DHODH INHIBITORS AND THEIR USE AS ANTIVIRAL AGENTS

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 Formula (I).

##STR00001##

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: ##STR00085## wherein: Z is C or N, and preferably is C; R.sup.1 is H, alkyl, cycloalkyl, heterocyclyl, —C(O)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or —C(O)-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 consisting of —OC(O)-alkyl, —OC(O)O-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the —C(O)—O—R.sup.1-group is joined to the —NH—R.sup.3-group to form together with the aromatic ring shown in Formula (I) a hetero ring system; R.sup.2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, hydroxyalkyl and —NO.sub.2, wherein each of said alkyl, alkenyl, alkynyl, aryl, alkoxy and aryloxy 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 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, or optionally R.sup.2 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 R.sup.2 is joined to the —NH—R.sup.3-group to form together with the aromatic ring shown in Formula (I) a hetero ring system; R.sup.3 is —C(O)-alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —C(O)-cycloalkyl, —C(O)O-cycloalkyl, —C(O)NH-cycloalkyl, —C(O)-aryl, —C(O)O-aryl, —C(O)NH-aryl, —C(O)-heteroaryl, —C(O)O— heteroaryl, —C(O)NH-heteroaryl, aryl substituted with R.sup.5, heteroaryl substituted with R.sup.5, —S(O.sub.2)—R.sup.9 or ##STR00086## wherein W is —(CH.sub.2).sub.n—, —O—(CH.sub.2).sub.n—, —NH—(CH.sub.2).sub.n—, —(CH.sub.2).sub.p-L-(CH.sub.2).sub.q—, —O—(CH.sub.2).sub.p-L-(CH.sub.2).sub.q— or —NH—(CH.sub.2).sub.p-L-(CH.sub.2).sub.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 O, S, NH, CH.sub.2, S(O) or C(O), wherein X preferably is O or S or NH or CH.sub.2; R.sup.4 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, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl and trialkylsilyl; R.sup.5 is aryloxy or arylalkyl or optionally R.sup.5 represents two substituents linked to each other to form together with the aryl or heteroaryl a polycyclic ring system; and R.sup.9 is alkyl, cycloalkyl or —W—X—R.sup.4.

2. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.1 is selected from the group consisting of H, ##STR00087## wherein R.sup.1 is preferably selected from the group consisting of H, ##STR00088## and more preferably is H.

3. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.1 is joined to the —NH—R.sup.3-group to form together with the aromatic ring shown in Formula (I) a hetero ring system, wherein said hetero ring system preferably comprises an oxazine or quinazolinone moiety so that the compound is represented by ##STR00089## with W preferably being —(CH.sub.2).sub.n—.

4. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.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, aryl, halogen, haloaryl, alkylaryl, arylalkyl, cycloalkyl, aryloxy, alkoxy substituted with aryl, alkyl substituted with heterocyclyl.

5. Compound according to claim 4, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.2 is ##STR00090## wherein R.sup.6 is H; halogen, preferably F; or aryl, preferably phenyl; R.sup.7 is H; halogen, preferably F; alkyl, preferably methyl; or aryl, preferably phenyl; and R.sup.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.

6. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.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 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.

7. Compound according to claim 6, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.2 is alkynyl, preferably ethynyl, which is substituted with a moiety selected from the group consisting of phenyl; phenyl substituted with 4-haloalkyl like 4-CF.sub.3; phenyl substituted with 4-alkyl like 4-C.sub.4H.sub.9 or 4-C.sub.6H.sub.13; phenyl substituted with 4-alkoxy like 4-ethoxy or 4-pentoxy; phenyl substituted 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 substituted with 2-alkyl, like 2-sec-butyl, 2-cycloalkyl, like 2-cyclohexyl, or 2-arylalkyl, like 2-benzyl.

8. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.2 is H; alkyl, preferably 5-alkyl like 5-methyl or 5-tBu; halogen, 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.sub.3; NO.sub.2, preferably 5-NO.sub.2; or aryl, preferably phenyl or biphenyl like 5-phenyl or 5-biphenyl.

9. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.2 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, wherein said hetero ring system is ##STR00091## so that the compound is preferably represented by ##STR00092##

10. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein at least one of R.sup.2 is joined to the —NH—R.sup.3-group to form together with the aromatic ring shown in Formula (I) a hetero ring system, wherein said hetero ring system preferably comprises a benzimidazole moiety, so that the compound is represented by ##STR00093## with R being e.g. alkyl.

11. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein R.sup.3 is (i) —C(O)-alkyl, —C(O)—O-alkyl or —C(O)—NH-alkyl, and preferably —C(O)-alkyl, with alkyl being methyl, ethyl or isopropyl, preferably ethyl; (ii) aryl, preferably phenyl, substituted with R.sup.5, with R.sup.5 being benzyl or phenoxy; ##STR00094## with W preferably being —(CH.sub.2).sub.n—, —O—(CH.sub.2).sub.n— or —NH—(CH.sub.2).sub.n—, and more preferably being —(CH.sub.2).sub.n—, and n being 1 to 6, preferably 1 to 3, more preferably 1; X being O or S or CH.sub.2 or SO or CO, and preferably O or S or CH.sub.2, and more preferably O; and R.sup.4 preferably being phenyl substituted with 2-sec-butyl, 4-sec-butyl, 2-tert-amyl, 2-tert-butyl, 4-tert-butyl, 2-tert-butyl-4-methyl, 2,6-di-tert-butyl-4-methyl, 2-methyl, 2,6-dimethyl, 3,5-dimethyl, 2,4-dimethyl, 2,3,5-trimethyl, 2,4,6-trimethyl, 2-isopropyl, 2-methyl-5-isopropyl, 5-methyl-2-isopropyl, 2,6-di-isopropyl, 2-ethyl, 2-propyl, 2-ethoxy, 2-cyclohexyl, 2-cyclopentyl, 2-adamantanyl-4-methyl, 2-benzyl, 2-benzyl-4-chloro, 2-phenyl, 3-phenyl, 4-phenyl, 1-naphthyl, 2-naphthyl, 4-phenoxy, 2,6-dichloro, 2-iodo or 2-bromo-4-methyl; ##STR00095## with W preferably being —(CH.sub.2).sub.p-L-(CH.sub.2).sub.q—, —O—(CH.sub.2).sub.p-L-(CH.sub.2).sub.q— or —NH—(CH.sub.2).sub.p-L-(CH.sub.2).sub.q—, with the linking group L preferably being heteroaryl and more preferably 1,4-triazole or 1,5-triazole, and p and q being 0 to 6, preferably 0 to 4, and more preferably 1 to 4, such as 1 to 2; X being O or S or CH.sub.2, and preferably O; and R.sup.4 preferably being phenyl substituted with 2-sec-butyl, 4-sec-butyl, 2-tert-amyl, 2-tert-butyl, 4-tert-butyl, 2-tert-butyl-4-methyl, 2,6-di-tert-butyl-4-methyl, 2-methyl, 2,6-dimethyl, 3,5-dimethyl, 2,4-dimethyl, 2,3,5-trimethyl, 2,4,6-trimethyl, 2-isopropyl, 2-methyl-5-isopropyl, 5-methyl-2-isopropyl, 2,6-di-isopropyl, 2-ethyl, 2-propyl, 2-ethoxy, 2-cyclohexyl, 2-cyclopentyl, 2-adamantanyl-4-methyl, 2-benzyl, 2-benzyl-4-chloro, 2-phenyl, 3-phenyl, 4-phenyl, 1-naphthyl, 2-naphthyl, 4-phenoxy, 2,6-dichloro, 2-iodo or 2-bromo-4-methyl; (v) —C(O)-heteroaryl, wherein the heteroaryl can be unsubstituted or substituted and preferably is N-pyrrole, N-indole or N-carbazole; (vi) —C(O)—NH-aryl, wherein the aryl can be unsubstituted or substituted, wherein the aryl preferably is unsubstituted and/or wherein the aryl preferably is phenyl; or (vii) —S(O.sub.2)—R.sup.9 with R.sup.9 being alkyl.

12. Compound according to claim 1, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, wherein the RNA virus is selected form 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 including Ebola virus (EBOV), Marburg virus (MARV), Human parainfluenza virus 3 (HPIV-3), Nipah virus (NiV) and Vesicular stomatitis virus (VSV); picorna viruses including coxsackievirus (CV); nidoviruses including Severe acute respiratory syndrome-related coronavirus (SARS-CoV), Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and Middle-East respiratory syndrome-related coronavirus (MERS-CoV); and reoviruses including reovirus type 1 (Reo-1).

