50) were calculated from the sigmoidal func- tions.
  • Infectious virus particles were determined by immunofocus as- say as previously described (Gunther et el., Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro. Antiviral Res. 2004, 63, 209-215). Briefly, 1x106 Vero cells per 96-well plates were inoculated with 50 m ⁇ of serial 10-fold dilutions of sample. The inoculum was removed after 1 h and replaced by a 1 %-methylcellulose - medium overlay.
  • cells were fixed with 4 % formaldehyde, washed with phosphate-buffered saline (PBS), and permeabilized with 0.5 % Triton X-100 in PBS. After washing with PBS and blocking with 2 % FCS in PBS, cell foci infected with EBOV, CCHFV or LASV were detected with nucleoprotein (NP)-specific monoclonal antibodies (LASV and CCHFV) or polyclonal antiserum (EBOV) against the whole virus. After washing, cells were incubated with peroxidase-labeled anti-mouse IgG. Foci were visualized with tetramethylbenzidine and counted.
  • PBS phosphate-buffered saline
  • permeabilized with 0.5 % Triton X-100 in PBS After washing with PBS and blocking with 2 % FCS in PBS, cell foci infected with EBOV, CCHFV or LASV were detected with nucleoprotein
  • Brequinar was assessed as reference inhibitor and a control without inhibitor but the equivalent amount of buffer instead was run for each test compound.
  • the compound stock solutions were diluted in Tris-HCl buffer to give nine different concentrations and each sample was treated with a freshly prepared substrate mixture containing L-DHO, CoQl and DCPIP.
  • 80 m ⁇ ice- cooled enzyme solution 87.5 mM
  • the absorp- tion of the mixture was monitored using a spectrophotometer (Berthold Technologies TriSta ⁇ S LB942 Multimode Reader, ICE software) with one data point per 10 seconds at an excitation wavelength of 600 nm and a temperature of 25 °C.
  • Vo is the calculated enzyme velocity without test compound and c is the concentration of added test compound.
  • Example 21 lymphocyte inhibition
  • Lymphocyte inhibition was determined by using human PBMCs (pe- ripheral blood mononuclear cells) as cell culture.
  • the inhibi- tor compound was added at 8 different concentrations with each determination in triplicate and one control without inhibitor.
  • T-cell stimulation was done by Cytostim, a reagent that binds T-cell receptors to MHC molecules of the antigen-presenting cells in an antibody-based manner and enables T-cell stimula- tion. Quantification was achieved by a flow cytometry-based method (Facs analysis) with staining of PBMCs with eFluor670 (eBioscience (TM)).
  • the PBMCs are assigned to their populations (CD4/CD8 T cells) by use of other markers.
  • the compound of Example 1 showed an IC50 of about 150 nM for CD4 and CD8 replication.
  • reaction was performed in triplicates in eppendorf tubes with total volumes of 300 ⁇ L containing MgCl ⁇ (5 mM), NADPH (5 mM), rat S9 fraction (1 mg) and the test compound (100 pM) in phosphate buffer (38.5 mM Na 2 HP0 4 , 11.5 mM KH 2 PO 4 , pH 7.3) . 7-
  • Ethoxycoumarin was assessed as reference inhibitor and a con- trol without inhibitor but an equivalent amount of buffer in- stead was run.
  • the ice cooled S9 fraction was added to a solu- tion of MgCl 2 and NADPH in PB and the resulting mixture was preincubated for 10 minutes at 37 °C in a shaker. Subsequently the reaction was started by addition of the test compound (50 ⁇ L), followed by threefold pipetting. After 0 h, 1 h and 3 h, samples of 50 ⁇ L were taken from the reaction, mixed with 150 ⁇ L ice-cooled methanol and centrifuged at 14000 rpm and 4 °C for 15 minutes. The supernatant was filtered with a syringe fiter, immediately quantified on HPLC and stored at -20 °C un- til LC/MS analysis.
  • Octanol and phosphate buffered saline (PBS, 137 mM NaCl, 2.7 mM KC1, 10 mM Na 2 HP0 4 , 2.0 mM KH 2 P0 4 , pH 7.4) were saturated with each other prior to the experiment.
  • Stock solutions of all test compounds (100 mM) were prepared in DMSO, stored at - 20 °C and diluted with the saturated PBS to 100 mM prior to the experiment. The experiment was performed in duplicates in 2 mL HPLC-vials. 300 ⁇ L of the test compound solution (100 mM) was overlayered with 300 ⁇ L saturated octanol.
  • the emulsions were vortexed for 1 min and shaken for 1 h at 180 rpm and 25 °C. After phase separation, the aqueous phases and the initial 100 mM compound solution were quantified on HPLC. Partition coefficients were calculated using the following equation: wherein areai n is the area under the curve in the chromatogram ob- tained for the initial, 100 pM compound solution and area aq is the area under the curve in the chromatogram ob- tained for one separated aqueous phase.
  • C acc (t) is the compound concentration in acceptor well at time t
  • Aperm is the area of the membrane filter (0.3 cm 2 ),
  • Vdon is the donor well volume (0.3 mL)
  • Vacc is the acceptor well volume (0.2 mL)
  • Ceq is the equilibrium concentration with where c don (t) is the compound concentration in donor well at time t.
  • compounds of formula (I) show a high metabolic stability and at the same time remarkable inhibition potency.
  • these advantageous properties are caused by the specific structure of the compounds of formula (I).

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Abstract

The present invention relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formulae (I), (II), (Ila) or (III).

Description

DHODH inhibitors and their use as antiviral agents
The present invention relates to anthranilic acid compounds useful as DHODH inhibitors, pharmaceutical compositions con- taining the compounds, and the use of the compounds and compo- sitions in methods of treatment of a disease, disorder or con- dition caused by an RNA virus.
While the demand for nucleotides is covered by the salvage pathway in resting cells, fast proliferating cells, like cells of the immune system, tumor cells, or virally infected cells are highly dependent on the de novo nucleotide synthesis. Ac- cordingly, the uses of inhibitors of the de novo nucleotide biosynthetic pathways have been investigated in the past.
Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in pyrimidine metabolism. DHODH catalyzes the fourth step of the de novo synthesis of uridine monophosphate (UMP), which is afterwards converted to all other pyrimidine nucleo- tides. An inhibition of DHODH and thus a suppression of de novo synthesis of UMP leads to a downregulation of the intracel- lular number of pyrimidine nucleotides. This can lead to limi- tations in cell growth and proliferation.
Munier-Lehmann et al. (J. Med. Chem. 2013, 56, 3148-3167) re- port about the potential use of DHODH inhibitors in several therapeutic fields, such as the treatment of autoimmune dis- eases, e.g. rheumatoid arthritis or multiple sclerosis, the prophylaxis of transplant rejection, the treatment of cancer, e.g. leukemia or malignant melanoma, the treatment of viral and parasite infections, e.g. malaria, as well as in crop sci- ence.
One of the most potent DHODH inhibitors is brequinar with an IC50 of about 10 nM. It has been investigated for cancer treat- ment and as an immunosuppressive drug in clinical trials. How- ever, due to a narrow therapeutic window and inconsistent pharmacokinetics the further development was cancelled.
Another well described DHODH inhibitor is teriflunomide that derives from the prodrug leflunomide. It is the first approved DHODH inhibitor for the treatment of rheumatoid arthritis and is also used against multiple sclerosis. Disadvantages of this drug are a long plasma half-life and liver toxicity.
Chen et al. (Transplant Immunology 23 (2010) 180 -184) de- scribe the use of two DHODH inhibitor compounds, ABR-222417 and ABR-224050, as immunosuppressive agent. In particular, ABR-222417 is reported to result in a marked increase in graft survival time when screened in a low-responder heart allograft transplantation model in rats.
WO 2005/075410 discloses the use of certain DHODH inhibitor compounds for the treatment of autoimmune diseases, inflamma- tory diseases, organ transplant rejection and malignant neoplasia.
Compared to autoimmune diseases and oncology, virology is a rather novel field of application of DHODH inhibitors. US 2014/0080768 Al and WO 2009/153043 Al generally mention the potential use of DHODH inhibitors for various diseases and disorders including some viral diseases, besides autoimmune diseases, immune and inflammatory diseases, cancer, destruc- tive bone disorders and others.
As regards DNA-viruses, Marschall et al. (Antiviral Res. 2013, 100, 640-648) focused on the in vivo antiviral efficacy of 3-
(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4- ylcarbomyl)thiophene-2-carboxylic acid by inhibition of cyto- megalovirus replication in mice. With respect to RNA-viruses, Wang et al. (J. Virol. 85 (2011), 6548-6556) investigated the inhibition of dengue virus (DENV) by NITD-982. While this com- pound demonstrated some in vitro potency, it did not show any efficacy in a mouse model.
Until now no DHODH inhibitor is used in antiviral therapy.
Therefore, there is still a need for compounds overcoming the above-mentioned drawbacks and problems. Accordingly, it is an object of the present invention to provide compounds which are suitable as antiviral agents and especially suitable to treat diseases, disorders or conditions caused by RNA viruses. In particular, it would be desirable to provide compounds having a high antiviral efficacy and at the same time a broad thera- peutic window, i.e. a broad range of doses at which the thera- peutic benefit is achieved without resulting in unacceptable side-effects or toxicity. Moreover, it would be desirable that the compounds are characterized by acceptable pharmacokinetic parameters, like ADME (Absorption, Distribution, Metabolism, and Excretion) properties. In addition, the compounds should be obtainable easily and in high yields avoiding cumbersome routes of synthesis.
It has surprisingly been found that the above problems are solved by the compounds defined below and in the appended claims.
Accordingly, in a first aspect the present invention relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula I: wherein:
W is C or N, and preferably is C;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C (0)-0-R1-group is joined to the -NH-group or -X-group shown in Formula (I) to form together with the W- containing aromatic ring shown in Formula (I) a hetero ring system;
R2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said al- kyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably independently selected from the group consisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substituted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -O-arylalkyl, aryl substi- tuted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl, or optionally R2 represents two substituents which are joined to form together with the aromatic ring shown in Formula I a substituted or unsubstituted ring or hetero ring system, or optionally at least one of R2 is joined to the -NH-group or -X-group shown in Formula (I) to form together with the W- containing aromatic ring shown in Formula (I) a hetero ring system;
R3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moi- ety is preferably independently selected from the group con- sisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substituted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -O-arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl;
X is 0 or NH, and preferably is NH; Y is CR4 or N, and preferably is CR4;
Z is 0, S, NH or CR52, and preferably is 0;
R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and preferably is H; and
R5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy and acetyl, and preferably is H.
It has been found that the above-defined compounds have a high antiviral efficacy. In particular, the compounds have been found to have a high antiviral activity against a wide spec- trum of viruses, especially a wide spectrum of RNA viruses. Hence, the compounds have been found to be promising candi- dates for in vivo applications as broad-spectrum antiviral drug.
