Novel inhibitors of cytomegalovirus

Abstract

The present invention relates to novel inhibitors of Cytomegalovirus (CMV) of formula (I), wherein Cy is an optionally substituted heterocycloalkyl group comprising 7 ring atoms containing three nitrogen atoms and four carbon atoms; or an optionally substituted heterocycloalkyl group comprising 8, 9 or 10 ring atoms comprising two or three nitrogen atoms with the remainder being carbon atoms; Ar1 is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S; and Ar2 is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; or a salt thereof.

Description

[0001] Novel Inhibitors of Cytomegalovirus

[0002] The present invention relates to novel inhibitors of Cytomegalovirus (CMV).

[0003] Cytomegalovirus (CMV) is a virus from the family Herpesviridae. Infection with CMV is very common since it is present worldwide and can affect anyone. On the whole, it is an infection which does not usually cause any serious health issues. Once the virus has infected a person, it will remain in that person’s body for the remainder of his or her life. In fact, it is latent for a long time and it does not tend to recurrent infection unless the person’s immune system is affected. Most people who are infected by the virus and who do not have serious health issues do not, on the whole, have any symptoms which might cause them to believe that they are infected with CMV. People who do develop some symptoms may suffer from a high temperature, swollen lymph glands, muscle pain or tiredness.

[0004] However, in the case of babies infected with the virus during pregnancy or childbirth and in people with a weak immune system, it is considered to be a significant public health problem since it can cause serious illnesses.

[0005] The virus is often transmitted from person to person through direct contact with body fluids such as saliva, sperm, blood, urine and other secretions. It may also be passed on through breast milk, in transplanted organs or cells (e.g., blood stem cells), during blood transfusions and from mother to child during pregnancy or childbirth.

[0006] When a woman becomes infected during pregnancy, there is a high risk that the virus will be passed on to the fetus. In this case, the baby is said to have congenital cytomegalovirus. Ninety percent of babies infected by the virus before birth are bom free of the virus’ symptoms. However, the remaining 10% can be affected by disorders such as deafness, blindness, physical and mental disability and even death. Moreover, approximately another 10% of the infected children, who are asymptomatic at birth, develop sequelae at a later time point. It has been the object of the present invention to provide novel inhibitors of Human Cytomegalovirus (HCMV).

[0007] The present invention provides compounds of formula (I): wherein

[0008] Cy is an optionally substituted heterocycloalkyl group comprising 7 ring atoms containing three nitrogen atoms and four carbon atoms; or an optionally substituted heterocycloalkyl group comprising 8, 9 or 10 ring atoms comprising two or three nitrogen atoms with the remainder being carbon atoms;

[0009] Ar1is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, 0 and S; and

[0010] Ar2is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, 0 and S; or a salt thereof.

[0011] Preferably, Cy is an optionally substituted diazocane group or an optionally substituted triazepane group.

[0012] Further preferably, Cy is a 1 ,2,5 triazepane group, a 1 ,4 diazocane group, or a 1 ,5 diazocane group. Moreover preferably, Cy is selected from the following groups:

[0013] Further preferred are compounds of formula (II) or a salt thereof:

[0014] Moreover preferred are compounds of formula (III) or a salt thereof:

[0015] (HI).

[0016] Further preferred are compounds of formula (IV) or a salt thereof: Moreover preferably, Ar1is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, 0 and S.

[0017] Further preferably, Ar1is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, 0 and S.

[0018] Moreover preferably, Ar1is an optionally substituted phenyl group.

[0019] Further preferably, Ar1is an optionally substituted pyridyl group.

[0020] Moreover preferably, Ar1is an optionally substituted heteroaryl group containing 9 ring atoms selected from C, N, 0 and S.

[0021] Further preferably, Ar1is unsubstituted.

[0022] Moreover preferably, Ar1is substituted by a halogen atom, a CN group, an OH group, a N3 group, a SFs group, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, 0 and S (wherein the optional substituents are preferably selected from halogen or a C1-6 alkyl group or a C1-6 heteroalkyl group), a heteroaralkyl group (e.g., a benzyloxy group), or a heteroalkylcycloalkyl group.

[0023] Further preferably, Ar1is substituted by a halogen atom, a CN group, a SFs group, a C1- 6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, or a heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, 0 and S.

[0024] Moreover preferably, Ar1is substituted by a halogen atom (e.g. F, Cl, Br), a CN group, a N3 group, an OH group, a SFs group, a methyl group, a CF3 group, an OCF3 group, an ethyl group, a CH2CF3 group, an i-propy I group, an n-butyl group, a t-butyl group, a CH2NHCOOC(CH3)3 group, a CH2COOCH2CH3 group, a COOCH2CH3 group, COOCH3 group, a methoxy group, a -C(CI)=CH2 group, an -SCF3 group, an ethoxy group, a cyclopropyl group, a cyclohexyl group, a benzyloxy group, a -N(CH2CH2)2O group, a - N(CH2CH2)2NH group, a -N(CH2CH2)2NMe, group a -N(CH2CH2)2NCOOC(CH3)3 group, a 4-tetrahydropyranyl group, a 3-oxethanyl group, a group of formula -OCH2-O-, a group of formula -OCF2-O-, a phenyl group or a group of the following formula:

[0025] Further preferably, Ar1is substituted by a halogen atom (e.g. F, Cl, Br), a CN group, a SFs group, a methyl group, a CF3 group, an ethyl group, a CH2CF3 group, an i-propyl group, an n-butyl group, a t-butyl group, a CH2COOCH2CH3 group, a COOCH2CH3 group, COOCH3 group, a methoxy group, a -C(CI)=CH2 group, an -SCF3 group, an ethoxy group, a cyclopropyl group, or a phenyl group.

[0026] Moreover preferably, Ar1is substituted by a halogen atom, a N3 group, a SFs group, a methyl group, a CF3 group, an OCF3 group, a CH2CF3 group, an i-propyl group, an n- butyl group, a t-butyl group, a CH2NHCOOC(CH3)3 group, a -C(CI)=CH2 group, an - SCF3 group, a cyclopropyl group, a cyclohexyl group, a benzyloxy group, a - N(CH2CH2)2O group, a -N(CH2CH2)2NH group, a -N(CH2CH2)2NMe, group a - N(CH2CH2)2NCOOC(CH3)3 group, a 4-tetrahydropyranyl group, a 3-oxethanyl group, a group of formula -O-CH2-O-, a group of formula -O-CF2-O-, a phenyl group or a group of the following formula:

[0027] Further preferably, Ar1is a phenyl group which is substituted by a halogen atom (especially by F or Cl), or by a C1-6 alkyl group, or by a C1-6 alkyloxy group (e.g. by one of the following groups: -CH(CH3)2; -OMe; -OCF3; -C4H9; -CH2CF3), or by a C3-7 cycloalkyl group.

[0028] Further preferably, Ar1is selected from the following groups:

[0029]

[0030] Further preferably, Ar2is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, 0 and S.