13. Compound, or a dimer or a pharmaceutically acceptable salt or solvate of said compound or dimer, having the general structure shown in Formula I: ##STR00096## wherein: Z is C or N, and preferably is C; R.sup.1 is H, alkyl, cycloalkyl, heterocyclyl, —C(O)-alkyl or a pharmaceutically acceptable cation, wherein the alkyl or —C(O)-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 consisting of —OC(O)-alkyl, —OC(O)O-alkyl, heterocyclyl, aryl and heteroaryl, or optionally the —C(O)—O—R.sup.1-group is joined to the —NH—R.sup.3-group to form together with the aromatic ring shown in Formula (I) a hetero ring system; R.sup.2 is one or more substituents independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, halogen, haloalkyl, hydroxyalkyl and —NO.sub.2, wherein each of said alkyl, alkenyl, alkynyl, aryl, alkoxy and aryloxy 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 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, or optionally R.sup.2 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 R.sup.2 is joined to the —NH—R.sup.3-group to form together with the aromatic ring shown in Formula (I) a hetero ring system; R.sup.3 is —C(O)-alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —C(O)-cycloalkyl, —C(O)O-cycloalkyl, —C(O)NH-cycloalkyl, —C(O)-aryl, —C(O)O-aryl, —C(O)NH-aryl, —C(O)-heteroaryl, —C(O)O— heteroaryl, —C(O)NH-heteroaryl, aryl substituted with R.sup.5, heteroaryl substituted with R.sup.5, —S(O.sub.2)—R.sup.9 or ##STR00097## wherein W is —(CH.sub.2).sub.n—, —O—(CH.sub.2).sub.n—, —NH—(CH.sub.2).sub.n—, —(CH.sub.2).sub.p-L-(CH.sub.2).sub.q—, —O—(CH.sub.2).sub.p-L-(CH.sub.2).sub.q— or —NH—(CH.sub.2).sub.p-L-(CH.sub.2).sub.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 O, S, NH, CH.sub.2, SO or CO, wherein X preferably is O or S or NH or CH.sub.2; R.sup.4 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, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, arylalkyl, alkylaryl, haloaryl, haloalkylaryl, haloalkyl and trialkylsilyl; R.sup.5 is aryloxy or arylalkyl or optionally R.sup.5 represents two substituents linked to each other to form together with the aryl or heteroaryl a polycyclic ring system; and R.sup.9 is alkyl, cycloalkyl or —W—X—R.sup.4; with the proviso that, when R.sup.3 is —C(O)-alkyl and the alkyl is methyl, then R.sup.2 is not H, halogen, phenyl, biphenyl or 2-Cl-4-CF.sub.3-phenoxy; with the further proviso that, when R.sup.3 is —C(O)-alkyl and the alkyl is ethyl or cyclopropyl, then R.sup.2 is not alkyl substituted with a phenyl ring which is unsubstituted at the 4-position, alkenyl substituted with a phenyl ring which is unsubstituted at the 4-position, alkynyl substituted with a phenyl ring which is unsubstituted at the 4-position, alkyoxy substituted with a phenyl ring which is unsubstituted at the 4-position, or aryloxy wherein the aryl of the aryloxy is a phenyl ring which is unsubstituted at the 4-position; with the further proviso that, when R.sup.3 is —C(O)-alkyl and the alkyl is substituted with halogen, then R.sup.2 is not alkyl or halogen; with the further proviso that, when R.sup.3 is aryl substituted with R.sup.5 and R.sup.5 is aryloxy, then the aryloxy is not phenoxy with the further proviso that, when R.sup.3 is —C(O)NH-aryl, then the aryl is not substituted with aryl or halogen.

14. Compound, or pharmaceutically acceptable salts or solvates of said compound, according to claim 13 having the following structure: ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102##

Description

EXAMPLES

[0157] In general, the compounds of Formula I, wherein R.sup.3 is

##STR00033##

can be prepared through the general routes described below in Scheme 1.

##STR00034##

[0158] For example, R.sup.2 can be H, 5-Me, 5-Br, 5-F, 5-OMe, 5-CF.sub.3, 5-NO.sub.2, 5-tBu, 4-F, 4-OMe, or annelated phenyl. X can be O, S, or NH. n can be 1 to 6. Moreover, R can be H or halogen or an aliphatic or aromatic moiety. For example, R can be selected from the group consisting of 2-sec-butyl, 4-sec-butyl, 2-tert-amyl, 2-tert-butyl, 4-tert-butyl, 2-tert-butyl-4-methyl, 2,6-di-tert-butyl-4-methyl, 2-methyl, 2,6-dimethyl, 3,5-dimethyl, 2,4-dimethyl, 2,3,5-trimethyl, 2,4,6-trimethyl, 2-isopropyl, 2-methyl-5-isopropyl, 5-methyl-2-isopropyl, 2,6-di-isopropyl, 2-ethyl, 2-propyl, 2-ethoxy, 2-cyclohexyl, 2-cyclopentyl, 2-adamantanyl-4-methyl, 2-benzyl, 2-benzyl-4-chloro, 2-phenyl, 3-phenyl, 4-phenyl, 1-naphthyl, 2-naphthyl, 4-phenoxy, 2,6-dichloro, 2-iodo, and 2-bromo-4-methyl.

[0159] Further derivatives of more lipophilic compounds of Formula I were synthesized via palladium catalyzed Suzuki cross coupling reaction according to Scheme 2.

##STR00035##

[0160] The structures were further modified by installing substituted phenyl residues at the 5 position of the anthranilic acid or in the 4′-position of the phenolic moiety. For example, R.sup.2 can be Ph, 3,5-Cl-Ph, 3-CF.sub.3-Ph, biphenyl, wherein R is ═H. Furthermore, R can be Br or 3-CF.sub.3-Ph, wherein R.sup.2 is H.

[0161] Anthranilic acids bearing a 1,4-triazole moiety in the linking unit between the anthranilic acid core structure and the phenol ether were synthesized using copper catalyzed click reaction according to Scheme 3.

##STR00036##

[0162] Compounds of Formula I, wherein R.sup.3 is aryl, were prepared through the general routes described below in Scheme 4.

##STR00037##

[0163] Unsubstituted and 5-OMe-substituted (R.sup.2) fenamic acid compounds with various aromatic residues (R.sup.3) were synthesized in that manner, such as R.sup.3=3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzylphenyl, 2-fluorenyl, [1,1′-biphenyl]-3-yl, 4-bromophenyl and [1,1′-biphenyl]-4-yl via 4-bromophenyl.

[0164] In order to mask the negative charge of the carboxylate under physiological conditions, prodrug moieties can be installed at the R.sup.1 position to enable penetration through the cell membrane and allow the release of the active carboxylic acid inside the cell. The synthesis was carried out directly starting from the synthesized anthranilic acids by treatment with the appropriate alkyl halides under basic conditions or by a nucleophilic opening of in situ formed 1,3-oxazine derivatives with the respective alcohol. The synthetic routes towards these prodrugs are outlined in Scheme 5.

##STR00038##

[0165] R.sup.2 substituted anthranilic acids bearing different amides were synthesized using different acid chlorides followed by palladium catalyzed Suzuki cross coupling reaction according to Scheme 6.

##STR00039##

[0166] For instance, R can be methyl, ethyl, isopropyl, cyclopropyl, n-butyl.

[0167] Various compounds, wherein R.sup.2 is phenyl or substituted phenyl, were synthesized according to Scheme 7.

##STR00040##

[0168] Suitable combinations of R.sup.6, R.sup.7 and R.sup.8 are given above in the general description.

[0169] 4-Pentynylbenzene ethynyl anthranilic acids bearing different amides were synthesized using different acid chlorides followed by palladium and copper catalyzed Sonogashira cross coupling reaction according to Scheme 8.

##STR00041##

[0170] R was selected from methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, and iso-valeryl.

[0171] Furthermore, various 5-ethynyl anthranilic acids were synthesized according to Scheme 9.

##STR00042##

[0172] Examples of suitable substituents R are given above in the general description.

[0173] Dimers of the compounds of the invention were synthesized via Suzuki-Miyaura cross coupling according to Scheme 10. These compounds were synthesized in analogy to Redoxal, a known DHODH inhibitor.

##STR00043##

[0174] Compounds with R.sup.1 being joined to the —NH—R.sup.3-group to form together with the aromatic ring of formula (I) a hetero ring system, such as a hetero ring system comprising an oxazine moiety, were synthesized according to Scheme 11.

##STR00044##

[0175] For example, R.sup.2 can be H, methyl, Br, F, —CF.sub.3, —OMe.

[0176] Compounds with R.sup.1 being joined to the —NH—R.sup.3-group to form together with the aromatic ring of formula (I) a hetero ring system, such as a hetero ring system comprising a quinazoline moiety, were synthesized according to Scheme 12.