Furthermore, the above-defined compounds have been found to act by inhibition of a host enzyme. This brings several advan- tages compared to inhibitors targeting viral enzymes, such as (i) a higher barrier to resistance, (ii) a broad coverage of different viruses that goes along with a preventative prepara- tion for new emerging virus infections, and (iii) allowing an- tiviral therapy of virus infections without druggable viral targets. In particular, the above-defined compounds have been found to act by inhibition of the host enzyme DHODH. The DHODH sets itself apart from other cellular targets by the fact that the host cell is able to overcome its temporary inhibition by the steady supply of pyrimidine nucleotides for resting cells via salvage pathway.
Besides showing a strong antiviral activity and strong inhibi- tion of hDHODH, the above-defined compounds show a high meta- bolic stability with no cleavage at the amide group and very reduced or even no hydroxylation. A good membrane permeability and good plasma stability are shown by the compounds of the invention as well. This underscores their position as promis- ing candidates for further in vivo pharmacokinetic studies.
In a preferred embodiment, the compound to be used according to the invention is represented by formula (I) and W is C. Ac- cordingly, the monoaromatic ring shown in Formula I is pref- erably a phenyl ring and the compounds to be used according to the invention are anthranilic acid derivatives.
In a preferred embodiment, the compound to be used according to the invention is represented by formula (I) and R1 is H. Thus, the compound is preferably present as a free anthranilic acid. However, under physiological conditions the free acid is deprotonated resulting in a negatively charged carboxylate. In order to mask this negative charge under physiological condi- tions, prodrug moieties can be installed at the R1 position to enable penetration through the cell membrane and allow the re- lease of the active carboxylic acid inside the cell.
Accordingly, besides H, R1 can be a pharmaceutically acceptable cation or alkyl, cycloalkyl, heterocyclyl or -C(0)-alkyl, wherein the alkyl or -C(0)-alkyl can be unsubstituted or op- tionally substituted with one or more moieties which can be the same or different, each moiety being independently select- ed from the group consisting of -0C(0)-alkyl, -OC(0)0-alkyl, heterocyclyl, aryl and heteroaryl. For example, R1 can be - C (0)-alkyl to form an anhydride prodrug moiety. Moreover, R1 can be alkyl substituted with -OC (0)0-alkyl to form an alkoxycarbonyloxyalkyl (POC) moiety. Furthermore, R1 can be al- kyl substituted with aryl which in turn is substituted with an -0-C (0)-alkyl group to form an acyloxybenzyl moiety. In one embodiment, R1 is selected from the group consisting of
and preferably is H.
In a further embodiment, R1 is selected from the group consist- ing
In a further embodiment, the -C (O)-0-R1-group can be joined to the -NH-group or -X-group shown in Formula (I) to form togeth- er with the monoaromatic ring shown in Formula (I) a hetero ring system. An example of such a hetero ring system is a quinazolinedione, such as Furthermore, the compounds to be used according to the inven- tion are characterized in that the aromatic ring of the anthranilic core is substituted by one or more R2 substituents. In a one embodiment, R2 is a substituent, in particular one substituent, as defined above.
In a preferred embodiment, R2 is H.
In another embodiment, R2 is aryl, preferably phenyl, which can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of alkyl, ar- yl, halogen, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl .
In another embodiment, R2 is wherein
R6 is H; halogen, preferably F; or aryl, preferably phenyl;
R7 is H; halogen, preferably F; alkyl, preferably methyl; or aryl, preferably phenyl; and
R8 is H; cycloalkyl, preferably cyclohexyl; aryl, preferably phenyl; haloaryl, preferably 4-F-phenyl; arylalkyl, preferably 4-ethyl-phenyl, 4-pentyl-phenyl; alkylaryl, preferably benzyl; aryloxy, preferably phenyloxy; arylalkoxy, preferably benzyloxy; or heterocyclylalkyl, preferably morpholinomethyl. In another embodiment, R2 is , wherein R6b, R7 and R8 are selected as shown in the following table:
In another embodiment, R2 is alkynyl, preferably ethynyl, which can be unsubstituted or optionally substituted with a moiety selected from the group consisting of aryl, aryl substituted with alkyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substituted with arylalkyl, aryl substi- tuted with alkoxy, aryl substituted with aryloxy, aryl substi- tuted with -O-arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl.
For instance, R2 is alkynyl, preferably ethynyl, which is sub- stituted with a moiety selected from the group consisting of phenyl; phenyl substituted with 4-haloalkyl like 4-CF3; phenyl substituted with 4-alkyl like 4-C4H9 or 4-OdHi3; phenyl substi- tuted with 4-alkoxy like 4-ethoxy or 4-pentoxy; phenyl substi- tuted with 4-aryloxy like 4-phenyloxy; phenyl substituted with arylalkoxy like 4-benzyloxy; phenyl substituted with 4-aryl like 4-phenyl; phenyl substituted with 4-cycloalkyl like 4- cyclohexyl; phenyl substituted with 4-arylalkyl like 4-benzyl; and alkyl, preferably methyl or butyl, which is substituted with aryloxy, preferably phenyloxy, which in turn is substi- tuted with 2-alkyl, like 2-sec-butyl, 2-cycloalkyl, like 2- cyclohexyl, or 2-arylalkyl, like 2-benzyl.
In another embodiment, R2 is alkynyl, preferably ethynyl, which is substituted with a moiety selected from the group consist- ing of
In another embodiment, R2 is alkynyl, preferably ethynyl, which is substituted with the foilwing moiety: wherein Y is independently selected from CR4 and N, and preferably is CR4;
R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and preferably is H;
R6 is heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl and heterocyclylalkyl can be unsubstituted or substituted with one or more ring system substituents which can be the same or different; and
R7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, alkoxy,
C(0)-alkyl, -C (0)-haloalkyl, -NH2, -NH-alkyl and -N (alkyl)2.
Particularly suitable R2-groups of this embodiment are de- scribed in further detail below in connection with the second aspect of the invention.
It is particularly preferred that R2 is a rather small, i.e. a sterically undemanding, substituent, such as H; alkyl, prefer- ably 5-alkyl like 5-methyl or 5-tBu; halogen, wherein halogen is preferably selected from F, Cl and Br, and/or wherein halo- gen is preferably 5-halogen like 5-Br or 5-F or 4-halogen like 4-F; alkoxy, preferably 5-alkoxy like 5-methoxy or 4-alkoxy like 4-methoxy; haloalkyl, preferably 5-CF3; NO2, preferably 5- NO2; or aryl, preferably phenyl or biphenyl like 5-phenyl or 5- biphenyl. Most preferably, all R2 are H.
In another embodiment, R2 represents two substituents which are joined to form together with the monoaromatic ring shown in Formula (I) a ring system or a hetero ring system. The ring system and the hetero ring system can be unsubstituted or op- tionally substituted, e.g. by a ring system substituent as de- fined herein. In particular, the ring system can comprise an aryl, such as e.g. a phenyl, annelated to the aromatic ring of Formula (I). In this embodiment the phenyl ring of the anthranilic core of the compounds of Formula (I) and the phe- nyl ring annelated to it form a polycylic aromatic hydrocar- bon, such as e.g. a naphthalene. In a further embodiment, the hetero ring system formed by joining two R2 substituents to- gether with the monoaromatic ring shown in Formula (I) is
In a further embodiment, at least one of R2 is joined to the -NH-group or -X-group to form together with the monoaromatic ring shown in Formula (I) a hetero ring system. An example of such a hetero ring system is a quinazolinedione.
Furthermore, it is preferred that the group X in formula (I) is NH.
In addition, it is preferred that the group Y in formula (I) is CR4, with R4 being H;
Furthermore, it is preferred that the group Z in formula (I) is 0.
Moreover, it is preferred that the group R3 in formula (I) is one or more substituents independently selected from the group consisting of H, alkyl, halogen and haloalkyl. In particular, the alkyl can be 2-methylbutan-2-yl, the halogen can be F, and/or the haloalkyl can be trifluoromethyl. In another preferred embodiment, the compound of the first as- pect of the invention can have the general structure shown in Formula la or Ib: wherein:
R3a is alkyl or haloalkyl; and
R3b is H or halogen, wherein the halogen is preferably F.
In this embodiment, the alkyl is preferably 2-methylbutan-2-yl and the haloalkyl is preferably trifluoromethyl.
Moreover, it is preferred that the compound of the first as- pect of the invention has the general structure shown in For- mula la or Ib, wherein R3a is an unsubstituted linear or branched Ci-C6-alkyl, an unsubstituted C3-C6-cycloalkyl, or a linear or branched C1-C6- haloalkyl; and
R3b is H or halogen.
Without wishing to be bound by a particular theory, it is as- sumed that the above specific R3a and R3b substituents provide a certain increase in lipophilicity resulting in inhibitory po- tency increase.
In a particularly preferred embodiment, the compound according to the first aspect of the invention has one of the following structures:
In a second aspect the present invention relates to a com- pound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula II or Formula Ila:
(H a) wherein:
W is C or N, and preferably is C;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl;
Y is independently selected from CR4 and N, and preferably is CR4;
R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and preferably is H;
R6 is heterocyclyl or heterocyclylalkyl, wherein the heterocyclyl and heterocyclylalkyl can be unsubstituted or substituted with one or more ring system substituents which can be the same or different and are described below;
R7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, alkoxy,
C(0)-alkyl, -C (0)-haloalkyl, -NH2, -NH-alkyl and -N (alkyl)2; and R8 is -C(O)-alkyl, -C(0)O-alkyl, -C(0)NH-alkyl, -C(0)- cycloalkyl, -C(0)O-cycloalkyl, -C(0)NH-cycloalkyl, -C(0)-aryl,
-C(0)0-aryl, -C(0)NH-aryl, -C(0)-heteroaryl, -0(0)0- heteroaryl, -C (0)NH-heteroaryl, aryl substituted with R10, o heteroaryl substituted with R10, -S(O2)-R11 or wherein
Z is - (CH2 ) n" , -0- (CH2 ) n- , -NH- (CH2 ) n- , - (CH2 ) p-L- (CH2 ) q- ,
-0- (CH2 ) p-L- (CH2) q- or -NH- (CH2 ) p-L- (CH2 ) q- , n is an integer from 1 to 6; p and q are integers independently selected from 0 to 6;
L is a linking group selected from the group consisting of heteroaryl, aryl, heterocyclyl and cycloalkyl;
X is 0, S, NH, CH2, S(0) or C(0), and preferably is 0, S or NH;
R9 is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of H, halo- gen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl and trialkylsilyl;
R10 is aryloxy or arylalkyl or optionally R10 represents two substituents linked to each other to form together with the aryl or heteroaryl a polycyclic ring system, wherein prefera- bly the polycyclic ring system is a naphthalene or fluorene; and R11 is alkyl, cycloalkyl or -Z-X-R9.
It has been found that also the above-defined compounds of the second aspect have a high antiviral efficacy and strong inhi- bition of the hDHODH host enzyme. Thus, also the compounds of the second aspect of the invention have been found to be prom- ising candidates for in vivo applications as broad-spectrum antiviral drug.