[0031] Moreover preferably, Ar2is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, 0 and S.

[0032] Further preferably, Ar2is substituted by one or two substituents which are independently selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc -OH, -OCH3 and -CN. Moreover preferably, Ar2is selected from the following groups:

[0033] Further preferably, Ar2is selected from the following groups:

[0034] Moreover preferred are compounds of formula (Ila) or a salt thereof: Further preferred are compounds of formula (Illa) or a salt thereof:

[0035] (Illa).

[0036] Moreover preferred are compounds of formula (IVa) or a salt thereof:

[0037] (IVa).

[0038] The most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.

[0039] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment of Ar1may be combined with any embodiment of Ar2).

[0040] The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 15 carbon atoms, especially from 1 to 10 (e.g. 1 , 2, 3 or 4) carbon atoms, for example a methyl (Me, CH3), ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

[0041] The expression C1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms. The expression C1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl (Me), CF3, CD3, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.

[0042] The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).

[0043] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2,2,2-trichloroethyl, a -C(CI)=CH2, difluoromethyl, fluoromethyl or a trifluoromethyl group.

[0044] The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group as defined above in which one or more (preferably 1 to 8; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO2 group. The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0045] Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). The term Ci-Ce heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from 0, S and / or N (especially 0 and / or N). The term C2-C6 heteroalkyl refers to a heteroalkyl group containing from 2 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from 0, S and / or N (especially 0 and / or N). The term C1-C4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1 , 2 or 3 heteroatoms selected from 0, S and / or N (especially 0 and / or N).

[0046] Further preferably, the expression heteroalkyl refers to an alkyl group as defined above (straight-chain or branched) in which one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, sulfur or nitrogen atom or a CO group; this group preferably contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen); this group may preferably be substituted by one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or OH, =0, SH, =S, NH2, =NH, N3, CN or NO2 groups.

[0047] Examples of heteroalkyl groups are groups of formulae: Ra-0-Ya-, Ra-S-Ya-, Ra-S0-Ya-, Ra-S02-Ya-, Ra-N(Rb)-S02-Ya-, Ra-S02-N(Rb)-Ya-, Ra-N(Rb)-Ya-, Ra-C0-Ya-

[0048] Ra-C(=NRd)-Ya-, Ra-0-C0-Ya-, Ra-C0-0-Ya-, Ra-C0-N(Rb)-Ya-, Ra-N(Rb)-C0-Ya-, Ra-N(Rb)-C(=NRd)-Ya-, Ra-0-C0-N(Rb)-Ya-, Ra-N(Rb)-C0-0-Ya-, Ra-N(Rb)-C0-N(Rc)-Ya- Ra-0-C0-0-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-0-CS-Ya-, Ra-CS-0-Ya- Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-0-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-0-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-0-CS-0-Ya-, Ra-S-C0-Ya-, Ra-C0-S-Ya-, Ra-S-C0-N(Rb)-Ya- Ra-N(Rb)-C0-S-Ya-, Ra-S-C0-0-Ya-, Ra-0-C0-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya- Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-, wherein Rabeing a hydrogen atom, a Ci-Ce alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rbbeing a hydrogen atom, a Ci-Ce alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rcbeing a hydrogen atom, a Ci-Ce alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rdbeing a hydrogen atom, a Ci-Ce alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group and Yabeing a bond, a Ci-Ce alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom. Further, one or more hydrogen atoms of the above groups may be replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, -OCD3, ethoxy, n-propyloxy, isopropyloxy, butoxy, te / Y-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, -SC Me, -NHAc, -CONH2, methoxyethyl, 1- methoxyethyl, 1 -ethoxyethyl, 2-m ethoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxym ethyl, carboxyethyl or carboxypropyl, / V-ethyl-ZV-methyl- carbamoyl or / V-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile (- CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0049] The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.

[0050] The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, 0, N and S). The expression heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g. -N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.

[0051] The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.

[0052] The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or triunsaturated.

[0053] The expression aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

[0054] The expression heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2- imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridyl (4-pyridonyl), 3,4-hydroxypyridyl (3,4-pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups.

[0055] The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 H-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0056] The expression heteroaralkyl refers to groups containing both aryl and / or heteroaryl groups and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group contains at least one heteroatom which is preferably selected from N, 0 and S. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, 0 and S) and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1 , 2 or 3 heteroatoms selected from 0, S and N and / or one or two cycloalkyl groups each containing 5 or 6 ring carbon atoms and / or one or two heterocycloalkyl groups, each containing 5 or 6 ring atoms comprising 1 , 2, 3 or 4 oxygen, sulfur or nitrogen atoms. Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl- heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl- alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkyl- cycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.

[0057] As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups.

[0058] The term halogen refers to F, Cl, Br or I.

[0059] The term "optionally substituted" refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two; especially preferably by one) substituents. If a group comprises more than one substituent, these substituents are independently selected, i.e. , they may be the same or different.

[0060] If a group is substituted by a cyclic group, such as e.g., a cycloalkyl group or a heterocycloalkyl group, this cyclic group may be bonded to said group via a single or double bond or this cyclic group may be annulated or fused to said group.

[0061] Examples for substituents are fluorine, chlorine, bromine and iodine and OH, SH, NH2, =0, -SO3H, -SO2NH2, -COOH, -COOMe, -COOEt, CH2OH, -COMe (Ac), -NHS02Me, - SO2NMe2, -CH2NH2, -NHAc, -SFs, -NHMe, -O-CH2-CH2-O-, -NMe2, -OCH3, -S02Me, - CONH2, -CN, -NHCONH2, -NHC(NH)NH2, -NOHCH3, -N3and -NO2 groups. Further examples of substituents are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C1-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C1-C19 heteroalkylcycloalkyl, Ce-C aryl, C1-C17 heteroaryl, C7-C20 aralkyl and C1-C19 heteroaralkyl groups; especially Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl and C1-C11 heteroaralkyl groups, further preferably Ci-Ce alkyl and Ci-Ce heteroalkyl groups.

[0062] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated.

[0063] The rings of any cycloalkyl aryl group, heterocycloalkyl aryl group, cycloalkyl heteroaryl group and heterocycloalkyl heteroaryl group may be bonded to each other via a single or double bond or these rings may be annulated.

[0064] It should be appreciated that certain compounds disclosed herein may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis / trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-lngold- Prelog or R / S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds disclosed herein may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.

[0065] According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and / or increases the formation of desired active metabolites. Accordingly, the present invention also encompasses the partially and fully deuterated compounds disclosed herein. The term hydrogen also encompasses deuterium.

[0066] The therapeutic use of the compounds disclosed herein, their salts (especially their pharmacologically acceptable salts), solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

[0067] The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a salt (especially a pharmaceutically acceptable salt), solvate or hydrate thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants.

[0068] The present invention further provides a compound or a pharmaceutical composition as described herein for use in the treatment or prevention of a herpesvirus infection.