##STR00045##

[0177] Anthranilic acids bearing a 1,5-triazole moiety in the linking unit between the anthranilic acid core structure and the phenol ether were synthesized according to Scheme 13.

##STR00046##

[0178] Compounds with one R.sup.2 being linked to the —NH—R.sup.3-group were synthesized according to Scheme 14, wherein R can be ethyl, R′ is preferably —C.sub.5H.sub.11, R.sup.6 is H, R.sup.7 is H and R.sup.8 is phenyl:

##STR00047##

Example 1

[0179] Preparation of

##STR00048##

[0180] 4.45 g (26.9 mmol) methyl-2-amino-5-methylbenzoate and 18.6 g (135 mmol) potassium carbonate were suspended in 200 mL acetone. 5.36 mL (67.4 mmol) 2-chloracetylchloride were added dropwise and the reaction mixture was stirred at room temperature for 2 hours. After addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate the phases were separated. The organic phase was washed with demineralised water and brine, dried over sodium sulfate, filtrated and the solvent was evaporated. The product precipitated by addition of petroleum ether 50-70 and was filtrated.

[0181] Yield: 6.08 g (21.1 mmol, 93%) of colorless crystals (methyl-2-(2-chloroacetamido)-5-methyl-benzoate).

[0182] To a suspension of 4.09 g (22.2 mmol) 2-benzylphenol and 14.5 g (44.4 mmol) caesium carbonate in 120 mL acetonitrile 4.88 g (20.2 mmol) methyl-2-(2-chloroacetamido)-5-methyl-benzoate were added. The reaction mixture was stirred for 17 hours at room temperature. Subsequently the solvent was evaporated and the crude product was purified by column chromatography (di-chloromethane/petroleum ether 50-70). The obtained methyl ester was dissolved in 100 mL THE and 40 mL of an aqueous sodium hydroxide solution (1 M) were added. After stirring 15 hours at room temperature the reaction mixture was adjusted to pH 1 with hydrochloric acid (1 M) and diluted with dichloromethane. After phase separation the aqueous phase was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by crystallization from dichloromethane/petroleum ether 50-70.

[0183] Yield over two steps: 7.14 g (19.0 mmol, 94%) of colorless crystals.

[0184] R.sub.f(CH.sub.2Cl.sub.2/CH.sub.3OH 19:1 v/v): 0.50.

[0185] .sup.1H-NMR: δ [ppm] (500 MHz, DMSO-d.sub.6): 13.62 (s, 1H, COOH), 11.85 (s, 1H, CONH), 8.58 (d, .sup.3J.sub.H,H=8.5 Hz, 1H, H-3), 7.84 (d, .sup.4J.sub.H,H=1.9 Hz, 1H, H-6), 7.45 (dd, .sup.3J.sub.H,H=8.6 Hz, .sup.4J.sub.H,H=2.2 Hz, 1H, H-4), 7.26-7.22 (m, 4H, H-2″, H-3″), 7.22-7.10 (m, 3H, H-3′, H-5′, H-4″), 7.03 (dd, .sup.3J.sub.H,H=7.0 Hz, 1H, H-6′), 6.94 (m, 1H, H-4′), 4.69 (s, 1H, OCH.sub.2), 4.18 (s, 2H, benzyl-CH.sub.2), 2.31 (s, 3H, CH.sub.3).

##STR00049##

[0186] .sup.13C-NMR: δ [ppm] (126 MHz, DMSO-d.sub.6): =169.3 (COOH), 166.9 (CONH), 154.8 (C-1′), 140.8 (C-1″), 137.8 (C-2), 134.7 (C-4), 132.3 (C-5), 131.3 (C-6), 130.3 (C-3′), 129.9 (C-2′), 128.8 (2×C-2″/C-3″), 128.2 (2×C-2″/C-3″), 127.5 (C-5′), 125.7 (C4″), 121.6 (C-4′), 116.3 (C-1), 112.3 (C-6′), 67.8 (OCH.sub.2), 34.9 (benzyl-CH.sub.2), 20.2 (CH.sub.3).

[0187] IR: {tilde over (ν)} [cm.sup.−1]: 3599, 3228, 3023, 1665, 1587, 1518, 1490, 1450, 1432, 1301, 1271, 1226, 1108, 1067, 1018, 861, 798, 749, 699, 666, 617, 531.

[0188] HRMS (ESI.sup.+) m/z=calcd for C.sub.23H.sub.22NO.sub.4: 376.1543 [M+H].sup.+, found: 376.1550.

Example 2

[0189] Preparation of

##STR00050##

[0190] 1.1 mL (1.1 g, 7.0 mmol) 2-Isopropylbenzenethiol, 1.94 g (14.0 mmol) potassium carbonate and 1.2 mL (2.2 g, 11 mmol) ethyl iodoacetate were suspended in 20 mL DMF. The reaction was stirred at 100° C. for 4 d and then diluted with water and di-chloromethane. After separation of the phases the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and the solvent was evaporated. To a solution of 1.67 g (7.00 mmol) ethyl 2-(2-isopropylphenylthio)acetate in 28 mL THE 21 mL of an aqueous sodium hydroxide solution (1 M) was added. The reaction was stirred at room temperature for 18 h, and then adjusted to pH 1 with hydrochloric acid (1 M). The reaction was diluted with dichloromethane and the phases were separated. After extraction of the aqueous phase with di-chloromethane twice the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by column chromatography (di-chloromethane/methanol).

[0191] Yield: 1.01 g (4.80 mmol, 69%) of a colorless solid.

[0192] 205 mg (0.975 mmol) 2-(2-Isopropylphenylthio)acetic acid, 261 mg (1.27 mmol) dicyclohexylcarbodiimide and 157 mg (1.36 mmol) N-hydroxysuccinimide in 30 mL acetonitrile were stirred at room temperature for 24 h. The suspension was filtrated and the solvent was evaporated. The crude product was purified by column chromatography (dichloromethane). 98 mg (0.32 mmol) N-succinimide 2-(2-isopropylphenylthio)acetate and 37 mg (0.27 mmol) anthranilic acid were dissolved in 5 mL acetonitrile and 0.05 mL (0.04 g, 0.3 mmol) diisopropylethylamine were added. The reaction was stirred at room temperature for 18 h and then the solvent was evaporated. The crude product was purified by column chromatography (dichloromethane/methanol) and by crystallization from dichloromethane/petroleum ether 50-70.

[0193] Yield: 69 mg (0.21 mmol, 79%) of a colorless solid.

[0194] R.sub.f (CH.sub.2Cl.sub.2/CH.sub.3OH 19:1 v/v): 0.37.

[0195] MP: 135° C.

[0196] .sup.1H-NMR: δ [ppm] (400 MHz, DMSO-d.sub.6): 13.61 (brs, 1H, COOH), 11.75 (s, 1H, NH), 8.51 (dd, .sup.3J.sub.H,H=8.5 Hz, .sup.4J.sub.H,H=0.9 Hz, 1H, H-3), 7.96 (dd, .sup.3J.sub.H,H=7.8 Hz, .sup.4J.sub.H,H=1.5 Hz, 1H, H-6), 7.59-7.53 (m, 1H, H-4), 7.35-7.32 (m, 1H, H-3′), 7.28 (dd, .sup.3J.sub.H,H=7.5 Hz, .sup.4J.sub.H,H=1.8 Hz, 1H, H-6′), 7.21-7.11 (m, 3H, H-5, H-4′, H-5′), 3.95 (s, 2H, CH.sub.2), 3.45 (sept, .sup.3J.sub.H,H=6.8 Hz, 1H, CH), 1.17 (d, .sup.3J.sub.H,H=6.8 Hz, 6H, CH(CH.sub.3).sub.2).

##STR00051##

[0197] .sup.13C-NMR: δ [ppm] (101 MHz, DMSO-d.sub.6) 169.2 (COOH), 167.5 (CONH), 147.2 (C-2′), 140.4 (C-2), 134.0 (C-4), 132.8 (C-1′), 131.1 (C-6), 128.0 (C-3′), 126.7, 126.6 (C-4′, C-5′), 125.5 (C-6′), 122.9 (C-5), 120.0 (C-3), 116.5 (C-1), 38.4 (CH.sub.2), 29.7 (CH), 23.1 (CH(CH.sub.3).sub.2).

[0198] IR: {tilde over (ν)} [cm.sup.−1]: 2960, 2925, 2867, 1684, 1605, 1586, 1523, 1471, 1450, 1401, 1298, 1258, 1229, 1163, 1145, 1083, 1051, 1017, 796, 755, 699, 648.