In addition, it has surprisingly been found that the compounds of the second aspect are less vulnerable for metabolism com- pared to the inhibitors described in WO 2020/225330. Without wishing to be bound by any theory, it is believed that due to the heterocyclyl or heterocyclylalkyl substituent R6 polarity is added and the compounds are less lipophilic which makes them less vulnerable for metabolism.
In a preferred embodiment of formula (II) and (Ila), R6 is se- lected from the group consisting of
Furthermore, in a preferred embodiment of formula (II) and (Ila), R7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, - C(0)-alkyl, -C(0)-haloalkyl, -NH-alkyl and -N (alkyl)2. Prefera- bly, the alkyl in the above R7 groups is methyl or ethyl. More- over, if R7 is halogen, it is preferaby F.
In a particularly preferred embodiment, the compound according to the second aspect of the invention has one of the following structures:
In a third aspect the present invention relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula III: ( H I ) wherein: W is N;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C (0)-0-R1-group is joined to the -NH-group or -X-group shown in Formula (III) to form together with the W-containing aromatic ring shown in Formula (III) a hetero ring system;
R2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said al- kyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably independently selected from the group consisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substituted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -O-arylalkyl, aryl substi- tuted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl, or optionally R2 represents two substituents which are joined to form together with the aromatic ring shown in Formula III a substituted or unsubstituted ring or hetero ring system, or optionally at least one of R2 is joined to the -NH-group or -X-group shown in Formula (III) to form together with the W- containing aromatic ring shown in Formula (III) a hetero ring system;
X is CH2, 0 or NH, and preferably is NH; and
R3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl , alkoxy, aryl, arylalkyl, heteroalkyl, heteroarylalkyl, amido, carbamoyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl, arylalkyl, heteroalkyl, heteroarylalkyl, amido, and carbamoyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably inde- pendently selected from the group consisting of hydroxyl, hal- ogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl sub- stituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substituted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -O-arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl; or optionally R3 represents two substituents which are joined to form together with the naphthyl ring system shown in Formu- la III a substituted or unsubstituted ring or hetero ring sys- tem.
It has been found that also the above-defined compounds of the third aspect have a very high antiviral efficacy and strong inhibition of the hDHODH host enzyme. Thus, also the compounds of the third aspect of the invention have been found to be promising candidates for in vivo applications as broad- spectrum antiviral drug.
In addition, it has surprisingly been found that the compounds of the third aspect show a high metabolic stability and good membrane permeability.
In a preferred embodiment of the third aspect of the inven- tion, the compound has the general structure shown in Formula Ilia: wherein R1, R2, W and X are as defined above in formula (III);
R3a is H, -CH3, -CF3, or halogen; and
R3b and R3C are the same or different and are independently se- lected from the group consisting of H, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl, trialkylsilyl and carbonyl substituents, such as amides or ureas. In a further embodiment, R3b and R3c are joined to each other to form - together with the ring they are attached to - a possibly substituted ring system.
Redoxal, a known DHODH inhibitor, is a compound synthesized via the coupling of two anthranilic acid compounds. Hence, al- so the compounds to be used according to the present invention can be present in the form of a dimer, i.e. two molecules hav- ing the structure of formula (I), (II) or (III) can be coupled to form a dimer. In the first and third aspect of the inven- tion, two molecules of formula (I) or two molecules of formula (III) are coupled via substituents R2 and/or R3. Thus, the phe- nyl ring of the first anthranilic acid core is coupled via R2 to R2 of the phenyl ring of the second anthranilic acid core or to R3 of the benzodioxole-type or naphthyl ring system of the second anthranilic acid core. In the second aspect of the in- vention, two molecules of formula (II) are coupled via sub- stituents R6/R7 and/or R8. Thus, the Y-containing monoaromatic ring of the first anthranilic acid core is coupled via R6 or R7 to R6 or R7 of the Y-containing monoaromatic ring of the second anthranilic acid core or to R8 of the second anthranilic acid core. Suitable routes of synthesis to provide dimers according to the invention are known and are described below.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as me- thyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substi- tuted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH (cycloalkyl), -N (alkyl)2, carboxy and -C(0)O-alkyl. Non- limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. Non-limiting examples of suitable alkenyl groups include ethenyl and propenyl. The term "substituted alkenyl" means that the alkenyl group may be sub- stituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substitu- ents which may be the same or different, each substituent be- ing independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non- limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitro- gen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxy- gen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for exam- ple, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable arylalkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl . The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls com- prise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substitu- ents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Pre- ferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, re- places an available hydrogen on the ring system. Ring system substituents may be the same or different, each being inde- pendently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)- NH (alkyl), YIY2N-, YiY2N-alkyl-, YiY2NC(0)-, YiY2NS02- and - S02NYIY2, wherein Y2 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substitu- ent" may also mean a single moiety which simultaneously re- places two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moi- ety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur at- oms present in the ring system. Preferred heterocyclyls con- tain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N (Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non- limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl , 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting exam- ples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl . The bond to the parent moiety is through the alkyl.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower al- kyl. Non-limiting examples of suitable hydroxyalkyl groups in- clude hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C (0)- or cycloalkyl-C(0)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Pre- ferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(0)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-0- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2- naphthalenemethoxy . The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the par- ent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting ex- amples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aryloxycarbonyl" means an aryl-O-C(0)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C (0)- group. Non- limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl . The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the par- ent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicat- ed group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious thera- peutic agent.
It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen atom(s) to satisfy the valences.
When any variable (e.g., aryl, etc.) occurs more than one time in any constituent or in Formula I, II or III, its definition on each occurrence is independent of its definition at every other occurrence. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, up- on administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of For- mula I, II or III or a salt and/or solvate thereof.
"Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution- phase and isolatable solvates. Non-limiting examples of suita- ble solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
The compounds of Formula I, II, Ila or III can form salts which are also within the scope of this invention. Reference to a compound of Formula I, II, Ila or III herein is under- stood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic ba- ses. In addition, when a compound of Formula I, II or III con- tains both a basic moiety, such as, but not limited to a pyri- dine or imidazole, and an acidic moiety, such as, but not lim- ited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physio- logically acceptable) salts are preferred, although other salts can also be useful. Salts of the compounds of the Formu- la I, II or III may be formed, for example, by reacting a com- pound of Formula I, II or III with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization .
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates , fumarates, hydro- chlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as low- er alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, dieth- yl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharma- ceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of Formula I, II, Ila or III, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present inven- tion.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substitu- ents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated with- in the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of the invention may, for exam- ple, be substantially free of other isomers, or may be ad- mixed, for example, as racemates or with all other, or other selected, stereoisomers.
The compounds of Formula I, II, Ila and III have pharmacologi- cal properties. In particular, the compounds of Formula I, II and III have found to be inhibitors of DHODH. Moreover, it has been found that the compounds of Formula I, II and III have a very high antiviral efficacy against various RNA viruses in an up to one-digit nanomolar range. In a preferred embodiment, the compounds to be used according to the invention are char- acterized by an IC50 of less than 1.0 mM or 0.7 mM, preferably less than 0.3 mM, more preferably less than 0.1 mM, like less than 0.08 mM or less than 0.05 mM or less than 0.04 mM or less than 0.02 mM, wherein the IC50 values are generated in an assay using LASV, EBOV or CCHFV using the assay described in the ex- amples herein. Moreover, the compounds are characterized by a low cytotoxicity, such as a CC50 of more than 1 mM, preferably more than 8 mM, more preferably more than 15 mM, like more than 30 mM or more than 50 mM or more than 70 mM or more than 100 mM. Hence, the compounds of Formula I, II, Ila or III are expected to be useful in the therapy of viral diseases, in particular in the treatment of treatment of a disease, disor- der or condition caused by an RNA virus.
As used herein, the term "RNA virus" refers to a virus that has RNA (ribonucleic acid) as its genetic material. This nu- cleic acid is usually single-stranded RNA (ssRNA) but may be double-stranded RNA (dsRNA). In particular, the RNA virus is a virus that belongs to Group III, Group IV or Group V of the Baltimore classification system of classifying viruses.
Preferably, the RNA virus which can be affected by the com- pounds of Formula I, II, Ila or III is selected from the group consisting of bunya viruses including Toscana virus (TOSV), hazara virus (HAZV), tahyna virus (TAHV), rift valley fever virus (RVFV), Lassa virus (LSAV), Punta Toro phlebovirus (PTV) and Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV); flavi viruses including yellow fever virus (YFV), dengue virus (DENV), tick-borne encephalitis virus (TBEV), zika virus (ZIKV) and Hepatitis C virus (HCV); toga viruses including Venezuelan equine encephalitis virus (VEEV), Sindbis virus (SINV) and Chikungunya virus (CHIKV); mononegaviruses includ- ing Ebola virus (EBOV), Marburg virus (MARV), Human parainfluenza virus 3 (HPIV-3), Nipah virus (NiV) and Vesicu- lar stomatitis virus (VSV); picorna viruses including coxsackievirus (CV); nidoviruses including corona viruses such as Severe acute respiratory syndrome-related coronavirus (SARS-CoV), Severe acute respiratory syndrome-related corona- virus 2 (SARS-CoV-2) and Middle-East respiratory syndrome- related coronavirus (MERS-CoV); influenza viruses and reoviruses including reovirus type 1 (Reo-1).
Hence, also disclosed is a method of treating a mammal (e.g., human) having a disease or condition associated with a virus, in particular RNA virus, by administering a therapeutically effective amount of at least one compound of Formula I, II, Ila or III, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
Moreover, the compounds according to the invention are suita- ble to be used for the treatment of autoimmune diseases, e.g. rheumatoid arthritis or multiple sclerosis, the prophylaxis of transplant rejection, the treatment of cancer, e.g. leukemia or malignant melanoma, the treatment of viral and parasite in- fections, e.g. malaria, as well as in crop science.
Moreover, pharmaceutical compositions comprising a compound of Formula I, II, Ila or III are also disclosed herein. The phar- maceutical composition comprises at least one compound of For- mula I, II, Ila or III, or a pharmaceutically acceptable salt or solvate of said compound, and at least one pharmaceutically acceptable carrier. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sug- ar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water- propylene glycol solutions for parenteral injection or addi- tion of sweeteners and opacifiers for oral solutions, suspen- sions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceuti- cally acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administra- tion. Such liquid forms include solutions, suspensions and emulsions. Preferably the compound to be used according to the invention is administered orally.
In a further aspect, the present invention also relates to a compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, having the general struc- ture shown in Formula I, II, Ila or III, as defined above.
The compounds of formula I, II and III described above, i.e. the compounds to be used in accordance with the first, second or third aspect of the invention, can be prepared in high yields using short routes of synthesis.