[0069] The present invention moreover provides the use of a compound or a pharmaceutical composition as described herein for the preparation of a medicament for use in the treatment or prevention of a herpesvirus infection.

[0070] According to a further preferred embodiment, the present invention provides a method for the treatment or prevention of a herpesvirus infection in a subject which comprises administering to the subject an effective amount of a compound disclosed herein, or a salt thereof.

[0071] According to a moreover preferred embodiment, the present invention provides a method for the treatment or prevention of a herpesvirus infection in a subject which comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound disclosed herein, or a salt thereof.

[0072] Preferred examples of the herpesvirus are beta-herpesviruses. Further preferred examples of the herpesvirus are human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and human cytomegalovirus (HCMV). The compounds of the present invention may especially preferably be used in the treatment or prevention of a Cytomegalovirus (CMV) infection; e.g., a Human Cytomegalovirus (HCMV) infection.

[0073] The present invention also relates to pro-drugs which are composed of a compound disclosed herein and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl- , acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl- oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound disclosed herein, carrying a hydroxy group (-OH): a sulfate, a phosphate (-OPO3 or -OCH2OPO3) or an ester of an amino acid.

[0074] Preferably, the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds disclosed herein.

[0075] Examples of salts (especially pharmacologically acceptable salts) of sufficiently basic compounds are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein.

[0076] The compounds described herein may be solvated, especially hydrated. The hydratization / hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water-free compounds. The solvates and / or hydrates may e.g. be present in solid or liquid form.

[0077] In general, the compounds and pharmaceutical compositions described herein will be administered by using the known and acceptable modes known in the art.

[0078] For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, and polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants. In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 0.1 mg to about 10,000 mg, preferably from about 1 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

[0079] EXAMPLES

[0080] I. Synthesis of the compounds of the present invention

[0081] Abbreviations and Acronyms

[0082] Abbreviations and Acronyms used in the description of the chemistry and in the Examples that follow are: aq. aqueous

[0083] Ar argon

[0084] Boc tert-Butyloxycarbonyl br. broad

[0085] CDCh deuterated chloroform

[0086] CD3OD deuterated methanol cHex cyclohexane cone. Concentrated d doublet

[0087] DCM dichloromethane

[0088] DIPEA Diisopropylethylamine

[0089] DMSO dimethylsulfoxide

[0090] DMSO-de deuterated dimethylsulfoxide

[0091] ESI electrospray

[0092] EtOAc ethyl acetate

[0093] EtOH ethanol h hour hept heptet

[0094] HCI hydrochloric acid

[0095] HPLC high performance liquid chromatography

[0096] H2O water

[0097] H2SO4 sulfuric acid m multiplet

[0098] MeCN acetonitrile

[0099] MeOH methanol min minutes

[0100] MS mass spectrometry

[0101] NaHCOs sodium hydrogencarbonate

[0102] NaCI sodium chloride

[0103] NaOH sodium hydroxide

[0104] Na2SO4 sodium sulfate

[0105] NMR nuclear magnetic resonance

[0106] NP normal phase

[0107] Ns 2-nosyl, 2-nitrobenzenesulfonyl q quartet quint quintet

[0108] RP reversed phase r. t. room temperature s singlet sat. saturated t triplet

[0109] TFA trifluoroacetic acid

[0110] LIPLC Ultra Performance Liquid Chromatography wt weight

[0111] 1. Methods of making the compounds of the present invention

[0112] In general, the compounds of the invention can be prepared by standard techniques known in the art, by known processes analogous thereto, and / or by the processes described herein, using starting materials which are either commercially available or producible according to conventional chemical methods. The particular processes to be utilised in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the type of substitution at various locations of the molecule and the commercial availability of the starting materials play a role in the path to be followed and in the chosen reaction conditions for the preparation of the specific compounds of this invention. Those factors are readily recognised by one of ordinary skill in the art.

[0113] The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.

[0114] 2. Experimental procedures

[0115] LC-MS method

[0116] HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using an Agilent 6130 Single Quadrupole LC / MS System equipped with 1260 Infinity II LC System.

[0117] Column: Gemini® 3 pm NX-C18, LC Column 50 x 2 mm

[0118] Eluents: A: H2O with 0.1 % formic acid and B: MeCN with 0.1 % formic acid.

[0119] Flash chromatography method

[0120] Flash chromatography was performed using Pure C-850 FlashPrep system in a flash mode. Reversed phase (RP) separations were performed using FlashPure EcoFlex C18 cartridges from Buchi with H2O - MeCN eluent. Normal phase separations were performed using FlashPure silica cartridges from Buchi.

[0121] Preparative HPLC method

[0122] Preparative HPLC was performed using a Pure C-850 FlashPrep system in the HPLC mode.

[0123] Column: Luna® Prep C18 5 pm, 21 .2 x 250 mm

[0124] Flow: 10 mL / min

[0125] Eluents: A: H2O with 0.1 % formic acid and B: MeCN with 0.1 % formic acid.

[0126] Accurate Mass method High resolution masses were obtained using Maxis II TM HD mass spectrometer (Broker).

[0127] NMR methods

[0128] Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a Broker Avance III (500MHz), Broker Avance III (600 MHz) or a Broker Avance III (700MHz) spectrometer with residual protonated solvent (CHCI3 5 7.26; MeOH 5 3.30; DMSO 5 2.49) as standard. The NMR data of the synthesized examples are in agreement with their corresponding structural assignments.

[0129] 2.1 Experimental Examples of the Invention

[0130] 2.1.1 Synthetic methods te / Y-Butyl (4-(( / V-(2-bromoethyl)-2-nitrophenyl)sulfonamido)butyl)carbamate was synthesized according to Chamakuri et al. (S. Chamakuri, M. M. Shah, D. C. H. Yang, C. Santini, D. W. Young, Org. Biomol. Chem., 2020, 18, 8844-8849).

[0131] 4-(( / V-(2-bromoethyl)-2-nitrophenyl)sulfonamido)butan-1-aminium trifluoroacetate (1)

[0132] TFA (3 mL) was added to a solution of te / t-butyl (4-(( / V-(2-bromoethyl)-2- nitrophenyl)sulfonamido)butyl)carbamate (3.3 g, 6.9 mmol) in CH2CI2 (30 mL). The reaction mixture was stirred for 2 h. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography (RP; MeCN : H2O). Yield: 2.0 g (59%).1H NMR (600 MHz, DMSO-d6): 5 = 8.05 (d, J = 7.9 Hz, 1 H), 8.00 (d, J = 7.8 Hz, 1 H), 7.93 - 7.89 (m, 1 H), 7.88 - 7.84 (m, 1 H), 7.80 - 7.72 (br s, 3 H), 3.67 - 3.62 (m, 2 H), 3.60 - 3.55 (m, 2 H), 3.35 - 3.29 (m, 2 H), 2.82 - 2.75 (m, 2 H), 1.61 - 1.54 (m, 2 H), 1.54 - 1.47 (m, 2 H) ppm.