[0199] HRMS (ESI.sup.+) m/z=calcd for C.sub.18H.sub.20NO.sub.3S: 330.1159 [M+H].sup.+, found: 330.1168.

Example 3

[0200] Preparation of

##STR00052##

[0201] 0.50 mL (0.45 g, 3.0 mmol) (rac)-2-sec-butylphenol, 0.46 g (3.4 mmol) potassium carbonate and 0.57 mL (0.77 g, 3.3 mmol) ethyl 4-bromobutyrate were suspended in 5 mL DMF. The reaction was stirred at 65° C. for 2 d and then diluted with water and dichloromethane. After separation of the phases the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by column chromatography (petroleum ether 50-70/dichloromethane). Yield: 751 mg (2.84 mmol, 95%) of a yellow oil (ethyl 4-(rac)-(2-sec-butylphenoxy)butyrate).

[0202] To a solution of 111 mg (0.420 mmol) ethyl 4-(rac)-(2-sec-butylphenoxy)butyrate in 1.8 mL THE 1.3 mL of an aqueous sodium hydroxide solution was added. The reaction was stirred at room temperature for 16 h, and then adjusted to pH 1 with hydrochloric acid (1 M). The reaction was diluted with dichloro-methane and the phases were separated. After extraction of the aqueous phase with dichloromethane twice the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by crystallization from dichloromethane/petroleum ether 50-70. Yield: 95 mg (0.40 mmol, 96%) of colorless crystals (4-(rac)-(2-sec-butylphenoxy)butyric acid).

[0203] To a solution of 190 mg (0.804 mmol) 4-(rac)-(2-sec-butylphenoxy)butyric acid in 5 mL dichloromethane 0.10 mL (0.15 g, 1.2 mmol) oxalyl chloride and a catalytic amount of DMF were added at 0° C. The reaction was heated at reflux for 3 h. After cooling to room temperature the solvent was evaporated. The obtained acid chloride was dissolved in dichloro-methane and added dropwise to a solution of 0.10 mL (0.12 g, 0.80 mmol) methyl anthranilate and 0.12 mL (0.088 g, 0.87 mmol) triethylamine in 5 mL dichloromethane. The reaction was stirred at room temperature for 2 h and then a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the mixture. After separation of the phases the aqueous phase was extracted with dichlormethane twice, the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by column chromatography (petroleum ether 50-70/dichloromethane). Yield: 292 mg (0.790 mmol, 98%) of a colorless sirup (methyl 2-(4-(rac)-(2-sec-butyl-phenoxy)butanamido)benzoate).

[0204] To a solution of 243 mg (0.658 mmol) methyl 2-(4-(rac)-(2-sec-butylphenoxy)butanamido)benzoate in 2.6 mL THE 2.0 mL of an aqueous sodium hydroxide solution was added. The reaction was stirred at room temperature for 18 h, and then adjusted to pH 1 with hydrochloric acid (1 M). The reaction was diluted with dichloromethane and the phases were separated. After extraction of the aqueous phase with dichloromethane twice the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by crystallization from dichloromethane/petroleum ether 50-70. Yield: 171 mg (0.482 mmol, 73%) of colorless crystals (title compound of Example 1).

[0205] R.sub.f (CH.sub.2Cl.sub.2/CH.sub.3OH 9:1 v/v): 0.25.

[0206] MP: 133° C.

[0207] .sup.1H-NMR: δ [ppm] (400 MHz, DMSO-d.sub.6): 13.60 (brs, 1H, COOH), 11.27 (s, 1H, NH), 8.53 (dd, .sup.3J.sub.H,H=8.3 Hz, .sup.4J.sub.H,H=0.6 Hz, 1H, H-3), 7.98 (dd, .sup.3J.sub.H,H=7.9 Hz, .sup.4J.sub.H,H=1.6 Hz, 1H, H-6), 7.61-7.55 (m, 1H, H-4), 7.16-7.08 (m, 3H, H-5, H-3′, H-5′), 6.92 (dd, .sup.3J.sub.H,H=8.8 Hz, 4J.sub.H,H=1.0 Hz, 1H, H-6′), 6.90-6.84 (m, 1H, H-4′), 4.02 (t, .sup.3J.sub.H,H=6.1 Hz, 2H, H-9), 3.02 (sext, .sup.3J.sub.H,H=7.0 Hz, 1H, CH), 2.60 (t, .sup.3J.sub.H,H=7.5 Hz, 2H, H-7), 2.09 (quin, .sup.3J.sub.H,H=6.6 Hz, 2H, H-8), 1.60-1.40 (m, 2H, CH.sub.2), 1.09 (d, .sup.3J.sub.H,H=7.0 Hz, 3H, CHCH.sub.3), 0.73 (t, .sup.3J.sub.H,H=7.4 Hz, 3H, CH.sub.2CH.sub.3).

##STR00053##

[0208] .sup.13C-NMR: δ [ppm] (101 MHz, DMSO-d.sub.6) 170.7 (CONH), 169.6 (COOH), 155.9 (C-1′), 141.0 (C-2), 134.9 (C-2′), 134.0 (C-4), 131.1 (C-6), 126.6 (C-3′), 126.4 (C-5′), 122.5 (C-5), 120.4 (C-4′), 119.8 (C-3), 116.4 (C-1), 111.6 (C-6′), 66.8 (C-9), 34.2 (C-7), 33.0 (CH), 29.3 (CH.sub.2), 24.6 (C-8), 20.4 (CHCH.sub.3), 12.0 (CH.sub.2CH.sub.3).

[0209] IR: {tilde over (ν)} [cm.sup.−1]: 2959, 2925, 2871, 1689, 1606, 1587, 1527, 1492, 1450, 1394, 1379, 1292, 1235, 1163, 1083, 1052, 974, 846, 754, 651, 524.

[0210] HRMS (ESI.sup.+) m/z=calcd for C.sub.21H.sub.26NO.sub.4: 356.1857 [M+H].sup.+, found: 356.1859.

Example 4

[0211] Preparation of

##STR00054##

[0212] 500 mg (2.16 mmol) 2-bromo-5-methoxybenzoic acid and 802 mg (4.33 mmol) 4-phenoxyaniline were dissolved in 5 mL of DMF. 150 mg (1.08 mmol) Potassium carbonate and 14 mg (0.22 mmol) copper powder were added and the reaction was heated to 150° C. for 2 h. The reaction mixture was allowed to reach room temperature and was then added dropwise to 7 mL hydrochloric acid (6 M). The resulting precipitate was collected by filtration with suction and washed with water. The crude product was purified by column chromatography (dichloromethane/methanol). Yield: 144 mg (0.430 mmol, 20%) of a yellow solid.

[0213] R.sub.f (CH.sub.2Cl.sub.2/CH.sub.3OH 9:1 v/v): 0.53.

[0214] MP: 168° C.

[0215] .sup.1H-NMR: δ [ppm] (400 MHz, CDCl.sub.3): 8.88 (s, 1H, NH), 7.53 (d, .sup.4J.sub.H,H=3.0 Hz, 1H, H-6), 7.37-7.31 (m, 2H, H-2′), 7.22-7.17 (m, 2H, H-3″), 7.14 (d, 3J.sub.H,H=9.1 Hz, 1H, H-3), 7.12-7.07 (m, 1H, H-4″), 7.06-6.99 (m, 5H, H-4, H-3′, H-2″), 3.81 (s, 3H, OCH.sub.3).

##STR00055##

[0216] .sup.13C-NMR: δ [ppm] (101 MHz, CDCl.sub.3): 173.1 (COOH), 157.8 (C-4′), 153.3 (C-1″), 151.1(C-5), 144.1 (C-2), 136.8 (C-1′), 129.9 (C-2′), 124.5 (C-4), 124.4 (C-3″), 123.2 (C-4″), 120.3 (C-2″), 118.5 (C-3′), 116.4 (C-3), 114.2 (C-6), 110.8 (C-1), 56.0 (OCH.sub.3).

[0217] IR: {tilde over (ν)} [cm.sup.−1]: 3345, 3041, 2914, 1730, 1644, 1594, 1584, 1516, 1487, 1462, 1441, 1342, 1258, 1217, 1167, 1148, 1070, 1043, 860, 747.

[0218] HRMS (ESI.sup.+) m/z=calcd for C.sub.20H.sub.18NO.sub.4: 336.1231 [M+H].sup.+, found: 336.1232.

Example 5

[0219] Preparation of

##STR00056##

[0220] To a solution of 2.02 g (10.0 mmol) 2-bromobenzoic acid in 80 mL methanol were added 2 mL sulphuric acid (conc.) at 0° C. The reaction was heated at reflux for 18 h. After cooling to room temperature the mixture was poured onto ice, neutralized with a saturated aqueous solution of sodium carbonate and extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated.