The invention disclosed herein is exemplified by the following examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
The following solvents and reagents may be referred to by their abbreviations:
DMAP 4-dimethylaminopyridine
DMF dimethylformamide
Et3N or Net3 triethylamine
Log D distribution coefficient
PBS phosphate buffered saline
PAMPA parallel artificial membrane permeability assay
THF tetrahydrofurane
TMEDA N,N,N',N'-tetramethylethylendiamin
TMG 1,1,3,3-tetramethylguanidin
TMSC1 trimethylsilyl chloride
TMSOTf trimethylsilyl triflate
Examples
In general, compounds of Formula I can be synthesized in ac- cordance with Scheme 1 (synthesis of benzofuran-2- ylmethanamine building block) and Scheme 2 (synthesis of ureidobenzoic acid building block).
Scheme 1: a: 0.1 eq. DMAP, 2 eq. cyclopentyl isocyanate, THF, 70 °C, 30 h. b: 1.05 eq. TMSOTf, 1.1 eq. TMEDA, Et20, rt, 1 h. c: 1.2 eq. TMSC1, Et20, -78 °C, 1 h. d: 2 eq. TMEDA, 2.2 eq. sec-buli,
Et20, -78 °C, 1 h. e. 11 eq. HC1, Me0H/H20/Et20, rt, 2h. f: 1.3 eq. IC1, CH2C12, 0°C, rt, 3h. g. 1 M NaOH, THF, rt, 4 h. h: 3 eq. TMG, 0.1 eq. Cul, 0.05 eq. PdCl2 (PPh3)2, 1.1 eq prop-2-in- l-ol, DMF, 40 °C, 20 h. i: 1.6 eq. thionyl chloride, THF, 50
°C, 90 min. j: 3 eq. NaN3, DMF, 50 °C, 15 h. k. H2, Pd/C, THF, rt, 20 h. 1: 2 eq. TMEDA, 2.2 eq. n-buli, Et20, -78 °C, 90 min. m: : 1.25 eq. I2, Et20, -78 °C, 90 min. n: 1.0 eq. IC1, 1.5 eq. CaC03, MeOH, H20, rt, 5 h.
Scheme 2: a. 0.5 eq. triphosgene, 2.1 eq. triethylamine, THF, 90 min. b: 0.8 eq. amine, THF, 15 h. c. H2, Pd/C, THF, rt, 20 h.
Furthermore, compounds of Formula II and Ila can be synthe- sized in accordance with Scheme 3.
Scheme 3:
Compounds of Formula II and Ila having various R8 substituents can be prepared through the general routes described in Schemes 1 to 14 of WO 2020/225330.
Example 1 :
The compound of Example 1 was synthesized in accordance with Schemes 1 and 2. Under nitrogen atmosphere, a 0 °C cooled solution of 2-(2- methylbutan-2-yl)phenol (3.50 mL, 3.43 g, 20.9 mmol, 1 eq.) and 4-(dimethylamino)pyridine (255 mg, 2.09 mmol, 0.1 eq) in abs. tetrahydrofurane (10 mL) was treated with cyclopentyl isocyanate (4.65 mL, 4.58 g, 41.3 mmol, 2 eq.). After stirring at 70 °C for 30 h the mixture was cooled to room temperature, treated with 1 M hydrogen chloride solution (42 mL) and ex- tracted with diethyl ether three times. The combined organic extracts were washed with sat. sodium bicarbonate solution and the separated aqueous phase was reextracted with diethyl ether. Next, the organic phases were combined, dried over so- dium sulfate and the solvents were removed in vacuo.
Yield: 5.73 g (20.8 mmol, 100 %) of a white solid.
In an inert atmosphere, a solution of trimethylsilyl triuoromethanesulfonate (4.0 mL, 4.9 g, 22 mmol, 1.05 eq.) in diethyl ether (30 mL) was added dropwise to a solution of 2- (2-methylbutan-2-yl)phenyl cyclopentylcarbamate (5.76 g, 20.9 mmol, 1 eq.) and tetramethylethylenediamine (3.5 mL, 2.7 g, 23 mmol, 1.1 eq.) in diethyl ether (160 mL). After 1 h stirring at room temperature, the reaction mixture was cooled to -78 °C, treated with trimethylsilyl chloride (3.3 mL, 2.8 g, 26 mmol, 1.2 eq.) and stirred at -78 °C for 1 h. TMEDA (6.3 mL, 4.9 g, 42 mmol, 2.0 eq.) and sec-butyl lithium solution (1.4 M in cyclohexane; 33 mL, 46 mmol, 2.2 eq.) were added succes- sively to the mixture that was afterwards stirred at -78 °C for 1 h. Finally, the thawing reaction mixture was treated with methanol (2.0 mL) and aqueous hydrogen chloride solution (2M, 125 mL, 0.25 mmol, 11 eq.) and stirred until room temper- ature was reached. The phases were separated, the aqueous phase was extracted with diethyl ether three times and the combined organic extracts were washed with sat. sodium bicar- bonate solution. After reextraction of the separated aqueous phase the combined organic phases were dried over sodium sul- fate, concentrated in vacuo and purified by column chromatog- raphy (silica gel, petroleum ether/dichloromethane 3:1 v/v).
Yield: 5.43 g (15.6 mmol, 75 %) of a white solid.
Under nitrogen atmosphere, a 0 °C cooled solution of 2—(2— methylbutan-2-yl)-6- (trimethylsilyl)phenyl cyclopentyl- carbamate (5.51 g, 15.9 mmol, 1.0 eq.) in abs. dichloromethane (200 mL) was carefully treated with a solution of iodo monochloride (3.35 g, 20.6 mmol, 1.3 eq.) in abs. dichloro- methane (20 mL). The reaction mixture was stirred for 3 h while warming up to room temperature and afterwards washed with sat. sodium thiosulfate solution twice. The combined aqueous phases were extracted with dichloromethane three times and the combined extracts were washed with brine. Dehydration over sodium sulfate, concentration in vacuo and purification via column chromatography (silica gel, petroleum ether/CH2Cl2 2:1 v/v) finally furnished the pure product.
Yield: 6.38 g (15.9 mmol, 100 %) of a white solid.
2-Iodo-6- (2-Methylbutan-2-yl) cyclopentylcarbamate (6.36 g, 15.9 mmol) was solved in tetrahydrofurane (60 mL) and treated with aqueous sodium hydroxide solution (1M; 48 mL). After vig- orous stirring for 4 h the resulting mixture was acidifed to pH 1 by addition of hydrogen chloride solution (1M) and subse- quently extracted with dichloromethane three times. The com- bined organic extracts were dried over sodium sulfate and con- centrated under reduced pressure. Finally, the crude product was purified by column chromatography (petroleum ether/CH2Cl2 5:1 v/v).
Yield: 4.25 g (14.7 mmol, 92 %) of a colorless liquid. The reaction was performed under inert conditions. To a solu- tion of 2-iodo-6-(2-methylbutan-2-yl)phenol (1.13 g, 3.88 mmol) in abs. N,N-dimethylformamide (4 mL) were successively added 1,1,3,3-tetramethylguanidine (1.5 mL, 1.3 g, 12 mmol), bis (triphenylphosphine)-palladium dichloride (146 mg, 194 pmol) and copper(I) iodide (74 mg, 0.39 mmol). After 5 min stirring at room temperature, the reaction mixture was treated dropwise with a solution of 2-propin-l-ol (0.24 mL, 0.23 g, 4.1 mmol) in abs. DMF (8 mL) and then stirred at 40 °C over- night. The resulting mixture was diluted with diethyl ether and washed with water and brine once each. The aqueous phases were reextracted with diethyl ether twice. Finally, after the combined organic phases were dried over sodium sulfate and the solvent was evaporated, the obtained crude product was puri- fied via column chromatography (silica gel, CH2CI2).
Yield: 738 mg (3.38 mmol, 87 %) of a yellowish liquid.
Dest. thionyl chloride (70 μL, 0.11 g, 0.96 mmol, 1.6 eq.) was added dropwise to a solution of 7-(2-Methylbutan-2- yl)benzofuran-2-ylmethanol (134 mg, 615 pmol) in abs. tetrahydrofurane (2 mL). The reaction mixture was stirred for 90 min at 50 °C and mixed with dichloromethane, water and brine afterwards. The separated aqueous phase was extracted with dichloromethane three times and all combined organic phases were dehydrated over sodium sulfate. Evaporation of the volatile components and subsequent column chromatography (sil- ica gel, petroleum ether/CH2Cl25:1 v/v) afforded the product.
Yield: 117 g (493 pmmol, 80 %) of a colorless oil.
Under inert conditions, 2- (Chloromethyl)-7-(2-Methylbutan-2- yl)benzofuran (556 mg,2.34 mmol) was solved in abs. N,N- dimethylformamide (7 mL) and treated with sodium azide (458 mg, 7.05 mmol). The suspension was stirred at 50 °C for 11 h, subsequently diluted with water and extracted with diethyl ether twice. The combined organic phases were dried over sodi- um sulfate and freed from solvent under reduced pressure. The crude product was purified via column chromatography (silica gel, petroleum ether/CH2Cl210:1 v/v).
Yield: 523 mg (2.15 mmol, 91 %) of colorless crystals.
The obtained 2-(azidomethyl)-7-(2-methylbutan-2-yl)benzofuran (500 mg, 2.05 mmol) was mixed with abs. tetrahydrofurane (20 mL) and palladium on carbon (Pd/C, 10 w%) and stirred under hydrogen atmosphere for 3 h. After dilution with dichloro- methane, the catalyst was removed by filtration and the solu- tion was concentrated under reduced pressure. The obtained crude product was purifed via column chromatography (silica gel, CH2CI2/CH3OH gradient 99:1 to 19:1 v/v).
Yield: 278 mg (1.28 mmol, 62 %) of a colorless liquid.
Under nitrogen atmosphere, benzyl anthranilate (363 mg, 1.60 mmol) was solved in abs. tetrahydrofurane (12 mL) and added slowly to a solution of triphosgene (0.24 g, 0.80 mmol) in abs. tetrahydrofurane (1 mL). After careful, dropwise addition of abs. triethylamine (0.44 mL, 0.32 g, 3.2 mmol), the milky reaction mixture was stirred for 90 min at room temperature. Subsequently, excess phosgene was removed by degassing and volatile reaction components were evaporated. The solid resi- due was suspended in abs. tetrahydrofurane (13 mL) and treated with 7- (2-Methylbutan-2-yl)benzofuran-2-yl)methanamine (278 mg, 1.28 mmol). The reaction mixture was stirred overnight, diluted with water and extracted with dichloromethane three times. Dehydration of the combined organic phases over sodium sulfate and subsequent evaporation of the solvents afforded the crude product that was finally purified via column chroma- tography (silica gel, petroleum ether/CH2Cl21:3 v/v). Yield: 485 mg (1.03 mmol, 81 %) of a colorless solid.