[0133] MS (ESI) calcd. for C12H19 BrN3O4S ([M]+): m / z = 380 / 382, exp.: 380 / 382 1-((2-Nitrophenyl)sulfonyl)-1,4-diazocane (2)

[0134] Compound 1 (2.0 g, 4.1 mmol) was dissolved under Ar in abs. THF (30 mL). K2CO3 (3.6 g, 26 mmol) was added and the mixture was stirred for 7 d at 55 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure yielding the crude product which was directly used for the next step. Yield: 1 .5 g tert-Butyl 4-((2-Nitrophenyl)sulfonyl)-1,4-diazocane-1 -carboxylate (3)

[0135] DMAP (98 mg, 0.8 mmol), EtsN (1.2 mL, 808 mg, 8 mmol) and BOC2O (1.7 g, 8 mmol) were added to a solution of crude 2 (1.2 g, 4 mmol) in CH2CI2 (30 mL). The reaction mixture was stirred for 18 h at r. t.. Volatiles were removed under reduced pressure and H2O and EtOAc were added to the residue. Phases were separated and aq. phase was extracted with EtOAc (2x). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane : EtOAc) yielding the desired compound. Yield: 181 mg (11 %).

[0136] 1H NMR (500 MHz, CD3OD): 5 = 8.00 - 7.94 (m, 1 H), 7.84 - 7.75 (m, 3 H), 3.55 - 3.40 (m, 6 H), 3.37 - 3.32 (m, 2 H), 1 .89 - 1 .72 (m, 4 H), 1 .47 (s, 9 H) ppm. tert-Butyl 1,4-Di azocane-1 -carboxylate (4)

[0137] To a solution of 3 (180 mg, 0.45 mmol) in abs. MeCN (4 mL) under Ar was added 4-(tert- butyl)benzenethiol (180 mg, 1.1 mmol) and K2CO3 (374 mg, 2.7 mmol). The reaction mixture was stirred for 20 h at r. t., filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C18, MeCN : H2O) yielding 36 mg (37%) of the desired product that was used for the next step without further characterization. tert-Butyl 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazocane-1 -carboxylate (5)

[0138] To a solution of 4 (36 mg, 0.17 mmol) in abs. DMF (2 mL) under Ar was added 4-amino- 1 ,2,5-oxadiazole-3-carboxylic acid (22 mg, 0.17 mmol), DIPEA (88 pL, 65 mg, 0.50 mmol) and HATLI (77 mg, 0.20 mmol). The reaction mixture was stirred for 15 h at r. t.. H2O was added and the mixture was extracted with EtOAc (2x). Combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (C18, MeCN : H2O) yielding 33 mg (60%) of the desired product that was used for the next step without further characterization.

[0139] 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazocan-1-ium Trifluoroacetate (6) TFA (0.2 mL) was added to a solution of 5 (32 mg, 0.1 mmol) in CH2CI2 (2 mL). The reaction mixture was stirred for 16 h at r. t. and concentrated under reduced pressure yielding the crude product (quantitative yield).

[0140] 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-methoxyphenyl)-1,4-diazocane-1- carboxamide (AR949)

[0141] The crude compound 6 (ca. 0.05 mmol) from the previous step was dissolved in abs. THF (1 mL). A solution of 1-isocyanato-4-methoxybenzene (7.3 mg, 0.05 mmol) in abs. THF (0.5 mL) was added and the mixture was stirred for 21 h at r. t. The reaction mixture was concentrated under reduced pressure and purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 12.7 mg (68%) of the desired compound. The compound exists as a ca. 1 : 1 mixture of conformers.

[0142] 1H NMR (500 MHz, DMSO-d6): 5 = 8.10 (s, 0.5 H), 8.08 (s, 0.5 H), 7.35 (d, J = 9.1 Hz, 1 H), 7.34 (d, J = 9.1 Hz, 1 H), 6.82 (d, J = 9.1 Hz, 2 H), 6.40 (s, 1 H), 6.36 (s, 1 H), 3.72 - 3.65 (m, 2 H), 3.70 (s, 3 H), 3.63 - 3.54 (m, 4 H), 3.51 - 3.44 (m, 2 H), 1 .86 - 1 .78 (m, 1 H), 1 .76 - 1 .66 (m, 2 H), 1 .65 - 1 .58 (m, 1 H) ppm.

[0143] 13C NMR (125 MHz, DMSO-de): 5 = 158.64, 158.43, 156.24, 155.84, 154.95, 154.80, 154.62, 154.59, 141.91 , 141.55, 133.32, 133.27, 122.32, 122.17, 122.13, 113.39, 113.35, 55.10, 50.27, 49.54, 48.63, 48.40, 47.67, 47.53, 46.62, 46.06, 25.70, 25.05, 24.98, 24.94 ppm.

[0144] MS (ESI) calcd. for C17H23N6O4 ([M+H]+): m / z = 375, exp.: 375.

[0145] 4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)- / V-(4-chlorophenyl)-1 ,4-diazocane-1 - carboxamide (AR950)

[0146] The crude compound 6 (ca. 0.05 mmol) from the previous step was dissolved in abs. THF (1 mL). A solution of 1 -chloro-4-isocyanatobenzene (7.6 mg, 0.05 mmol) in abs. THF (0.5 mL) was added and the mixture was stirred for 21 h at r. t. The reaction mixture was concentrated under reduced pressure and purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 16.3 mg (86%) of the desired compound. The compound exists as a ca. 1 : 1 mixture of conformers.

[0147] 1H NMR (500 MHz, DMSO-d6): 5 = 8.36 (s, 0.5 H), 8.35 (s, 0.5 H), 7.53 (d, J = 8.9 Hz, 1 H), 7.52 (d, J = 8.9 Hz, 1 H), 7.28 (d, J = 8.9 Hz, 2 H), 6.40 (s, 1 H), 6.36 (s, 1 H), 3.74 -

[0148] 3.66 (m, 2 H), 3.65 - 3.54 (m, 4 H), 3.53 - 3.46 (m, 2 H), 1.85 - 1.78 (m, 1 H), 1.76 -

[0149] 1 .67 (m, 2 H), 1 .65 - 1 .58 (m, 1 H) ppm.

[0150] 13C NMR (125 MHz, DMSO-de): 5 = 158.67, 158.46, 156.27, 155.86, 154.54, 154.39, 141.89, 141.52, 139.45, 139.42, 128.04, 128.01 , 125.44, 125.41 , 121.61 , 121.47, 50.18, 49.50, 48.67, 48.36, 47.67, 47.55, 46.75, 46.13, 25.69, 25.01 , 24.96, 24.93 ppm.

[0151] MS (ESI) calcd. for C16H20CIN6O3 ([M+H]+): m / z = 379, exp.: 379.