[0221] Yield: 2.06 g (9.58 mmol, 95%) of a colorless liquid.

[0222] 200 mg (0.930 mmol) Methyl 2-bromobenzoate and 290 mg (1.58 mmol) 4-benzylaniline were dissolved in 20 mL DME and 128 mg (0.140 mmol) Pd.sub.2(dba).sub.3, 232 mg (0.372 mmol) rac-BINAP and 334 mg (2.42 mmol) potassium carbonate were added. The reaction was heated at reflux for 16 h. After cooling to room temperature the suspension was diluted with dichloromethane and filtrated. The obtained filtrate was then diluted with water. After separation of the phases the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by column chromatography (petroleum ether 50-70/ethyl acetate).

[0223] Yield: 265 mg (0.836 mmol, 90%) of a pale yellow solid.

[0224] To a solution of 215 mg (0.677 mmol) methyl 2-(4-benzylphenylamino)benzoate in 13 mL THE 2.5 mL of an aqueous sodium hydroxide solution (1 M) was added. The reaction was heated at reflux for 48 h, and then adjusted to pH 1 with hydrochloric acid (1 M). The reaction was diluted with dichloro-methane and the phases were separated. After extraction of the aqueous phase with dichloromethane twice the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by crystallization from dichloromethane/petroleum ether 50-70.

[0225] Yield: 190 mg (0.627 mmol, 93%) of colorless crystals.

[0226] R.sub.f (CH.sub.2Cl.sub.2/CH.sub.3OH 19:1 v/v): 0.43.

[0227] MP: 184° C.

[0228] .sup.1H-NMR: δ [ppm] (400 MHz, DMSO-d.sub.6): 13.02 (brs, 1H, COOH), 9.58 (s, 1H, NH), 7.89 (dd, .sup.3J.sub.H,H=8.0 Hz, .sup.4J.sub.H,H=1.6 Hz, 1H, H-6), 7.37-7.13 (m, 11H, H-3, H-4, H-2′, H-3, H-2″, H-3″, H-4″), 6.76-6.71 (m, 1H, H-5), 3.91 (s, 2H, CH.sub.2).

##STR00057##

[0229] .sup.13C-NMR: δ [ppm] (101 MHz, DMSO-d.sub.6): 170.0 (COOH), 147.4 (C-2), 141.4 (C-4′), 138.4 (C-1′), 136.3 (C-1″), 134.2 (C-4), 131.8 (C-6), 129.7 (C-3′), 128.7 (C-3″), 128.4 (C-2′), 125.9 (C-4″), 121.9 (C-2″), 117.1 (C-5), 113.5 (C-3), 112.2 (C-1), 40.5 (CH.sub.2).

[0230] IR: {tilde over (ν)} [cm.sup.−1]: 3331, 3023, 2838, 1651, 1597, 1573, 1513, 1495, 1421, 1322, 1260, 1161, 1148, 1083, 1042, 888, 751.

[0231] HRMS (ESI.sup.+) m/z=calcd for C.sub.20H.sub.18NO.sub.2: 304.1332 [M+H].sup.+, found: 304.1345.

Example 6

[0232] Preparation of

##STR00058##

[0233] 3.49 g (15.0 mmol) methyl-2-amino-5-bromobenzoate and 10.4 g (75.0 mmol) potassium carbonate were suspended in 300 mL acetone. 3.30 mL (37.5 mmol) propionylchloride were added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. After addition of ethyl acetate and a saturated aqueous solution of sodium bicarbonate the phases were separated. The organic phase was washed with demineralised water and brine, dried over sodium sulfate, filtrated and the solvent was evaporated. The product precipitated by addition of petroleum ether 50-70 and was filtrated.

[0234] Yield: 3.91 g (13.6 mmol, 91%) of colorless crystals (methyl-5-bromo-2-propionamidobenzoate).

[0235] 1.2 g (4.0 mmol) methyl-5-bromo-2-propionamidobenzoate, 0.87 g (4.4 mmol) 4-biphenylboronic acid and 0.46 g (0.40 mmol) tetrakis(triphenylphosphine)palladium were dissolved in 2.2 mL ethanol and 10 mL toluene. After addition of 4.0 mL of a 2 M aqueous sodium carbonate solution the reaction mixture was stirred at 100° C. overnight and subsequently diluted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The phases were separated, the organic layer was washed with water and brine, dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by column chromatography (dichloromethane/petroleum ether 50-70).

[0236] To a solution of the obtained methyl ester in 8.0 mL THF 3 mL of an aqueous sodium hydroxide solution (1 M) was added. The reaction was stirred at room temperature overnight, and then adjusted to pH 1 with hydrochloric acid (1 M). The reaction was diluted with dichloromethane and the phases were separated. After extraction of the aqueous phase with dichloro-methane twice the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by crystallization from dichloro-methane/petroleum ether 50-70.

[0237] Yield over two steps: 1.1 g (3.2 mmol, 80%) of colorless crystals.

[0238] R.sub.f (CH.sub.2Cl.sub.2/CH.sub.3OH 19:1 v/v): 0.26.

[0239] .sup.1H-NMR: δ [ppm] (400 MHz, DMSO-d.sub.6): 13.79 (s, 1H, COCH), 11.15 (s, 1H, CONH), 8.63 (d, .sup.3J.sub.H,H=8.8 Hz, 1H, H-5), 8.29 (d, .sup.4J.sub.H,H=2.4 Hz, 1H, H-2), 7.97 (dd, .sup.3J.sub.H,H=8.7 Hz, .sup.4J.sub.H,H=2.4 Hz, 1H, H-6), 7.77 (s, 4H, H-2′, H-3′), 7.75-7.68 (m, 2H, H-2″), 7.53-7.47 (m, 2H, H-3″), 7.43-7.33 (m, 1H, H-4″), 2.44 (q, .sup.3J.sub.H,H=7.5 Hz, 2H, CH.sub.2), 1.15 (t, .sup.3J.sub.H,H=7.5 Hz, 3H, CH.sub.3).

##STR00059##

[0240] .sup.13C-NMR: δ [ppm] (101 MHz, DMSO-d.sub.6): 172.0 (CONH), 169.5 (COOH), 140.3 (C-4), 139.1 (C-1″), 139.1 (C-4′), 137.7 (C-1′), 133.4 (C-1), 132.0 (C-6), 129.0 (C-3″), 128.6 (C-2), 127.6 (C-4″), 127.3 (C-2′/C-3′), 126.8 (C-2′/C-3′), 126.6 (C-2″), 120.5 (C-5), 116.8 (C-3), 30.7 (CH.sub.2), 9.4 (CH.sub.3).

[0241] IR: {tilde over (ν)} [cm.sup.−1]: 2876, 2775, 2593, 1707, 1646, 1586, 1483, 1448, 1318, 1212, 834, 798, 764, 730, 695.

[0242] HRMS (ESI.sup.+) m/z=calcd for C.sub.22H.sub.20NO.sub.3: 346.1438 [M+H].sup.+, found: 346.1443.

Example 7

[0243] Preparation of

##STR00060##

[0244] The compound was synthesized using the procedure following the synthesis of Example 6, with the exception of using 2-fluorobiphenyl-4-boronic acid. 0.30 g (1.0 mmol) methyl-5-bromo-2-propionamidobenzoate, 0.25 g (1.1 mmol) 2-fluorobiphenyl-4-boronic acid and 0.12 g (0.10 mmol) tetrakis(triphenylphosphine)-palladium, 0.55 mL ethanol, 2.2 mL toluene, 1.0 mL of a 2 M aqueous sodium carbonate solution and 2.0 mL of an aqueous sodium hydroxide solution (1 M) were used.

[0245] Yield over two steps: 0.13 g (0.35 mmol, 35%) of colorless crystals.

[0246] R.sub.f (CH.sub.2Cl.sub.2/CH.sub.3OH 19:1 v/v): 0.26.

[0247] .sup.1H-NMR: δ [ppm] (600 MHz, DMSO-d.sub.6): 13.82 (s, 1H, COOH), 11.17 (s, 1H, CONH), 8.63 (d, .sup.3J.sub.H,H=8.7 Hz, 1H, H-5), 8.29 (d, .sup.4J.sub.H,H=2.4 Hz, 1H, H-2), 8.00 (dd, .sup.3J.sub.H,H=8.7 Hz, .sup.4J.sub.H,H=2.4 Hz, 1H, H-6), 7.69-7.62 (m, 1H, H-2′), 7.62-7.56 (m, 4H, H-5′, H-6′, H-2″), 7.50 (t, .sup.3J.sub.H,H=7.7 Hz, 2H, H-3″), 7.45-7.39 (m, 1H, H-4″), 2.44 (q, .sup.3J.sub.H,H=7.5 Hz, 2H, CH.sub.2), 1.14 (t, .sup.3J.sub.H,H=7.5 Hz, 3H, CH.sub.3).