Benzyl 2- (3-((7-(2-methylbutan-2-yl)benzofuran-2- yl)methyl)ureido) benzoate (453 mg, 0.96 mmol) was mixed with abs. tetrahydrofurane (10 mL) and palladium on carbon (45 mg) and stirred under hydrogen atmosphere for 19 h. After dilution with dichloromethane, the catalyst was removed by filtration and the solution was concentrated under reduced pressure. The obtained crude product was purified via multiple purification steps using column chromatography (silica gel, petroleum ether/CH2Cl2/CH3COOH 16:4:1 v/v and CH2C12/CH30H 50:1 v/v).
Yield: 52.0 mg (0.137 mmol, 13 %) of a white solid.
CH NMR (500 MHz, DMSO-d6): d [ppm] = 13.30 (s, 1H, COOH) 10.30 (s, 1H, NH-a), 8.38 (dd, 3JHH = 8.4 Hz, 4JHH = 0.5 Hz, 1H, H-3), 8.12-8.00 (m, 1H, NH-b), 7.91 (dd, 3J HH = 7.9 Hz, 4JHH = 1.7
Hz, 1H, H-6), 7.48 (ddd, 3JHH = 8.7 Hz, 7.3 Hz, 4JHH = 1.6 Hz,
1H, H-4), 7.41 (dd, 3JHH = 7.6 Hz, 4JHH = 1.1 Hz, 1H, H-4'),
7.13 (t, 3JHH = 7.6 Hz, 1H, H-5'), 7.06 (dd, 3JHH = 7.6 Hz, 4JHH
= 1.1 Hz, 1H, H-6'), 7.00-6.94 (m, 1H, H-5), 6.67 (s, 1H, H-
3'), 4.45 (d, 3JHH = 5.7 Hz, 2H, H-7), 1.88 (q, 3JHH = 7.4 Hz,
2H, H-9), 1.39 (s, 6H, H-ll), 0.57 (t, 3JHH = 7.4 Hz, 3H, H-
10).
13C NMR (125 MHz, DMSO-d6): d [ppm] = 169.5 (COOH), 155.4
(CONH), 154.7 (C—2'), 152.2 (C-7'a), 142.9 (C-2), 140.6 (C- 1"), 133.6 (C-4), 132.2 (C-7'), 130.8 (C-6), 128.6 (C-3'a),
122.6 (C-5'), 121.4 (C-6'), 120.2 (C-5), 119.2 (C-3), 118.8
(C-4'), 114.8 (C-l), 102.7 (C-3'), 37.4 (C-7), 36.9 (C-8),
33.6 (C—9), 27.2 (C-ll), 9.3 (C-10).
ATR-IR: v [cm-1] = 3230, 2962, 2875, 1683, 1659, 1606, 1586,
1557, 1466, 1452, 1413, 1384, 1321, 1266, 1237, 1161, 1088,
1044, 949, 922, 859, 807, 745, 717, 696, 657, 630, 612, 565, 524, 482, 452, 425, 406.
HRMS (ESI+): m/z = 379.1665 (379.1663 calculated for [M-H]”). Mp= 138.3 °C
Example 2:
Preparation
The compound of Example 2 was synthesized using the procedure of Schemes 1 and 2.
2- (Trifluoromethyl)phenyl cyclopentylcarbamate was synthesized via the procedure described in Example 1, using 2- (triuoromethyl)phenol (1.19 mL, 1.62 g, 9.98 mmol) as phenol derivative and 1.24 mL (1.22 g, 11.0 mmol) cyclopentyl isocyanate .
Yield: 2.50 g (9.16 mmol, 92 %) of a colorless solid. In an inert atmosphere, a solution of trimethylsilyl triuoromethanesulfonate (0.25 mL, 0.31 g, 1.4 mmol, 1.05 eq.) in diethyl ether (2 mL) was added dropwise to a solution of 2- (trifluoromethyl)phenyl cyclopentylcarbamate (360 mg, 1.32 mmol, 1 eq.) and tetramethylethylenediamine (TMEDA, 0.22 mL, 0.17 g, 1.4 mmol, 1.1 eq.) in diethyl ether (8 mL). After 1 h stirring at room temperature, the reaction mixture was cooled to -78 °C and treated with TMEDA (0.40 mL, 0.31 g, 2.6 mmol, 2 eq.) and n-butyl lithium solution (1.4 M in cyclohexane; 1.85 mL, 2.6 mmol, 2 eq.) successively. At -78 °C, the mixture was stirred for 90 min, treated with a solution of iodine (0.42 g, 1.6 mmol, 1.25 eq.) in diethyl ether (1 mL) and again stirred for 90 min. Finally, the thawing reaction mixture was treated with methanol (0.2 mL) and aqueous hydrogen chloride solution (2M, 8 mL, 16 mmol, 12 eq.) and stirred until room temperature was reached. The phases were separated, the aqueous phase was extracted with diethyl ether three times and the combined or- ganic extracts were washed with sat. sodium bicarbonate solu- tion. After reextraction of the separated aqueous phase the combined organic phases were dried over sodium sulfate, con- centrated in vacuo and puri_ed by column chromatography (sili- ca gel, petroleum ether/ethyl acetate gradient 50:1 to 10:1 v/v).
Yield: 315 mg (789 pmol, 60 %) of a colorless solid.
2-Iodo-6- (trifluoromethyl) cyclopentylcarbamate was converted to the target compound 2-(3-((7-(trifluoromethyl)benzofuran-2- yl)methyl)ureido)benzoic acid in seven steps, analogous to Ex- ample 1.
CH NMR (500 MHz, DMSO-d6): d [ppm] = 13.50 (brs, 1H, COOH)
10.77 (brs, 1H, NH-a), 8.36 (dd, 3JHH = 8.5 Hz, 4JHH = 1.1 Hz,
1H, H-3), 8.10 (brs, 1H, NH-b), 7.95-7.89 (m, 2H, H-6, H-4'),
7.60 (d, 3J HH = 7.6 Hz, 1H, H-6'), 7.46-7.38 (m, 2H, H-4, H-
5'), 7.97-6.92 (m, 1H, H-5), 6.91 (s, 1H, H-3'), 4.49 (d, 3JHH =
5.6 Hz, 2H, H-7).
13C NMR (125 MHz, DMSO-d6): d [ppm] = 169.8 (COOH), 158.4 (C-
2'), 154.8 (CONH), 149.5 (C-7'a), 142.7 (C-2), 133.0 (C-4),
131.0 (C-6), 130.0 (C-3'a), 125.8 (C-4'), 123.4 (q, 1J CF =
272.1 Hz, CF3)) 123.0 (C-5'), 120.8 (q, 3JCF = 4.4 Hz, C-6')
120.1 (C-5), 118.9 (C-3), 116.5 (C-l), 112.7 (q, 2JCF = 33.6
Hz, C—7'), 103.4 (C-3'), 36.8 (C-7).
19F NMR (565 MHz, DMSO-d6): d [ppm] = -59.47 (CF3).
ATR-IR: v [cm-1] = 3330, 2928, 2883, 2652, 2559, 1687, 1651, 1561, 1430, 1412, 1325, 1293, 1267, 1241, 1171, 1131, 1118, 1085, 1051, 945, 817, 755, 740, 733, 707, 667, 612, 597, 560,
522, 482, 456, 418
HRMS (ESI”): m/z = 377.0749 (377.0755 calculated for [M-H]”).
Mp = 179.5 °C Example 3:
The compound of Example 3 was synthesized using the procedure of Schemes 1 and 2.
4-Fluoro-2- (trifluoromethyl)phenol was synthesized by treating a solution of 1.80 g (10.0 mmol, 1.0 equiv.) 4-fluoro-2- (trifluoromethyl)phenol in 5 mL methanol and with a suspension of 1.50 g (15.0 mmol, 1.5 equiv.) calcium carbonate in 6 mL water and a solution of 1.62 g (10.0 mmol, 1.0 equiv.) iodine monochloride in 4 mL methanol, successively. The reaction mix- ture was stirred at room temperature for 5 h before it was di- luted with water and dichloromethane. After phase separation, the aqueous phase was extracted three times with dichloro- methane. The combined organic phases were washed with brine and saturated sodium thiosulphate solution, once each. The or- ganic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. Purifcation of the crude prod- uct was performed by column chromatography (silica gel, PE/CH2C12 4 :1 v/v).
Yield: 2.23 g (7.28 mmol, 73 %) of a yellow oil.
4-Fluoro-2-iodo-6- (trifluoromethyl)phenol was converted to the target compound 2- (3-((7-(trifluoromethyl)benzofuran-2- yl)methyl)ureido)benzoic acid in six steps, analogous to Exam- ple 1 and 2.
1H NMR (600 MHz, DMSO-d6): d [ppm] = 13.35 (brs, 1H, COOH)
10.30 (brs, 1H, NH-a), 8.38 (dd, 3JHH = 8.6 Hz, 4JHH = 1.2 Hz,
1H, H-3), 8.21 (t, 3JHH = 5.7 Hz, 1H, NH-b), 7.92 (dd, 3JHH =
8.6 Hz, 4JHH = 1.2 Hz, 1H, H-6), 7.79 (dd, 3JHH = 8.5 Hz, 4JHH =
2.6 Hz, 1H, H-4'), 7.56 (dd, 3JHH = 9.2 Hz, 4JHH = 2.6 Hz, 1H,
H-6'), 7.49 (ddd, 3JHH = 8.7 Hz, 3JHH = 7.2 Hz, 4JHH = 1.8 Hz,
1H, H-4), 7.98 (ddd, 3JHH = 8.1 Hz, 3JHH = 7.2 Hz, 4JHH = 1.2 Hz,
1H, H-5), 6.92 (s, 1H, H-3'), 4.49 (d, 3JHH = 5.5 Hz, 2H, H-7).
13C NMR (150 MHz, DMSO-d6): d [ppm] = 169.5 (COOH), 160.4 (C- 2'), 157.5 (d, = 238.3 Hz, C-5'), 154.6 (CONH), 145.9 (C- 7'a), 142.8 (C-2), 134.2 (C-4), 131.5 (d, 3JCF = 10.9 Hz, 3'a),
131.0 (C-6), 122.5 (d, = 269.9 Hz, CF3), 120.4 (C-5), 119.2
(C-3), 114.7 (C-l), 111.6 (d, 2JCF = 25.0 Hz, C-4'), 108.9 (dq, 2JCF = 29.7 Hz, 3JCF = 4.9 Hz, C-6'), 103.9 (d, 4JCF = 4.9 Hz, C- 3'), 36.8 (C—7).
19F NMR (565 MHz, DMSO-d6): _[ppm] = -59.75 (CF3), -118.86 (C-
5'-F).
ATR-IR: v [cm-1] = 3333, 2913, 2648, 1686, 1655, 1607, 1586,
1561, 1474, 1437, 1428, 1410, 1370, 1328, 1318, 1267, 1183,
1162, 1130, 1114, 1085, 997, 953, 917, 866, 827, 762, 754,
729, 705, 681, 665, 629, 586, 559, 519, 492, 442, 415.
HRMS (ESI+): m/z = 395.0467 (395.0660 calculated for [M-H]”). Example 4:
The compound of Example 4 was synthesized in accordance with Scheme 3.