[0152] 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-(trifluoromethoxy)phenyl)-1,4- diazocane-1 -carboxamide (VK883)

[0153] The crude compound 6 (ca. 0.1 mmol) from the previous step was dissolved in abs. DMF (1 mL). A solution of 1 -isocyanato-4-(trifluoromethoxy)benzene (41 mg, 0.2 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 21 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 16.7 mg (39%) of the desired compound. The compound exists as a ca. 1 : 1 mixture of conformers.

[0154] 1H NMR (500 MHz, DMSO-d6): 5 = 8.43 (s, 0.5 H), 8.42 (s, 0.5 H), 7.60 (d, J = 9.2 Hz, 1 H), 7.59 (d, J = 9.2 Hz, 1 H), 7.24 (d, J = 9.1 Hz, 2 H), 6.40 (s, 1 H), 6.36 (s, 1 H), 3.76 -

[0155] 3.67 (m, 2 H), 3.66 - 3.54 (m, 4 H), 3.54 - 3.47 (m, 2 H), 1.86 - 1.79 (m, 1 H), 1.77 -

[0156] 1 .67 (m, 2 H), 1 .65 - 1 .58 (m, 1 H) ppm.

[0157] 13C NMR (150 MHz, DMSO-de): 5 = 158.68, 158.47, 156.27, 155.86, 154.58, 154.43, 142.67, 141.89, 141.52, 139.75, 139.71 , 121.22, 121.09, 121.06, 119.33, 50.15, 49.49, 48.68, 48.35, 47.67, 47.51 , 46.75, 46.14, 25.66, 24.97, 24.92 ppm.

[0158] 19F NMR (564 MHz, DMSO-de): 5 = -57.06 ppm.

[0159] MS (ESI) calcd. for C17H20F3N6O4 ([M+H]+): m / z = 429, exp.: 429.

[0160] 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-butylphenyl)-1,4-diazocane-1- carboxamide (VK884)

[0161] The crude compound 6 (ca. 0.1 mmol) from the previous step was dissolved in abs. DMF (1 mL). A solution of 1 -butyl-4-isocyanatobenzene (35 mg, 0.2 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 21 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 16.2 mg (41 %) of the desired compound. The compound exists as a ca. 1 : 1 mixture of conformers.

[0162] 1H NMR (500 MHz, DMSO-d6): 5 = 8.15 (s, 0.5 H), 8.13 (s, 0.5 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.40 (s, 1 H), 6.36 (s, 1 H), 3.73 - 3.66 (m, 2 H), 3.64 - 3.54 (m, 4 H), 3.52 - 3.45 (m, 2 H), 2.53 - 2.48 (m, 2 H, the signal overlaps with the signal of DMSO-ds), 1.86 - 1 .78 (m, 1 H), 1 .76 - 1 .67 (m, 2 H), 1 .65 - 1 .58 (m, 1 H), 1.56 - 1 .47 (m, 2 H), 1.34 - 1 .24 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm.

[0163] 13C NMR (125 MHz, DMSO-de): 5 = 158.66, 158.45, 156.26, 155.85, 154.79, 154.64, 141.92, 141.55, 137.97, 137.93, 135.82, 135.77, 127.94, 127.91 , 120.47, 120.32, 50.26, 49.53, 48.70, 48.41 , 47.63, 47.56, 46.65, 46.08, 34.15, 33.29, 25.69, 25.02, 24.91 , 21.66, 13.78 ppm.

[0164] MS (ESI) calcd. for C20H29N6O3 ([M+H]+): m / z = 401 , exp.: 401 .

[0165] 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-isopropylphenyl)-1,4-diazocane-1- carboxamide (VK855)

[0166] The crude compound 6 (ca. 0.07 mmol) from the previous step was dissolved in a mixture of abs. DMF (0.5 mL) and DIPEA (0.5 mL). A solution of 1 -isocyanato-4-isopropylbenzene (32 mg, 0.2 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 16 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 20 mg (74%) of the desired compound.

[0167] The compound exists as a ca. 1 : 1 mixture of conformers.

[0168] 1H NMR (500 MHz, DMSO-d6): 5 = 8.15 (s, 0.5 H), 8.13 (s, 0.5 H), 7.37 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 2 H), 6.46 - 6.26 (m, 2 H), 3.73 - 3.66 (m, 2 H), 3.64 - 3.54 (m, 4 H), 3.53 - 3.46 (m, 2 H), 2.81 (sept, J = 6.9 Hz, 1 H), 1 .85 - 1.78 (m, 1 H), 1.75 - 1.67 (m, 2 H), 1.64 - 1.58 (m, 1 H), 1.17 (d, J = 6.9 Hz, 6 H) ppm.

[0169] 13C NMR (125 MHz, DMSO-de): 5 = 158.65, 158.45, 156.26, 155.85, 154.82, 154.66, 141.98, 141.93, 141.55, 138.08, 138.04, 125.89, 125.86, 120.47, 120.31 , 50.23, 49.52, 48.68, 48.40, 47.60, 47.54, 46.63, 46.06, 32.77, 25.67, 25.00, 24.88, 24.04 ppm.

[0170] MS (ESI) calcd. for C19H27N6O3 ([M+H]+): m / z = 387, exp.: 387.

[0171] 4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)- / V-(4-cyclopropylphenyl)-1 ,4-diazocane-1 - carboxamide (VK941)

[0172] A solution of 4-cyclopropylaniline (27 mg, 0.2 mmol) in CH2CI2 (5 mL) was slowly added to a solution of 4-nitrophenyl chloroformate (40 mg, 0.2 mmol) in CH2CI2 (5 mL) at 0 °C. Pyridine (0.1 mL) was slowly added to the resulting suspension at 0 °C. The reaction mixture was stirred for 3 h at r. t.. A solution of the crude compound 6 (ca. 0.14 mmol) in abs. DMF (1 mL) and DIPEA (1 mL) was added and the reaction mixture was stirred for 16 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 24 mg (45%).

[0173] The compound exists as a ca. 1 : 1 mixture of conformers.

[0174] 1H NMR (500 MHz, DMSO-d6): 5 = 8.14 (s, 0.5 H), 8.12 (s, 0.5 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 2 H), 6.40 (s, 1 H), 6.36 (s, 1 H), 3.73 - 3.65 (m, 2 H), 3.63 - 3.54 (m, 4 H), 3.52 - 3.45 (m, 2 H), 1.88 - 1.78 (m, 2 H), 1.75 - 1 .67 (m, 2 H), 1 .65 - 1 .57 (m, 1 H), 0.91 - 0.84 (m, 2 H), 0.61 - 0.55 (m, 2 H) ppm.

[0175] 13C NMR (125 MHz, DMSO-de): 5 = 158.65, 158.44, 156.26, 155.85, 154.77, 154.62, 141.92, 141.55, 137.76, 137.72, 137.01 , 136.96, 125.14, 125.10, 120.48, 120.33, 50.25, 49.52, 48.68, 48.40, 47.63, 47.55, 46.64, 46.07, 25.69, 25.03, 24.91 , 14.50, 8.84 ppm. MS (ESI) calcd. for C19H25N6O3 ([M+H]+): m / z = 385, exp.: 385.