##STR00061##

[0248] .sup.13C-NMR: δ [ppm] (151 MHz, DMSO-d.sub.6): 172.1 (CONH), 169.4 (COOH), 159.5 (d, .sup.1J.sub.C,F=246 Hz, C-3′), 140.7 (C-4), 140.1 (d, .sup.3J.sub.C,F=8.3 Hz, C-1′), 134.7 (C-1″) 132.1 (C-1), 131.2 (d, .sup.3J.sub.C,F=4.0 Hz, C-5′), 128.8 (C-Aryl), 128.7 (C-Aryl), 128.7 (C-Aryl), 128.6 (C-Aryl), 127.9 (C-4″), 127.0 (d, .sup.2J.sub.C,F=13.3 Hz, C-4′), 122.6 (d, .sup.4J.sub.C,F=4.0 Hz, C-6′), 120.4 (C-5), 116.8 (C-3), 113.7 (d, .sup.2J.sub.C,F=23.9 Hz, C-2′), 30.7 (CH.sub.2), 9.3 (CH.sub.3).

[0249] .sup.19F-NMR: δ [ppm] (565 MHz, DMSO-d.sub.6): −117.8 (m, Aryl-F).

[0250] IR: {tilde over (ν)} [cm.sup.−1]: 3321, 1610, 1558, 1488, 1412, 1386, 1192, 1158, 1135, 906, 823, 788, 764, 694, 671.

[0251] HRMS (ESI.sup.+) m/z=calcd for C.sub.22H.sub.19FNO.sub.3: 364.1349 [M+H].sup.+, found: 346.1351.

Example 8

[0252] Preparation of

##STR00062##

[0253] An oven dried microwave vial was charged with 286 mg (1.00 mmol) methyl 5-bromo-2-propionamidobenzoate, 116 mg (0.10 mmol) tetrakis(triphenylphosphine)palladium(0), 38 mg (0.20 mmol) copper(I) iodine and was sealed with a cap. The reaction vessel was evacuated and filled with N.sub.2 followed by 3 mL dry acetonitrile, 1.1 mL of dry triethyl amine and 292 μL (259 mg, 1.50 mmol) 4-ethynyl-pentylbenzene. The reaction was stirred for 1 h at 80° C. (100 Watt), cooled and diluted with dichloro-methane and the solvent was evaporated. The crude product was purified by column chromatography (dichloromethane: 100%). Product containing fraction were pooled and evaporated to dry-ness. Methyl 5-((4-pentylphenyl)ethynyl)-2-propionamidobenzoate was dissolved in 5 mL of THE and treated with 3 mL of an aqueous sodium hydroxide solution (1 M). The reaction was stirred at room temperature for 20 h, and then adjusted to pH 1 with hydrochloric acid (1 M). The reaction was diluted with dichloromethane and the phases were separated. After extraction of the aqueous phase with dichloromethane twice the combined organic layers were dried over sodium sulfate, filtrated and the solvent was evaporated. The crude product was purified by crystallization from dichloromethane/petroleum ether 50-70.

[0254] Yield over two steps: 292 mg (0.80 mmol, 80%) of colorless crystals (5-((4-pentylphenyl)ethynyl)-2-propionamidobenzoic acid).

[0255] .sup.1H-NMR: δ [ppm] (600 MHz, DMSO-d.sub.6): 13.89 (brs, 1H, COOH), 11.22 (s, 1H, NH), 8.57 (d, 3J.sub.H,H=8.7 Hz, 1H, H-3), 8.08 (d, .sup.4J.sub.H,H=2.1 Hz, 1H, H-6), 7.73 (dd, .sup.3J.sub.H,H=8.7 Hz, .sup.4J.sub.H,H=2.2 Hz, 1H, H-4), 7.49-7.43 (m, 2H, H-2′), 7.27-7.21 (m, 2H, H-3′), 2.59 (t, .sup.3J.sub.H,H=8.7 Hz, 2H, H-a), 2.44 (q, .sup.3J.sub.H,H=7.5 Hz, 2H, CH.sub.2), 1.57 (p, .sup.3J.sub.H,H=7.6 Hz, 2H, H-b), 1.35-1.21 (m, 4H, H-c, H-d), 1.13 (t, .sup.3J.sub.H,H=7.5 Hz, 3H, CH.sub.3), 0.86 (t, .sup.3J.sub.H,H=7.1 Hz, 3H, H-e).

##STR00063##

[0256] .sup.13C-NMR: δ [ppm] (151 MHz, DMSO-d.sub.6): 172.1 (CONH), 168.8 (COOH), 143.4 (C-4′), 140.8 (C-2), 136.4 (C-4), 133.9 (C-6), 131.3 (C-2′), 128.7 (C-3′), 120.0 (C-3), 119.4 (C-1′), 116.5 (C-1 or C-5), 116.2 (C-1 or C-5), 89.3 (C-1″), 87.7 (C-2″), 34.9 (C-a), 30.8 (C-c), 30.7 (CH.sub.2), 30.3 (C-b), 21.9 (C-d), 13.9 (C-e), 9.23 (CH.sub.3).

[0257] HRMS (ESI.sup.+) m/z=calcd for C.sub.23H.sub.26NO.sub.3: 364.1907 [M+H].sup.+, found: 364.1914.

Example 9

[0258] Preparation of

##STR00064##

[0259] Methyl 5-bromo-2-isobutyramidobenzoate was synthesized using a procedure generally following the synthesis of methyl 5-bromo-2-propionamidobenzoate, with the exception of using 2.60 mL (2.66 g, 25.0 mmol) of isobutyryl chloride instead of propionyl chloride.

[0260] Yield: 2.55 g (8.50 mmol, 85%) of colorless crystals (methyl 5-bromo-2-isobutyramidobenzoate).

[0261] 2-Isobutyramido-5-((4-pentylphenyl)ethynyl)benzoic acid was synthesized using a procedure generally following the synthesis of 5-((4-pentylphenyl)ethynyl)-2-propionamidobenzoic acid, with the exception of using 300 mg (1.00 mmol) of methyl 5-bromo-2-isobutyramidobenzoate instead of methyl 5-bromo-2-propionamidobenzoate.

[0262] Yield over two steps: 296 mg (0.78 mmol, 78%) of a colorless amorphous solid (2-isobutyramido-5-((4-pentyl-phenyl) ethynyl)benzoic acid).

[0263] .sup.1H-NMR: δ [ppm] (600 MHz, DMSO-d.sub.6): 13.92 (brs, 1H, COOH), 11.30 (s, 1H, NH), 8.58 (d, 3J.sub.H,H=8.7 Hz, 1H, H-3), 8.09 (d, .sup.4J.sub.H,H=2.1 Hz, 1H, H-6), 7.72 (dd, .sup.3J.sub.H,H=8.7 Hz, .sup.4J.sub.H,H=2.1 Hz, 1H, H-4), 7.49-7.42 (m, 2H, H-2′), 7.27-7.19 (m, 2H, H-3′), 2.63-2.54 (m, 3H, H-a, CH(CH.sub.3).sub.2, 1.56 (p, .sup.3J.sub.H,H=7.6 Hz, 1H, H-b), 1.33-1.22 (m (4H, H-c, H-d), 1.18 (d, .sup.3J.sub.H,H=6.9 Hz, 6H, CH(CH.sub.3).sub.2, 0.85 (t, .sup.3J.sub.H,H=7.1 Hz, 3H, H-e).

##STR00065##

[0264] .sup.13C-NMR: δ [ppm] (151 MHz, DMSO-d.sub.6): 175.2 (CONH), 168.9 (COOH), 143.4 (C-4′), 141.0 (C-2), 136.4 (C-4), 133.9 (C-6), 131.3 (C-2′), 128.7 (C-3′), 120.0 (C-3), 119.4 (C-1′), 116.6 (C-1 or C-5), 116.3 (C-5 or C-1) 89.3 (C-1″), 87.7 (C-2″), 36.5 (CH(CH.sub.3).sub.2), 35.0 (C-a), 30.8 (C-c), 30.3 (C-b), 21.9 (C-d), 19.1 (CH(CH.sub.3).sub.2), 13.9 (C-e).

[0265] HRMS (ESI.sup.+) m/z=calcd for C.sub.24H.sub.28NO.sub.3: 378.2064 [M+H].sup.+, found: 378.2073.