A mixture of 4-(4-iodophenyl)morpholine (0.78 mL, 3.46 mmol, 1.0 eq.), Copper iodide (32.9 mg, 0.173 mmol, 5 mol%), abs. tetrahydrofuran (6 mL) and triethylamine (17 mL) was degassed with nitrogen for 30 minutes. Then, Pd(PPha)4 (200 mg, 0.173 mmol, 5 mol%) and ethynyltri (methyl)silane (1.29 mL, 9.34 mmol, 2.7 eq.) were added to the mixture. After stirring at room temperature for 20 h the reaction was quenched by the addition of water and extracted with ethyl acetate three times. The combined organic layer was dried over sodium sul- fate, filtered and concentrated in vacuo. The crude product was purified via column chromatography (dichloromethane + 0.5% v/v acetone).
Yield: 678 mg (2.61 mmol, 76%) of an orange solid.
Under nitrogen atmosphere, 4-(4-((trimethylsilyl)ethyn- yl)phenyl)morpholine (372 mg, 1.43 mmol, 1.0 eq.) was dis- solved in methanol (12 mL) and potassium carbonate (990 mg, 7.16 mmol, 5.0 eq.) was added. After stirring for 4 h at room temperature the mixture was filtered and evaporated under low pressure. The crude product was re-dissolved in dichloro- methane and washed with water. Then, the organic layer was dried over sodium sulfate, filtered and concentrated under vacuo. The crude product was purified by column chromatography (dichloromethane + 1% v/v acetone).
Yield: 205 mg (1.10 mmol, 77%) of an orange solid.
Copper iodide (5.7 mg, 0.030 mmol, 5 mol%) was added to a so- lution of methyl-5-iodo-2-propionamidoanthranilate (200 mg, 0.600 mmol, 1.0 eq.) in abs. tetrahydrofuran (3 mL) and tri- ethylamine (4 mL). After the mixture was degassed with nitro- gen for 30 minutes Pd(PPh3)4 (34.7 mg, 0.030 mmol, 5 mol%) and 4- (4-ethynylphenyl)morpholine (169 mg, 0.901 mmol, 1.5 eq.) were added. The resulting mixture was stirred for 4 h at room temperature and then quenched by the addition of water. The aqueous phase was extracted with dichloromethane three times and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified via column chromatography (petroleum ether/ethyl acetate 2:1 v/v).
Yield: 156 mg (0.397 mmol, 66%) of a yellow solid.
Methyl 5- ((4-cyclohexylphenyl)ethynyl)-2-propionamidobenzoate (149 mg, 0.378 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL) and sodium hydroxide solution (1 M, 2 mL) was added. After stirring for 18 h tetrahydrofuran was removed under re- duced pressure and the product was precipitated by the addi- tion of hydrogen chloride solution (1 M, 3 mL). The solid was filtered and washed with water.
Yield: 137 mg (0.362 mmol, 96%) of a slightly yellow solid.
1H-NMR (400 MHz, DMSO-d6): d [ppm] = 11.30 (s, 1H, NHCO) , 8.55
(d, 3JH,H = 8.8 Hz, 1H, H-3), 8.05 (d, 2JH,H = 2.1 Hz, 1H, H-6),
7.67 (dd, 3JH,H = 8.7 Hz, 2JH,H = 2.2 Hz, 1H, H-4), 7.40 (cl, 3CH,H
= 8.8 Hz, 2H, H-2" ), 6.95 (d, 3JH,H = 9.0 Hz, 2H, H-3" ), 3.78- 3.69 (m, 4H, H-2'" ), 3.21-3.14 (m, 4H, H-1'" ), 2.42 (c[, 3CH,H
= 7.5 Hz, 2H, CH2), 1.13 (t, 3JH,H = 7.5 Hz, 3H, C¾ ).
13C-NMR (101 MHz, DMSO-de): d [ppm] = 172.1 (NHCO), 168.9 (COOH), 150.8 (C-4" ), 140.5 (C-2), 136.0 (C-4), 133.6 (C-6),
132.4 (C-2" ), 119.9 (C-3), 116.8 (C-5), 116.8 (C-l), 114.4
(C-3" ), 111.5 (C-l" ), 90.0 (C-2'), 86.7 (C-l'), 65 9 (C-
2'" ), 47.4 (C-l'" ), 30.7 (CH2), 9.29 (CH3).
ATR-IR: v [cm-1] = 2972, 2923, 2835, 2613, 1686, 1584, 1518, 1380, 1288, 1228, 1182, 1107, 926, 791, 729.
HRMS (ESI+): m/z 379.1691 [M+H]+ (calculated: 379.1653 [M+H]+).
Examples 5-16:
Furthermore, using the general procedure of Scheme 3, the fol- lowing compounds of Formula II were synthesized:
In cases where the aryl halides were not commercially availa- ble they were synthesized using copper catalyzed Ullman- Goldberg coupling reaction according to the following scheme.
Further aryl iodides were synthesized via nucleophilic aro- matic substitution (Scheme 5) or boric acid/glycerol catalyzed double michael addition reaction, respectively (Scheme 6). Scheme 6:
4-Morpholinobenzene ethynyl anthranilic acid bearing an urea function was synthesized using 4-nitrophenyl chloroformate and dimethylamine followed by palladium and copper catalyzed sonogashira cross coupling reaction according to Scheme 7.
Scheme 7:
1. 1.5 eq. 4-nitrophenyl chloroformate,
Comparative Example 17:
The compound of Example 17 was synthesized in accordance with Scheme 2. Under nitrogen atmosphere, benzyl anthranilate (341 mg, 1.50 mmol) was solved in abs. tetrahydrofurane (10 mL) and added slowly to a solution of triphosgene (156 mg, 525 pmol) in abs. tetrahydrofurane (1 mL). After careful, dropwise addition of abs. triethylamine (0.42 mL, 0.30 g, 3.0 mmol), the milky re- action mixture was stirred for 90 min at room temperature. Subsequently, excess phosgene was removed by degassing and volatile reaction components were evaporated. The solid resi- due was suspended in abs. tetrahydrofurane (10 mL/mmol) and treated with naphthyl-l-amine (193 mg, 1.35 mmol). The reac- tion mixture was stirred overnight, diluted with water and ex- tracted with dichloromethane three times. Dehydration of the combined organic phases over sodium sulfate and subsequent evaporation of the solvents afforded the crude product that was finally purfied via column chromatography (silica gel, CH2CI2).
Yield: 409 mg (1.03 mmol, 76 %) of a colorless solid.
Benzyl 2-(3-(naphthalen-l-yl)ureido)benzoate (371 mg, 937 pmol) was mixed with abs. tetrahydrofurane (10 mL) and palla- dium on carbon (37 mg) and stirred under hydrogen atmosphere for 19 h. After dilution with dichloromethane, the catalyst was removed by filtration and the solution was concentrated under reduced pressure. The obtained crude product was puri- fied via multiple purification steps using column chromatog- raphy (silica gel, CH2CI2/CH3OH gradient 30:1 to 10:1 v/v).
Yield: 186 g (606 pmol, 65 %) of a white solid.
CH NMR (400 MHz, DMSO-d6): d [ppm] = 11.18 (brs, 1H, NH-a), 9.55 (s, 1H, NH-b), 8.34 (dd, 3JHH = 8.5 Hz, 4JHH = 1.1 Hz, 1H, H-3), 8.20-8.09 (m, 1H, H-8'), 8.00-7.87 (m, 2H, H-6, H-5'),
7.73 (d, 3JHH = 8.2 Hz, 1H, H-4'), 7.69 (d, 3JHH = 7.4 Hz, 1H, H-2'), 7.58-7.50 (m, 2H, H-6', H-7'), 7.49 (t, 3JHH = 8.2 Hz, 1H, H-3'), 7.44 (ddd, 3JHH = 8.6 Hz, 3JHH = 7.1 Hz, 4JHH = 1.7
Hz, 1H, H-4), 6.97 (t, 3JHH = 7.6 Hz, 1H, H-5).
13C NMR (125 MHz, DMSO-d6): d [ppm] = 169.8 (COOH), 153.6
(CONH), 142.1 (C—2), 134.2 (C-8'a), 133.8 (C-4'a), 132.5 (C-
4), 131.0 (C-6), 128.3 (C- 1'), 128.1 (C-5'), 125.9-125.6 (C-
3', C-6', C-7'), 124.6 (C-4'), 122.9 (C-8'), 121.5 (C-2'),
120.5 (C-5), 119.5 (C-3), 117.1 (C-l).
ATR-IR: v [cm-1] = 3186, 3056, 1666, 1583, 1505, 1474, 1447,
1391, 1342, 1318, 1290, 1271, 1251, 1162, 865, 780, 752, 657,
618, 542, 524, 493, 449, 418.
HRMS (ESI+): m/z = 345.0616 (345.0636 calculated for [M+K]+). The compound of Example 18 was synthesized in accordance with Scheme 8.
3-Aminoisonicotinic acid (553 mg, 4.00 mmol, 1 eq.) was sus- pended in abs. tetrahydrofurane (2 mL) and 1-naphthyl isocyanate (1.2 mL, 0.85 g, 5.0 mmol, 1.25 eq.) was added dropwise. The reaction mixture was stirred under reflux for 16 hours and treated with a small amount of methanol, subsequent- ly. After evaporating the solvent, the crude product was puri- fied by column chromatography (silica gel, CH2CI2/CH3OH/CH3COOH 100:10:3 v/v). lE NMR (600 MHz, DMSO-d6): d [ppm] = 12.46 (brs, 1H, NH-a), 9.51 (s, 1H, NH-b), 9.42 (s, 1H, H-2) 8.17-8.12 (m, 1H, H-8'), 8.09 (d, 3JHH = 4.9 Hz, 1H, H-6), 8.94-7.89 (m, 1H, H-5'), 7.74 (d, 3JHH = 4.9 Hz, 1H, H-5), 7.71 (d, 3JHH = 8.2 Hz, 1H, H-4'),
7.65 (d, 3JHH = 7.4 Hz, 1H, H-2'), 7.55-7.50 (m, 2H, H-6', H-
7'), 7.48 (t, 3JHH = 7.8 Hz,ΐH, H-3'). 13C NMR (151 MHz, DMSO-d6): d [ppm] = 167.9 (COOH), 153.8
(CONH), 141.4 (C—2), 141.1 (C-6), 137.4 (C-3), 134.6 (C ■8'a),
133.8 (C-4'a), 130.5 (C-4), 128.4 (C-l'), 128.0 (C-5'), 125.8 (C-6'), 125.7 (C-3'), 125.4 (C-7'), 124.4 (C-4'), 124.0 (C-5), 123.2 (C—8'), 121.6 (C-2').
ATR-IR: v [cm-1] = 3264, 2921, 2851, 1665, 1630, 1582, 1547,
1504, 1428, 1380, 1345, 1309, 1275, 1258,1238, 792, 770, 741,
711, 674.
HRMS (ESI+): m/z 308.1040 (308.1030 calculated for [M+H]+).