[0176] 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-(2,2,2-trifluoroethyl)phenyl)-1,4- diazocane-1 -carboxamide (VK942)

[0177] A solution of 4-(2,2,2-trifluoroethyl)ani line (35 mg, 0.2 mmol) in CH2CI2 (5 mL) was slowly added to a solution of 4-nitrophenyl chloroformate (40 mg, 0.2 mmol) in CH2CI2 (5 mL) at 0 °C. Pyridine (0.1 mL) was slowly added to the resulting suspension at 0 °C. The reaction mixture was stirred for 3 h at r. t.. A solution the crude compound 6 (ca. 0.14 mmol) in abs. DMF (1 mL) and DIPEA (1 mL) was added and the reaction mixture was stirred for 16 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 52 mg (87%).

[0178] The compound exists as a ca. 1 : 1 mixture of conformers.

[0179] 1H NMR (600 MHz, DMSO-d6): 5 = 8.30 (s, 0.5 H), 8.28 (s, 0.5 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.40 (s, 1 H), 6.36 (s, 1 H), 3.76 - 3.66 (m, 2 H), 3.65 - 3.47 (m, 8 H), 1 .85 - 1 .79 (m, 1 H), 1 .76 - 1 .68 (m, 2 H), 1 .65 - 1.59 (m, 1 H) ppm.

[0180] 13C NMR (150 MHz, DMSO-de): 5 = 158.68, 158.46, 156.28, 155.87, 154.66, 154.51 , 141.90, 141.53, 140.21 , 140.17, 130.12, 130.09, 129.19, 127.36, 125.52, 123.69, 123.48, 120.18, 120.03, 50.21 , 49.50, 48.72, 48.39, 47.62, 47.58, 46.71 , 46.12, 37.91 (q, JC-F = 28 Hz), 25.67, 25.00, 24.90 ppm.

[0181] HRMS (ESI) calcd. for C18H22F3N6O3 [M+H]+: m / z = 427.1705, found 427.1700. fert-Butyl 5-(4-Amino-1, 2, 5-oxadiazole-3-carbonyl)-1,5-diazocane-1 -carboxylate (7) te / Y-Butyl 1 ,5-diazocane-1 -carboxylate (100 mg, 0.47 mmol) was dissolved in abs. DMF (5 mL). 4-Amino-1 ,2,5-oxadiazole-3-carboxylic acid (65 mg, 0.5 mmol) was added followed by DIPEA (0.17 mL, 129 mg, 1 mmol) and HATU (228 mg, 0.6 mmol). The resulting mixture was stirred for 18 h at r. t.. The reaction was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (C18; H2O : MeCN). Yield: 148 mg (96%).

[0182] 1H NMR (500 MHz, DMSO-d6): 5 = 6.36 (s, 1 H), 6.34 (s, 1 H), 3.75 - 3.69 (m, 2 H), 3.68 - 3.61 (m, 2 H), 3.42 - 3.33 (m, 4 H), 1.92 - 1 .79 (m, 4 H), 1 .33 (s, 4.5 H), 1 .29 (s, 4.5 H) ppm.

[0183] MS (ESI) calcd. for Cu sNsNaC ([M+Na]+): m / z = 348, exp.: 348. 5-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-1,5-diazocan-1-ium Trifluoroacetate (8)

[0184] TFA (1 mL) was added to the solution of 7 (128 mg, 0.4 mmol) in CH2CI2 (4 mL). The reaction mixture was stirred for 2 h at r. t. Volatiles were removed under reduced pressure. The crude product was used for the next step without further purification.

[0185] MS (ESI) calcd. for C9H16N5O2 ([M]+): m / z = 226, exp.: 226.

[0186] 5-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-isopropylphenyl)-1,5-diazocane-1- carboxamide (VK853)

[0187] The crude compound 8 (ca. 0.1 mmol) from the previous step was dissolved in abs. DMF (1 mL). A solution of 1 - 1-isocyanato-4-isopropylbenzene (24 mg, 0.15 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 21 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 29 mg (75%) of the desired compound.

[0188] 1H NMR (500 MHz, DMSO-d6): 5 = 7.99 (s, 1 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H), 6.33 (s, 2 H), 3.74 - 3.69 (m, 2 H), 3.69 - 3.64 (m, 2 H), 3.57 - 3.50 (m, 4 H), 2.80 (septet, J = 6.9 Hz, 1 H), 1.94 - 1.84 (m, 4 H), 1.16 (d, J = 6.9 Hz, 6 H) ppm.13C NMR (125 MHz, DMSO-de): 6 = 158.25, 156.12, 154.43, 141.85, 141.52, 138.07, 125.79, 120.67, 50.04, 48.51 , 47.41 , 47.25, 32.76, 28.75, 26.34, 24.04 ppm.

[0189] MS (ESI) calcd. for C19H27N6O3 ([M+H]+): m / z = 387, exp.: 387.

[0190] 5-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-(trifluoromethoxy)phenyl)-1,5- diazocane-1 -carboxamide (VK888)

[0191] The crude compound 8 (ca. 0.1 mmol) from the previous step was dissolved in abs. DMF (1 mL). A solution of 1 - 1-isocyanato-4-(trifluoromethoxy)benzene (31 mg, 0.15 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 21 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 24 mg (56%) of the desired compound.

[0192] 1H NMR (500 MHz, DMSO-d6): 5 = 8.27 (s, 1 H), 7.50 (d, J = 9.2 Hz, 2 H), 7.20 (d, J = 9.2 Hz, 2 H), 6.31 (s, 2 H), 3.76 - 3.70 (m, 2 H), 3.70 - 3.63 (m, 2 H), 3.60 - 3.50 (m, 4 H), 1.97 - 1.83 (m, 4 H) ppm.

[0193] 13C NMR (125 MHz, DMSO-de): 5 = 158.25, 156.12, 154.17, 142.60, 141.49, 139.75, 121.34, 120.96, 120.17 (q, JC-F = 255 Hz), 49.95, 48.41 , 47.44, 47.30, 28.58, 26.20 ppm.19F NMR (564 MHz, DMSO-de): 5 = -57.04 ppm.

[0194] MS (ESI) calcd. for C17H20F3N6O4 ([M+H]+): m / z = 429, exp.: 429.

[0195] 5-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)- / V-(4-chlorophenyl)-1 ,5-diazocane-1 - carboxamide (VK889)

[0196] The crude compound 8 (ca. 0.1 mmol) from the previous step was dissolved in abs. DMF (1 mL). A solution of 1 - 1 -chloro-4-isocyanatobenzene (23 mg, 0.15 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 21 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 20 mg (53%) of the desired compound.