Example 10: Assays

[0266] Virus Yield Reduction Assay:

[0267] The amount of each virus and the duration of the assay have been calibrated by trial so that the replication is still in log phase of growth at the time of readout and the Ct standard deviations of qRT-PCR quantification (quadruplicate) is below 0.5. Approximate multiplicity of infection (MOI) range from 0.001 to 0.1 depending on the strain.

[0268] One day prior to infection 5×10.sup.4 Vero E6 cells were seeded in 100 μl of medium (with 2.5% FCS) in each wells of a 96-well titer plates. The next day, 8 two-fold serial dilutions of the compounds (beginning at 20 μM final concentration, down to 0.16 μM), in triplicates or quadruplicates, were added to the cells (25 μl/well, in 2.5% FCS containing medium). Four Virus Control (VC) wells (per virus) were supplemented with 25 μl medium containing 0.1% DMSO and four cells control wells were supplemented with 50 μl of medium. Fifteen minutes later, 25 μl of a virus mix containing the appropriate amount of viral stock diluted in medium (2.5% FCS) was added to the 96-well plates.

[0269] Cells were cultivated for 2 to 4 days after which 100 μl of the supernatant were collected for viral RNA purification. The infected supernatants were transferred to 96 wells S-Bloc from QIAgen preloaded with VXL mix and extract by the Cador Patho-gen 96 QIAcube HT kit run on QIAcube HT automat according to Qiagen protocol. Purified RNAs were eluted in 80 μl of water. Viral RNAs (vRNAs) were then quantified by real time one step RT-PCR to determine viral RNA yield (SuperScript III Platinium one-step RT-PCR from Invitrogen, or GoTaq Probe 1-step RT-PCR system from Promega), using 7.5 μl of RNA and 12.5 μl of RT-PCR mix using standard cycling parameters. The four control wells were replaced by four 2 log dilutions of an appropriate T7-generated RNA standards of known quantities for each viral genome (100 copies to 100 millions copies).

[0270] IC50 (Half Maximal Inhibitory Concentration) Determination:

[0271] Mean Inhibition of Virus Yield is Equal to:

[00001]$\mathrm{Virus}\mathrm{inhibition}\left(\mathrm{in}\%\right)=100*\frac{\stackrel{\_}{n_{\mathrm{vRNA}}}\left(\mathrm{VC}\right)-\stackrel{\_}{n_{\mathrm{vRNA}}}\left(\mathrm{drug}\mathrm{treated}\right)}{\stackrel{\_}{n_{\mathrm{vRNA}}}\left(\mathrm{VC}\right)}$

[0272] The inhibition values (expressed as percent inhibition, in linear scale) obtained for each drug concentration (expressed in μM, in log scale) are plotted using Kaleidagraph plotting software (Synergy Software) and the best sigmoidal curve, fit-ting the mean values, is determined by a macro in the software: (Inhibition, Y is given by Y=100/1+(m0/m1).sup.m2). This macro allows determining the best curve fit and the m1 and m2 parameters, wherein m1 corresponds to IC50.

[0273] Cytotoxicity Assay:

[0274] One day prior to the assay 5×10.sup.4 Vero E6 cells (or 10.sup.5 HEK 293 cells) were seeded in 100 μl of medium (with 2.5% FCS) in each wells of a 96-well titer plates. The next day, two-fold serial dilutions of the compounds (beginning at 200 μM final concentration, down to 6.2 μM), in triplicates (“drug ex-posed”), were added to the cells (25 μl/well, in 2.5% FCS containing medium). Six cell control (“cell control”) wells were supplemented with 25 μl medium containing two-fold serial dilution of an equivalent amount of DMSO. Eight wells were not seeded by cells and served as background control of fluorescence for the plates (“background control”).

[0275] Cells were cultivated for 3 (HEK 293) or 4 (Vero E6) days after which the supernatant was removed and replaced with 70 μl of medium containing CellTiter-Blue reagent (Promega) and further incubated for 90 min at 37° C. Fluorescence (560/590 nm) of the plates indicating reduction of resazurin to resorufin were then read on a TECAN Infinite M 200 Pro reader. The cell viabilities, in percent, were calculated from the fluorescence (F) as:

[00002]$\mathrm{Cell}\mathrm{viability}\left(\mathrm{in}\%\right)=100*\frac{\stackrel{\_}{F}\left(\mathrm{drug}\mathrm{exposed}\right)-\stackrel{\_}{F}\left(\mathrm{Background}\mathrm{control}\right)}{\stackrel{\_}{F}\left(\mathrm{cell}\mathrm{control}\right)-\stackrel{\_}{F}\left(\mathrm{Background}\mathrm{control}\right)}$

[0276] The antiviral activity obtained with the compounds of the examples in simian, mouse, hamster and human cell lines against several RNA virus families is shown the tables below.

TABLE-US-00002 Cell Virus Parameter Example line family Virus [uM] 1 2 3 4 5 Simian BUNYA TOSV IC.sub.50 0.09 0.55 ± 0.05 0.07 ± 0.01 0.08 0.325 Vero CC.sub.50 60 ± 15 110 ± 10  18.5 ± 1.5  71 ± 1  77.5 E6 HAZV IC.sub.50 0.05 0.7 ± 0.2 0.11 0.12 0.360 CC.sub.50 60 ± 15 110 ± 10  18.5 ± 1.5  71 ± 1  77.5 TAHV IC.sub.50 0.17 0.27 0.04 0.1 0.450 CC.sub.50 60 ± 15 110 ± 10  18.5 ± 1.5  71 ± 1  77.5 RVFV IC.sub.50 0.09 ≈2 0.16 0.02 n.d..sup.a CC.sub.50 60 ± 15 110 ± 10  18.5 ± 1.5  71 ± 1  FLAVI YFV IC.sub.50 0.2 0.7 ± 0.2 0.11 0.22 n.d..sup.a CC.sub.50 60 ± 15 110 ± 10  18.5 ± 1.5  71 ± 1  44 37.9 DENV IC.sub.50 0.19 n.d..sup.a 0.11 0.18 n.d..sup.a CC.sub.50 60 ± 15 18.5 ± 1.5  71 ± 1  TBEV IC.sub.50 0.22 n.d..sup.a 0.08 0.12 n.d..sup.a CC.sub.50 60 ± 15 18.5 ± 1.5  71 ± 1  ZIKV IC.sub.50 n.d..sup.a n.d..sup.a 0.11 n.d..sup.a n.d..sup.a CC.sub.50 18.5 ± 1.5  TOGA VEEV IC.sub.50 0.07 n.d..sup.a 0.03 0.06 n.d..sup.a CC.sub.50 60 ± 15 18.5 ± 1.5  71 ± 1  Mouse BUNYA RVFV IC.sub.50 0.04 n.d..sup.a 0.17 n.d..sup.a n.d..sup.a L929 CC.sub.50 60 n.d..sup.a 70 FLAVI TBEV IC.sub.50 0.08 n.d..sup.a 0.3 0.16 n.d..sup.a CC.sub.50 60 n.d..sup.a 70 TOGA VEEV IC.sub.50 n.d..sup.a n.d..sup.a 0.6 0.22 >1 CC.sub.50 n.d..sup.a 70 60 Hamster BUNYA RVFV IC.sub.50  0.7 ± 0.03 n.d..sup.a n.d..sup.a 0.85 n.d..sup.a BHK-21 CC.sub.50 140 125 FLAVI YFV IC.sub.50 n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a CC.sub.50 125 TBEV IC.sub.50 n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a CC.sub.50 125 TOGA VEEV IC.sub.50 0.36 n.d..sup.a n.d..sup.a 1.3 n.d..sup.a CC.sub.50 140 125 Human BUNYA RVFV IC.sub.50 0.28 0.5 0.05 0.13 n.d..sup.a SW13 CC.sub.50 60 n.d..sup.a n.d..sup.a 75 FLAVI TBEV IC.sub.50 0.67 0.93 0.1 0.38 n.d..sup.a CC.sub.50 60 n.d..sup.a n.d..sup.a 75 TOGA VEEV IC.sub.50 0.1 1.5 0.13 0.22 n.d..sup.a CC.sub.50 60 n.d..sup.a n.d..sup.a 75 Human BUNYA RVFV IC.sub.50 0.04 ± 0.02 0.4 0.015 n.d..sup.a n.d..sup.a HEK-293 CC.sub.50 80 n.d..sup.a n.d..sup.a 125 TOGA VEEV IC.sub.50 n.d..sup.a 0.45 0.05 n.d..sup.a n.d..sup.a CC.sub.50 n.d..sup.a n.d..sup.a .sup.anot determined,