Example 19: Antiviral Assay
Viruses
CCHFV strain Afg-09 2990 (Olschlager et al., Complete sequence and phylogenetic characterisation of Crimean-Congo hemorrhagic fever virus from Afghanistan. J. Clin. Virol. 2011, 50, 90-92) had been isolated at BNITM laboratory and passaged £3 times before it has been used in this study. LASV strain Ba366 (Lecompte et al., J. Mastomys natalensis and Lassa fever, West Africa. Emerg. Infect. Dis. 2006, 12, 1971-1974) has beenproduced recombinantly and has been passaged at BNITM la- boratory £3 times. EBOV strain Mayinga 1976 has been provided around 1980 by the Center for Disease Control, Atlanta, Geor- gia. The passage history since 1976 is not documented. All vi- rus stocks have been grown on Vero 81 cells, quantified by immunofocus assay (see below) and stored at -80°C until use.
Antiviral and toxicity testing in vitro
All test compounds were dissolved in DMSO at a concentration of 100 mM and stored at 20 °C. Vero 81 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 3 % fetal calf serum (FCS) and streptomycin/penicillin and seed- ed at a density of 1 x 104 cells per well of a 96-well plate one day before infection. Cells were inoculated with LASV Ba366, CCHFV Afg 09-2990 or EBOV Mayinga at a multiplicity of infection (MOI) of 0.01 in the BSL-4 laboratory. The inoculum was removed after 1 h and replaced by fresh medium complement- ed with different concentrations of compound. Concentration of infectious virus particles in cell culture supernatant was measured three days (LASV and CCHFV) or four days (EBOV) post infection (p.i.) by immunofocus assay. Cell growth and viabil- ity under compound treatment was determined by the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide (MTT) method as described previously (Gunther et el., Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro. Antiviral Res. 2004, 63, 209-215). A sigmoidal dose-response curve was fitted to the data using Prism GraphPad 6.0 (GraphPad Soft- ware). The inhibitory concentrations that reduced the virus titer by 50 % (IC50) were calculated from the sigmoidal func- tions.
Virus titration
Infectious virus particles were determined by immunofocus as- say as previously described (Gunther et el., Application of real-time PCR for testing antiviral compounds against Lassa virus, SARS coronavirus and Ebola virus in vitro. Antiviral Res. 2004, 63, 209-215). Briefly, 1x106 Vero cells per 96-well plates were inoculated with 50 mΐ of serial 10-fold dilutions of sample. The inoculum was removed after 1 h and replaced by a 1 %-methylcellulose - medium overlay. After three days of incubation, cells were fixed with 4 % formaldehyde, washed with phosphate-buffered saline (PBS), and permeabilized with 0.5 % Triton X-100 in PBS. After washing with PBS and blocking with 2 % FCS in PBS, cell foci infected with EBOV, CCHFV or LASV were detected with nucleoprotein (NP)-specific monoclonal antibodies (LASV and CCHFV) or polyclonal antiserum (EBOV) against the whole virus. After washing, cells were incubated with peroxidase-labeled anti-mouse IgG. Foci were visualized with tetramethylbenzidine and counted.
The antiviral activity obtained with compounds of the examples against several RNA virus families is shown in the table be- low. determined
Example 20: hDHODH Enzyme Assay
Expression and purification of the enzyme was carried out fol- lowing the protocol of DAS et al. (SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Ac- tivity. ACS Med. Chem. Lett. 2013, 4, 517-521). The prepared enzyme stock solution (325 mM) was thawed to 0 °C and careful- ly diluted to 87.5 nM with ice-cooled Tris-HCl buffer (50 mM Tris-HCl, 0.1 % Triton X-100, pH 8.0)). Stock solutions of all test compounds (100 mM), L-DHO (250 mM) and CoQl (250 mM) were prepared in DMSO, stored at -20 °C and thawed to room tempera- ture before use. The reaction was performed in triplicates in a 96 well plate with total volumes of 200 mT containing L- dihydroorotate (L-DHO; 0.10 mM), coenzyme Q1 (CoQl; 25 mM), 2,6-dichlorophenolindophenol (DCPIP; 60 mM), HsDHODH29-396 (35 nM) and the test compound (varying concentrations) in Tris-HCl buffer. Brequinar was assessed as reference inhibitor and a control without inhibitor but the equivalent amount of buffer instead was run for each test compound. The compound stock solutions were diluted in Tris-HCl buffer to give nine different concentrations and each sample was treated with a freshly prepared substrate mixture containing L-DHO, CoQl and DCPIP. By simultaneous addition of 80 mΐ ice- cooled enzyme solution (87.5 mM) per well and immediate mixing by thorough pipetting, the reaction was started. The absorp- tion of the mixture was monitored using a spectrophotometer (Berthold Technologies TriSta^S LB942 Multimode Reader, ICE software) with one data point per 10 seconds at an excitation wavelength of 600 nm and a temperature of 25 °C. During the first 200 s from enzyme addition, linear initial enzyme velocites were recorded, from which the IC50 values were cal- culated by non-linear fitting (Origin software) to the follow- ing equation: wherein v is the determined initial, linear enzyme velocity,
Vo is the calculated enzyme velocity without test compound and c is the concentration of added test compound.
The obtained hDHODH inhibition data are shown in the table be- low:
The compound of Example 18 showed a percentual inhibition of hDHODH at a 1 mM concentration of 91% and an IC50 of 81 nM. Example 21: lymphocyte inhibition
Lymphocyte inhibition was determined by using human PBMCs (pe- ripheral blood mononuclear cells) as cell culture. The inhibi- tor compound was added at 8 different concentrations with each determination in triplicate and one control without inhibitor. T-cell stimulation was done by Cytostim, a reagent that binds T-cell receptors to MHC molecules of the antigen-presenting cells in an antibody-based manner and enables T-cell stimula- tion. Quantification was achieved by a flow cytometry-based method (Facs analysis) with staining of PBMCs with eFluor670 (eBioscience (TM)). The PBMCs are assigned to their populations (CD4/CD8 T cells) by use of other markers.
The compound of Example 1 showed an IC50 of about 150 nM for CD4 and CD8 replication.
Example 22: ADME properties
Absorption, distribution, metabolism and excretion properties of selected inhibitors were determined.
S9 Metabolism assay
Stock solutions of all test compounds (100 mM) were prepared in DMSO, stored at-20 °C and diluted in PB to 600 mM prior to the assay. Rat liver S9 fractions (SigmaAldrich, Lot # SLCC9026 and # SLCB2232) were combined, aliquoted (200 μL), stored at -80 °C and thawed to 0 °C before use. The reaction was performed in triplicates in eppendorf tubes with total volumes of 300 μL containing MgClå (5 mM), NADPH (5 mM), rat S9 fraction (1 mg) and the test compound (100 pM) in phosphate buffer (38.5 mM Na2HP04, 11.5 mM KH2PO4, pH 7.3) . 7-
Ethoxycoumarin was assessed as reference inhibitor and a con- trol without inhibitor but an equivalent amount of buffer in- stead was run. The ice cooled S9 fraction was added to a solu- tion of MgCl2 and NADPH in PB and the resulting mixture was preincubated for 10 minutes at 37 °C in a shaker. Subsequently the reaction was started by addition of the test compound (50 μL), followed by threefold pipetting. After 0 h, 1 h and 3 h, samples of 50 μL were taken from the reaction, mixed with 150 μL ice-cooled methanol and centrifuged at 14000 rpm and 4 °C for 15 minutes. The supernatant was filtered with a syringe fiter, immediately quantified on HPLC and stored at -20 °C un- til LC/MS analysis.
Octanol-Water Partition Coefficient (logD)
Octanol and phosphate buffered saline (PBS, 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HP04, 2.0 mM KH2P04, pH 7.4) were saturated with each other prior to the experiment. Stock solutions of all test compounds (100 mM) were prepared in DMSO, stored at - 20 °C and diluted with the saturated PBS to 100 mM prior to the experiment. The experiment was performed in duplicates in 2 mL HPLC-vials. 300 μL of the test compound solution (100 mM) was overlayered with 300 μL saturated octanol. The emulsions were vortexed for 1 min and shaken for 1 h at 180 rpm and 25 °C. After phase separation, the aqueous phases and the initial 100 mM compound solution were quantified on HPLC. Partition coefficients were calculated using the following equation: wherein areain is the area under the curve in the chromatogram ob- tained for the initial, 100 pM compound solution and areaaq is the area under the curve in the chromatogram ob- tained for one separated aqueous phase.
Determination of Membrane Permeability (PAMPA Assay)
Stock solutions of all test compounds (100 mM) were prepared in DMSO, stored at -20 °C and diluted with phosphate buffered saline (PBS, 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HP04, 2.0 mM KH2PO4, pH 7.4) to 200 mM prior to the experiment. The assay was performed in triplicates in a 96 well Corning Gentest Pre- coated PAMPA Plate System, which was stored at -20 °C and thawed to room temperature for 1 h prior to the assay. Wells of the donor plate were filled with 300 μL of the compound so- lutions (200 mM) and 200 μL PBS were added to the wells of the receiver plate. Two controls without inhibitor but an equiva- lent amount of buffer instead was run. Bubble-free assembling of the two plates was followed by 5 h incubation at 25 °C. Fi- nally, the plates were carefully separated from each other. 150 μL of each well of both plates were transferred to black 96-well FluoroNunc™ plates and quantified on fluorescence spectrophotometer (Berthold Technologies TriStar2S LB942 Multi- mode Reader, ICE software). Membrane Permeabilities were calculated using the following equation: wherein
Cacc(t) is the compound concentration in acceptor well at time t,
Aperm is the area of the membrane filter (0.3 cm2),
Vdon is the donor well volume (0.3 mL),
Vacc is the acceptor well volume (0.2 mL) and
Ceq is the equilibrium concentration with where cdon(t) is the compound concentration in donor well at time t.
The obtained results are shown in the following table.
The above data show that the tested compounds have acceptable ADME properties that encourage further in vivo pharmacokinetic studies for the development of treatments of RNA virus dis- eases. In particular, the compounds showed a high metabolic stability.
While compounds having an amide bond, such as showed a cleavage of the amide bond (see hydrolysis study in S9 extract of rat liver shown in Figure 1; identified via LC- MS), the compounds of Examples 1 and 2 showed no amide cleav- age (see Figure 2 (Example 1) and Figure 3 (Example 2)). Also the compound of Example 18 did not show amide cleavage.
The following tables further illustrate the advantageous prop- erties of the compounds according to the invention.
As can be seen, compounds of formula (I) show a high metabolic stability and at the same time remarkable inhibition potency. In particular, these advantageous properties are caused by the specific structure of the compounds of formula (I). The spe- cific heteroaryl substituent, in particular in case of Y=0 and Z=CH, i.e. in case of benzofurane derivatives, provides a cer- tain rigidity in the linker fragment leading to the improve- ments compared to the corresponding non-benzofurane deriva- tives.