[0197] 1H NMR (500 MHz, DMSO-d6): 5 = 8.20 (s, 1 H), 7.43 (d, J = 9.0 Hz, 2 H), 7.24 (d, J = 9.0 Hz, 2 H), 6.30 (s, 2 H), 3.75 - 3.70 (m, 2 H), 3.70 - 3.63 (m, 2 H), 3.58 - 3.50 (m, 4 H), 1.96 - 1.84 (m, 4 H) ppm.

[0198] 13C NMR (125 MHz, DMSO-de): 5 = 158.24, 156.13, 154.12, 141.47, 139.46, 127.93, 125.30, 121.71 , 49.94, 48.40, 47.43, 47.28, 28.57, 26.19 ppm.

[0199] MS (ESI) calcd. for C16H20CIN6O3 ([M+H]+): m / z = 379 / 381 , exp.: 379 / 381.

[0200] 5-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-butylphenyl)-1,5-diazocane-1- carboxamide (VK890)

[0201] The crude compound 8 (ca. 0.1 mmol) from the previous step was dissolved in abs. DMF (1 mL). A solution of 1 - 1 -butyl-4-isocyanatobenzene (26 mg, 0.15 mmol) in abs. THF (3 mL) was added and the mixture was stirred for 21 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding 23 mg (58%) of the desired compound.1H NMR (500 MHz, DMSO-d6): 6 = 7.98 (s, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.01 (d, J = 8.5 Hz, 2 H), 6.32 (s, 2 H), 3.74 - 3.69 (m, 2 H), 3.69 - 3.63 (m, 2 H), 3.57 - 3.49 (m, 4 H), 2.50 - 2.46 (m, 2 H), 1 .95 - 1 .84 (m, 4 H), 1 .55 - 1 .46 (m, 2 H), 1 .33 - 1 .24 (m, 2 H), 0.88 (t, J = 7.3 Hz, 3 H) ppm.

[0202] 13C NMR (125 MHz, DMSO-de): 5 = 158.26, 156.12, 154.43, 141.51 , 137.96, 135.69, 127.83, 120.65, 50.03, 48.49, 47.40, 47.24, 34.16, 33.29, 28.76, 26.34, 21 .67, 13.78 ppm. MS (ESI) calcd. for C20H29N6O3 ([M+H]+): m / z = 401 , exp.: 401 .

[0203] 5-Benzyl 1,2-Di-ferf-butyl 1,2,5-Triazepane-1,2,5-tricarboxylate (9)

[0204] 5-Benzyl 1 ,2-di-ferf-butyl 1 ,2,5-triazepane-1 ,2,5-tricarboxylate (9) was synthesized according to Park ef a / . (J. Fluorine Chemistry 130 (2009), 1001 - 1010). To a solution of benzyl bis-(chloroethyl)carbamate (1.9 g, 6.9 mmol) and di-ferf-butyl hydrazine-1 ,2- dicarboxylate (1.6 g, 6.9 mmol) in toluene (20 mL) was added aq. NaOH (6.9 mL, 50%) and Et4NBr (220 mg, 1.1 mmol). The mixture was stirred for 18 h at reflux, cooled to r. t., H2O was added and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (cyclohexane : EtOAc). Yield: 1.1 g (37%).

[0205] Di-ferf-butyl 1,2,5-Triazepane-1,2-dicarboxylate (10)

[0206] Di-ferf-butyl 1 ,2,5-triazepane-1 ,2-dicarboxylate (10) was synthesized according to Park et al. (J. Fluorine Chemistry 130 (2009), 1001 - 1010). Pd / C (265 mg, 10%) was added to the solution of 5-benzyl 1 ,2-di-ferf-butyl 1 ,2,5-triazepane-1 ,2,5-tricarboxylate (9) (1.1 g, 2.5 mmol) in MeOH (20 mL) under Ar. Ar was replaced by hydrogen and the mixture was hydrogenated (1 atm) at r. t. for 18 h. The reaction mixture was filtered through Celite and Celite was washed with MeOH. The filtrate was concentrated at reduced pressure. Yield: 710 mg (94%).

[0207] Di-ferf-butyl 5-((4-lsopropylphenyl)carbamoyl)-1,2,5-triazepane-1,2-dicarboxylate (11)

[0208] To a solution of 1 -isocyanato-4-isopropylbenzene (129 mg, 0.8 mmol) in dry THF (5 mL) was added a solution of the compound 10 (195 mg, 0.65 mmol) in dry THF (5 mL). The reaction mixture stirred for 16 h at r.t.. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (cyclohexane: EtOAc = 75 : 25 to 50 : 50) yielding the desired compound. Yield: 218 mg (72%). The compound was used for the next step without further characterization.

[0209] Di-ferf-butyl 5-((4-(2,2,2-Trifluoroethyl)phenyl)carbamoyl)-1,2,5-triazepane-1,2- dicarboxylate (12)

[0210] A solution of 4-(2,2,2-trifluoroethyl)ani line (88 mg, 0.5 mmol) in CH2CI2 (5 mL) was slowly added to a solution of 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) in CH2CI2 (5 mL) at r.t.. Pyridine (0.2 mL, 200 mg, 2.4 mmol) was slowly added to the resulting suspension. The reaction mixture was stirred for 3 h at r. t. A solution of 10 (158 mg, 0.52 mmol) in DMF (3 mL) and DIPEA (1 mL) was added and the reaction mixture was stirred for 16 h at r. t. Volatiles were removed under reduced pressure. Brine was added and the mixture was extracted with EtOAc (3x). Combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (cyclohexane: EtOAc = 100 : 0 to 20: 80) yielding 235 mg (94%) of the desired product. The compound was used for the next step without further characterization.

[0211] 1-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- / V-(4-isopropylphenyl)-1,2,5-triazepane-5- carboxamide (VK697)

[0212] TFA (1 mL) was added to the solution of the compound 11 (64 mg, 0.14 mmol), in CH2CI2 (4 mL) at r. t. The reaction was stirred for 2 h at r. t. and the volatiles were removed under reduced pressure. The residue was dissolved in DMF (5 mL). DIPEA (0.2 mL, 154 mg, 1.2 mmol) and 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (12 mg, 0.1 mmol) were added under Ar followed by HATU (114 mg, 0.3 mmol). The reaction mixture was stirred for 18 h at r. t. and then concentrated under reduced pressure. The residue was purified by flash chromatography (C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). The product containing fractions were lyophilized yielding the desired product. Yield: 13 mg (25%).

[0213] 1H NMR (500 MHz, DMSO-de): 5 [ppm] = 8.30 (s, 1 H), 7.37 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 8.5 Hz, 2 H), 6.23 (s, 2 H), 5.56 (t, J = 6.2 Hz, 1 H), 3.88 - 3.84 (m, 2 H), 3.76 - 3.72 (m, 2 H), 3.59 - 3.55 (m, 2 H), 2.87 - 2.77 (m, 3 H), 1 .17 (d, J = 6.9 Hz, 6 H) ppm.

[0214] 13C NMR (125 MHz, DMSO-de) 5 [ppm] = 160.69, 154.74, 154.61 , 144.94, 141.94, 138.07, 125.94, 120.29, 50.61 , 48.90, 47.32, 43.99, 32.79, 24.07 ppm.