TABLE-US-00003 Cell Virus Parameter Example line family Virus [uM] 6 7 8 9 Simian BUNYA TOSV IC.sub.50 0.12 0.11 0.01 0.01 Vero CC.sub.50 10 15 ± 0 8 4 E6 HAZV IC.sub.50 0.12 0.07 0.008 0.012 CC.sub.50 10 15 ± 0 8 4 TAHV IC.sub.50 n.d..sup.a 0.12 0.01 n.d..sup.a CC.sub.50 15 ± 0 8 RVFV IC.sub.50 0.14 0.12 0.006 0.01 CC.sub.50 10 15 ± 0 8 4 FLAVI YFV IC.sub.50 n.d..sup.a n.d..sup.a 0.006 0.016 CC.sub.50 8 4 DENV IC.sub.50 n.d..sup.a n.d..sup.a 0.005 0.023 CC.sub.50 8 4 TBEV IC.sub.50 0.12 ± 0.01 0.013 0.07 0.0117 CC.sub.50 10 15 ± 0 8 4 ZIKV IC.sub.50 n.d..sup.a n.d..sup.a 0.009 0.023 CC.sub.50 8 4 TOGA VEEV IC.sub.50 0.12 0.12 0.007 0.0107 CC.sub.50 10 15 8 4 Mouse BUNYA RVFV IC.sub.50 0.003 0.0055 0.002 n.d..sup.a L929 CC.sub.50 15 9 5 FLAVI TBEV IC.sub.50 0.009 0.004 0.0015 n.d..sup.a CC.sub.50 15 9 5 TOGA VEEV IC.sub.50 0.009 0.007 0.003 n.d..sup.a CC.sub.50 15 9 5 Hamster BUNYA RVFV IC.sub.50 >0.2 n.d..sup.a 0.016 0.043 BHK-21 CC.sub.50 n.d..sup.a 7.5 50 FLAVI YFV IC.sub.50 >0.2 n.d..sup.a 0.022 0.055 CC.sub.50 n.d..sup.a 7.5 55 TBEV IC.sub.50 n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a CC.sub.50 7.5 55 TOGA VEEV IC.sub.50 n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a CC.sub.50 7.5 55 Human BUNYA RVFV IC.sub.50 n.d..sup.a n.d..sup.a 0.008 0.011 SW13 CC.sub.50 20 17 FLAVI TBEV IC.sub.50 n.d..sup.a n.d..sup.a 0.013 0.014 CC.sub.50 20 17 TOGA VEEV IC.sub.50 n.d..sup.a n.d..sup.a 0.013 0.014 CC.sub.50 20 17 Human BUNYA RVFV IC.sub.50 n.d..sup.a n.d..sup.a 0.0015 <<0.0016 HEK-293 CC.sub.50 n.d..sup.a n.d..sup.a FLAVI TBEV IC.sub.50 n.d..sup.a n.d..sup.a 0.0031 0.0044 CC.sub.50 n.d..sup.a n.d..sup.a TOGA VEEV IC.sub.50 0.019 0.014 0.0015 0.0015 CC.sub.50 n.d..sup.a n.d..sup.a n.d..sup.a n.d..sup.a .sup.anot determined

Example 11: ADME Properties

[0277] Absorption, distribution, metabolism and excretion properties of selected inhibitors were determined and shown in the following table.

TABLE-US-00004 Ex. 1 Ex. 3 Ex. 6 Ex. 8 Ex. 9 Solubility (PBS 167 ± 7   1540 ± 50   61 ± 17 18 ± 6  13 ± 6  pH 7.4) [μM].sup.a Plasma protein 99 ± 0  99 ± 0  100 ± 0   n.d. n.d. binding [%].sup.b Log D (PBS pH 2.62 ± 0.03 2.59 ± 0.03 3.07 ± 0.05 4.6 ± 0.3 n.d. 7.4/octanol) Hepatic n.d. n.d. 49 ± 0  70 ± 3  45 ± 8  microsome stability [% remaining at 1 h].sup.d Plasma stability 75 ± 0  85 ± 4  94 ± 6  114 ± 5   98 ± 3  [% remaining at 2 h].sup.b .sup.aat ambient temperature (20° C.) .sup.b1 μm, 37° C., mouse plasma diluted with 1 volume of PBS pH 7.4 .sup.cPBS pH 7.4, 5% DMSO; ambient temperature; membrane: dodecane 2% phosphatidylcholine .sup.d1 μm, 37° C., 0.5 mg/mL microsomes of mouse liver; cofactor: NADPH

[0278] The above data show that the tested compounds have acceptable ADME properties. The 5-ethynyl derivative of Example 8 is more stable than the compound of Example 6, but has lower solubility.

[0279] A hydrolysis study of the compound of Example 3 in mouse liver extract is shown in FIG. 1. The results of this test show a cleavage of the amide bond, while the ether bond remained in-tact. Apparently, the amide bond in Example 6 is more stable (see FIG. 2).

Example 12

[0280] Preparation of

##STR00066##

[0281] The compound of Example 12 was synthesized in accordance with Scheme 15.

##STR00067##

[0282] The carbamate compound of Example 12 has been found to have an IC.sub.50 of 190 nM (TOSV) and a CC.sub.50 of 51 μM. It is characterized by a high metabolic stability in a S9 fraction (rat).

Example 13

[0283] Preparation of

##STR00068##

[0284] The compound of Example 13 was synthesized in accordance with Scheme 16.

##STR00069##

[0285] The urea compound of Example 13 has been found to have an IC.sub.50 of 128 nM (TOSV) and a CC.sub.50 of more than 25 μM. It is characterized by a high metabolic stability in a S9 fraction (rat).

Example 14

[0286] Preparation of

##STR00070##

[0287] The compound of Example 14 was synthesized in accordance with Scheme 17.

##STR00071##

[0288] The compound of Example 14 has been found to have an IC.sub.50 of 9 μM (TOSV) and a CC.sub.50 of 40 μM.

Example 15

[0289] Preparation of

##STR00072##

[0290] The compound of Example 15 was synthesized in accordance with Scheme 1. It has been found to have an IC.sub.50 of about 0.5 μM (TOSV) and a CC.sub.50 of more than 25 μM.

Example 16

[0291] Preparation of

##STR00073##

[0292] The compound of Example 16 was synthesized in accordance with Scheme 1. It has been found to have an IC.sub.50 of 4 μM (TOSV) and a CC.sub.50 of 37 μM.

Example 17

[0293] Preparation of

##STR00074##

[0294] The compound of Example 17 was synthesized in accordance with Scheme 1. It has been found to have an IC.sub.50 of 6 μM (TOSV) and a CC.sub.50 of 32 μM.

Example 18

[0295] Preparation of

##STR00075##

[0296] The compound of Example 18 was synthesized in accordance with Scheme 14. It has been found to have an IC.sub.50 of 123 nM (TOSV) and a CC.sub.50 of more than 25 μM.

Example 19

[0297] Preparation of

##STR00076##

[0298] The compound of Example 19 was synthesized in accordance with Scheme 14. It has been found to have an IC.sub.50 of 118 nM (TOSV) and a CC.sub.50 of 8 μM.

Example 20

[0299] Preparation of

##STR00077##

[0300] The compound of Example 20 was synthesized in accordance with Scheme 11. It has been found to have an IC.sub.50 of 0.6 μM (TOSV) and a CC.sub.50 of 75 μM.

Example 21

[0301] Preparation of

##STR00078##

[0302] The compound of Example 21 was synthesized in accordance with Scheme 11. It has been found to have an IC.sub.50 of 0.8 μM (TOSV) and a CC.sub.50 of more than 100 μM.

Example 22

[0303] Preparation of

##STR00079##

[0304] The compound of Example 22 was synthesized in accordance with Scheme 11. It has been found to have an IC.sub.50 of 0.3 μM (TOSV) and a CC.sub.50 of 17 μM.

Example 23

[0305] Preparation of

##STR00080##

[0306] The compound of Example 23 was synthesized in accordance with Scheme 12. It has been found to have an IC.sub.50 of 6 μM (TOSV) and a CC.sub.50 of more than 200 μM.

Example 24

[0307] Preparation of

##STR00081##

[0308] The compounds of Example 24 were synthesized in accordance with Scheme 18 with R.sup.10 being methyl, ethyl, n-propyl, n-butyl, iso-propyl and iso-butyl.

##STR00082##

[0309] The obtained yield was 23 to 51% (first step of Scheme 18) and 65 to 79% (second step of Scheme 18), respectively. The methyl sulfonamide (R.sup.10 being methyl) has been found to have an IC.sub.50 of 1.5 μm (TOSV).

Example 25

[0310] Preparation of

##STR00083##

[0311] The compounds of Example 25 can be synthesized in accordance with Scheme 19 with R.sup.10 being as defined in Example 24.

##STR00084##