Claims

Claims
1. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula I: wherein:
W is C or N, and preferably is C;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, each moiety being independently selected from the group consisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C (0)-0-R1-group is joined to the -NH- group or -X-group shown in Formula (I) to form together with the W-containing aromatic ring shown in Formula (I) a hetero ring system;
R2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said alkyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, wherein each moiety is preferably independently se- lected from the group consisting of hydroxyl, halogen, al- kyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substi- tuted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -0- arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl, or optionally R2 represents two substituents which are joined to form together with the aromatic ring shown in Formula I a substituted or unsubstituted ring or hetero ring system, or optionally at least one of R2 is joined to the -NH- group or -X-group shown in Formula (I) to form together with the W-containing aromatic ring shown in Formula (I) a hetero ring system;
R3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, wherein each moiety is preferably independently se- lected from the group consisting of hydroxyl, halogen, al- kyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substi- tuted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -0- arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl;
X is 0 or NH, and preferably is NH;
Y is CR4 or N, and preferably is CR4;
Z is 0, S, NH or CR52, and preferably is 0;
R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and pref- erably is H; and
R5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy and acetyl, and preferably is H.
2. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to claim 1, wherein R2 is H.
3. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to claim 1 or 2, wherein Y is CR4 and R4 is H.
4. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to anyone of claims 1 to 3, wherein R3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen and haloalkyl.
5. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to claim 4, wherein the alkyl is 2-methylbutan-2-yl, the hal- ogen is F, and/or the haloalkyl is trifluoromethyl.
6. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to anyone of claims 1 to 4, said compound having the general structure shown in Formula la or lb: wherein:
R3a is alkyl or haloalkyl; and
R3b is H or halogen, wherein the halogen is preferably F.
7 . Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to claim 6, wherein the alkyl is 2-methylbutan-2-yl and the haloalkyl is trifluoromethyl.
8. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to anyone of claims 1 to 7, having the following formula:
9. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, said compound having the general structure shown in Formula I: wherein:
W is C or N, and preferably is C;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, each moiety being independently selected from the group consisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C(0)-0-R1-group is joined to the -NH- group or -X-group shown in Formula (I) to form together with the W-containing aromatic ring shown in Formula (I) a hetero ring system;
R2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said alkyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, wherein each moiety is preferably independently se- lected from the group consisting of hydroxyl, halogen, al- kyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substi- tuted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -0- arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl, or optionally Rz represents two substituents which are joined to form together with the aromatic ring shown in Formula I a substituted or unsubstituted ring or hetero ring system, or optionally at least one of R2 is joined to the -NH- group or -X-group shown in Formula (I) to form together with the W-containing aromatic ring shown in Formula (I) a hetero ring system;
R3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, wherein each moiety is preferably independently se- lected from the group consisting of hydroxyl, halogen, al- kyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substi- tuted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -0- arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl;
X is 0 or NH, and preferably is NH;
Y is CR4 or N, and preferably is CR4;
Z is 0, S, NH or CR52, and preferably is 0;
R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and pref- erably is H; and
R5 is independently selected from the group consisting of H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy and acetyl, and preferably is H.
10. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula II or Formula Ila: (H a) wherein:
W is C or N, and preferably is C;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C(0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, each moiety being independently selected from the group consisting of -OC(0)-alkyl, -OC(0)0-alkyl, heterocyclyl, aryl and heteroaryl;
Y is independently selected from CR4 and N, and preferably is CR4; R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and pref- erably is H;
R6 is heterocyclyl or heterocyclylalkyl , wherein the heterocyclyl and heterocyclylalkyl can be unsubstituted or substituted with one or more ring system substituents which can be the same or different ;
R7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, alkoxy, -C (0)-alkyl, -C (0)-haloalkyl, -NH2, -NH-alkyl and -N (alkyl)2; and
R8 is -C (0)-alkyl, -C (0)0-alkyl, -C (0)NH-alkyl, -C (0)- cycloalkyl, -C (0)O-cycloalkyl, -C(0)NH-cycloalkyl, -C (0)- aryl, -C (0)0-aryl, -C (0)NH-aryl, -C (0)-heteroaryl, -0(0)0- heteroaryl, -C (0)NH-heteroaryl, aryl substituted with R10, heteroaryl substituted with R10, -S(02)-R11 or wherein
Z is -(CHz)n-, -0-(CHz)n-, -NH-(CHz)n-, -(CHZ)p-L-(CH2)q-,
-0-(CHz)p-L-(CHz)q- or -NH-(CHZ)P-L-(CHZ)q-, n is an integer from 1 to 6; p and q are integers independently selected from 0 to 6;
L is a linking group selected from the group consisting of heteroaryl, aryl, heterocyclyl and cycloalkyl; X is 0, S, NH, CH2, S (0) or C (0), and preferably is 0, S or NH;
R9 is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of H, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl and trialkylsilyl;
R10 is aryloxy or arylalkyl or optionally R10 represents two substituents linked to each other to form together with the aryl or heteroaryl a polycyclic ring system, wherein preferably the polycyclic ring system is a naph- thalene or fluorene; and
R11 is alkyl, cycloalkyl or -Z-X-R9.
11. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to claim 10, wherein R6 is selected from the group consisting of
12. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to anyone of claims 10 to 11, having the following formula:
13. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, said compound having the general structure shown in Formula II or Formula Ila:
(H a) wherein :
W is C or N, and preferably is C; R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or —C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, each moiety being independently selected from the group consisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl;
Y is independently selected from CR4 and N, and preferably is CR4;
R4 is H, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy or acetyl, and pref- erably is H;
R6 is heterocyclyl or heterocyclylalkyl , wherein the heterocyclyl and heterocyclylalkyl can be unsubstituted or substituted with one or more ring system substituents which can be the same or different ;
R7 is one or more substituents independently selected from the group consisting of H, halogen, alkyl, haloalkyl, alkoxy, -C (0)-alkyl, -C (0)-haloalkyl, -NH2, -NH-alkyl and -N (alkyl)2; and
R8 is-C (0)-alkyl, -C (0)0-alkyl, -C (0)NH-alkyl, -C (0)- cycloalkyl, -C (0)O-cycloalkyl, -C(0)NH-cycloalkyl, -C (0)- aryl, -C (0)0-aryl, -C (0)NH-aryl, -C (0)-heteroaryl, -0(0)0- heteroaryl, -C (0)NH-heteroaryl, aryl substituted with R10, heteroaryl substituted with R10, -S(02)-R11 or wherein Z is - (CH2)n-, -0-(CH2)n-, -NH-(CH2)n-, -(CH2)P-L-(CH2)q-,
-0- (CH2)P-L- (CH2)q- or -NH-(CH2)p-L-(CH2)q-, n is an integer from 1 to 6; p and q are integers independently selected from 0 to 6;
L is a linking group selected from the group consisting of heteroaryl, aryl, heterocyclyl and cycloalkyl;
X is 0, S, NH, CH2, S (0) or C (0), and preferably is 0, S or NH;
R9 is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group con- sisting of H, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl and trialkylsilyl;
R10 is aryloxy or arylalkyl or optionally R10 represents two substituents linked to each other to form together with the aryl or heteroaryl a polycyclic ring system, wherein preferably the polycyclic ring system is a naph- thalene or fluorene; and
R11 is alkyl, cycloalkyl or -Z-X-R9.
14. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use in a method for the treatment of a disease, disorder or condition caused by an RNA virus, said compound having the general structure shown in Formula III: wherein:
W is N;
R1 is H, alkyl, cycloalkyl, heterocyclyl, -C (0)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or -C(0)-alkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, each moiety being independently selected from the group consisting of -OC (0)-alkyl, -OC (0)0-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the -C (0)-0-R1-group is joined to the -NH- group or -X-group shown in Formula (III) to form together with the W-containing aromatic ring shown in Formula (III) a hetero ring system;
R2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, hydroxyalkyl and -NO2, wherein each of said alkyl, alkenyl, alkynyl, aryl, alkoxy, cycloalkyl, halocycloalkyl, heterocyclyl and aryloxy can be unsubstituted or optionally substituted with one or more moieties which can be the same or differ- ent, wherein each moiety is preferably independently se- lected from the group consisting of hydroxyl, halogen, al- kyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl substituted with cycloalkyl, aryl substi- tuted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -0- arylalkyl, aryl substituted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substituted with arylalkyl, or optionally R2 represents two substituents which are joined to form together with the aromatic ring shown in Formula III a substituted or unsubstituted ring or hetero ring system, or optionally at least one of R2 is joined to the -NH- group or -X-group shown in Formula (III) to form together with the W-containing aromatic ring shown in Formula (III) a hetero ring system;
X is CH2, 0 or NH, and preferably is NH; and
R3 is one or more substituents independently selected from the group consisting of H, alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl, arylalkyl, heteroalkyl, heteroarylalkyl, amido, carbamoyl, wherein each of said alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocyclyl, alkoxy, aryl, arylalkyl, heteroalkyl, heteroarylalkyl, amido, and carbamoyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, wherein each moiety is preferably independently selected from the group consisting of hydroxyl, halogen, alkyl, haloalkyl, aryl, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl, aryl substituted with haloaklkyl, aryl sub- stituted with cycloalkyl, aryl substituted with arylalkyl, aryl substituted with alkoxy, aryl substituted with aryloxy, aryl substituted with -O-arylalkyl, aryl substi- tuted with aryl, aryloxy, aryloxy substituted with alkyl, aryloxy substituted with cycloalkyl and aryloxy substitut- ed with arylalkyl; or optionally R3 represents two substituents which are joined to form together with the naphthyl ring system shown in Formula III a substituted or unsubstituted ring or hetero ring system.
15. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, for use according to anyone of claims 1 to 8, 10 to 12 and 14, wherein the RNA virus is selected form the group consisting of bunya vi- ruses including Toscana virus (TOSV), hazara virus (HAZV), tahyna virus (TAHV), rift valley fever virus (RVFV), Lassa virus (LSAV), Punta Toro phlebovirus (PTV) and Crimean- Congo hemorrhagic fever orthonairovirus (CCHFV); flavi vi- ruses including yellow fever virus (YFV), dengue virus (DENV), tick-borne encephalitis virus (TBEV), zika virus (ZIKV) and Hepatitis C virus (HCV); toga viruses including Venezuelan equine encephalitis virus (VEEV), Sindbis virus (SINV) and Chikungunya virus (CHIKV); mononegaviruses in- cluding Ebola virus (EBOV), Marburg virus (MARV), Human parainfluenza virus 3 (HPIV-3), Nipah virus (NiV) and Ve- sicular stomatitis virus (VSV); picorna viruses including coxsackievirus (CV); nidoviruses including corona viruses such as Severe acute respiratory syndrome-related corona- virus (SARS-CoV), Severe acute respiratory syndrome- related coronavirus 2 (SARS-CoV-2) and Middle-East respir- atory syndrome-related coronavirus (MERS-CoV); influenza viruses and reoviruses including reovirus type 1 (Reo-1).
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