[0215] MS (ESI) calcd. for C17H24N7O3 ([M+H]+): m / z = 374, exp.: 374. 1 -(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)- / V-(4-(2,2,2-trifluoroethyl)phenyl)-1 ,2,5- triazepane-5-carboxamide (VK716)

[0216] TFA (1 mL) was added to the solution of the compound 12 (220 mg, 0.4 mmol) in CH2CI2 (4 mL) at r. t. The reaction was stirred for 3 h at r. t. and the volatiles were removed under reduced pressure. The residue was dissolved in DMF (5 mL). DIPEA (0.2 mL, 154 mg, 1 .2 mmol) and 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (52 mg, 0.4 mmol) were added under Ar followed by HATU (190 mg, 0.5 mmol). The reaction mixture was stirred for 18 h at r. t. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 54 mg (33%).

[0217] 1H NMR (500 MHz, DMSO-de): 5 [ppm] = 8.44 (s, 1 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.23 (s, 2 H), 5.57 (t, J = 6.2 Hz, 1 H), 3.90 - 3.83 (m, 2 H), 3.79 - 3.71 (m, 2 H), 3.63 - 3.57 (m, 2 H), 3.53 (q, JH-F = 11 .6 Hz, 2 H), 2.90 - 2.82 (m, 2 H) ppm.

[0218] 13C NMR (125 MHz, DMSO-de) 5 [ppm] = 160.71 , 154.74, 154.48, 144.93, 140.21 , 130.19, 126.48 (q, JC-F = 276 Hz), 123.50, 120.01 , 50.58, 48.86, 47.34, 44.05, 37.90 (q, JC-F = 28 Hz) ppm.

[0219] 19F NMR (470 MHz, DMSO-de): - 64.71 ppm.

[0220] MS (ESI) calcd. for C16H19F3N7O3 ([M+H]+): m / z = 414, exp.: 414.

[0221] 3. Activity of the compounds against HCMV infection

[0222] To determine the activity of the novel CMV inhibitors the following assay was used: Normal human dermal fibroblasts (NHDF; obtained from Millipore, Darmstadt, Germany) were seeded into 96-well microtiter cell culture plates (10,000 cells / well) and propagated in Dulbecco’s modified Eagle medium containing 10% FCS, 100 U / ml penicillin, 100 pg / ml streptomycin and 2 mM L-glutamine (DMEM). The next day, cells were infected with a GFP-expressing HCMV strain (Borst and Messerle, 2000) at a low infection dose (multiplicity of infection [MOI] of 0.05 PFU / ml).

[0223] Inhibitors were initially dissolved in DMSO at a concentration of 10 mM (stock solutions) and then further diluted in DMEM medium. 3 h after virus inoculation the cell culture medium was replaced with DMEM containing the inhibitor at appropriate concentrations (3 wells per concentration [triplicates]). Depending on the activity of individual inhibitors, the examined concentrations ranged from 10 pM to low nanomolar values, applying 2- fold dilution steps. After incubation for 7 days the GFP signals of infected cell cultures in individual wells were measured with a plate reader (Cytation 3 Cell Imaging Multi-Mode Reader; Biotek, VT, USA). In wells without inhibitor, the GFP-expressing virus underwent two rounds of infection during the 7-day incubation period, resulting in spread of the viral infection to the majority of the cells and strong GFP expression (corresponding to 100% infection). GFP signals of inhibitor-treated cultures were calculated in relation to the untreated cultures (in %). Dose response curves are exemplarily shown for some of the inhibitors (Figure 1 ). The maximal inhibition is determined by the GFP signal resulting from cells that were infected in the first round, i.e. following inoculation of cultures with the HCMV-GFP variant (approx. 1 of 20 cells) [i.e. in the absence of further virus production and viral spread].

[0224] Figure 1 shows the activity of some of the HCMV inhibitors. The indicated substances were tested for inhibition of HCMV infection using the assay described in the text. Untreated cultures served as controls (black, dotted lines). Means + / - SD are depicted using GraphPad Prism software version 5.0. Concentrations of the inhibitors are indicated on the X-axis. Results are representative of 3 experiments performed.

[0225] 4. Antiviral potencies of the novel HCMV inhibitors

[0226] Half-maximal activity of the inhibitors (effective concentration 50 [EC50]) were calculated using CDD Vault software (Collaborative Drug Discovery; Burlingame, CA; www.collaborativedrug.com). The EC50 values as well as the structures of the inhibitor series are listed in Table 1 . Table 1 : Antiviral potencies of HCMV inhibitors

Claims

Claims1. A compound of formula (I):whereinCy is an optionally substituted heterocycloalkyl group comprising 7 ring atoms containing three nitrogen atoms and four carbon atoms; or an optionally substituted heterocycloalkyl group comprising 8, 9 or 10 ring atoms comprising two or three nitrogen atoms with the remainder being carbon atoms;Ar1is an optionally substituted phenyl group; an optionally substituted naphthyl group or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, 0 and S; andAr2is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, 0 and S; or a salt thereof.

2. A compound according to claim 1 , wherein Cy is an optionally substituted diazocane group or an optionally substituted triazepane group.

3. A compound according to claim 1 , wherein Cy is a 1 ,2,5 triazepane group, a 1 ,4 diazocane group, or a 1 ,5 diazocane group.

4. A compound according to claim 1 , wherein Cy is selected from the following groups:

5. A compound according to claim 1 of formula (II), (III), or (IV); or a salt thereof:

6. A compound according to any one of the preceding claims, wherein Ar1is an optionally substituted phenyl group.

7. A compound according to any one of the preceding claims, wherein Ar1is unsubstituted or substituted by a halogen atom, a CN group, an OH group, a C1-6 alkyl group, a C1-6 alkyloxy group, or a C3-7 cycloalkyl group.

8. A compound according to any one of the preceding claims 1 to 5, wherein Ar1is selected from the following groups:

9. A compound according to any one of the preceding claims, wherein Ar2is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, 0 and S.

10. A compound according to any one of the preceding claims, wherein Ar2is substituted by one or two substituents which are independently selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc, -OH, -OCH3 and -CN.

11. A compound according to any one of the preceding claims, wherein Ar2is selected from the following groups:

12. A compound according to any one of the preceding claims of formula (Ila), (Illa), or (IVa):wherein Ar1is defined as in any one of the preceding claims; or a salt thereof.

13. Pharmaceutical composition comprising a compound according to anyone of the preceding claims and optionally one or more carrier substances and / or one or more adjuvants.

14. Compound according to any one of claims 1 to 12 or pharmaceutical composition according to claim 13 for use as a medicament.

15. Compound according to any one of claims 1 to 12 or pharmaceutical composition according to claim 13 for use in the treatment or prevention of a herpesvirusinfection; especially for use in the treatment or prevention of a Cytomegalovirus (CMV) infection.

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