EP4665726A1

EP4665726A1 - Novel inhibitors of cytomegalovirus

Info

Publication number: EP4665726A1
Application number: EP24704818.4A
Authority: EP
Inventors: Mark BRÖNSTRUP; Martin Messerle; Nanaji Arisetti; Simon KALVERKAMP; Vadim KOROTKOV; Shahab NAHREVANIAN; Till ORTH; Jessica RÜCKERT; Thomas F. Schulz; Steffi STEPHEN; Karen Wagner
Original assignee: Helmholtz Zentrum fuer Infektionsforschung HZI GmbH; Medizinische Hochschule Hannover
Current assignee: Helmholtz Zentrum fuer Infektionsforschung HZI GmbH; Medizinische Hochschule Hannover
Priority date: 2023-02-16
Filing date: 2024-02-14
Publication date: 2025-12-24
Also published as: AU2024221841A1; WO2024170639A1; JP2026505488A; CN120693334A

Abstract

The present invention relates to novel inhibitors of Cytomegalovirus (CMV) of formula (I), wherein Cy is an optionally substituted 1,4 diazepane group; 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

Novel Inhibitors of Cytomegalovirus

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

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.

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.

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.

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 born 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).

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

Cy is an optionally substituted 1 ,4 diazepane group;

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

Preferably, Cy is unsubstituted or substituted by one or two substituents that are independently selected from -F, -CH3, -OH, -COOH, -CONH2, and =0.

Further preferably, Cy is unsubstituted or substituted by one or two substituents that are independently selected from -F, C1-4 alkyl, -OH, -COOH, -CONH2, and =0.

Moreover preferably, Cy is unsubstituted or substituted by one or two substituents that are independently selected from -F, -CH3, and -CH(CH3)2. Further preferably, Cy is selected from the following groups:

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

(II)-

Moreover preferably, Ar¹ is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S.

Further preferably, Ar¹ is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S.

Moreover preferably, Ar¹ is an optionally substituted phenyl group. Further preferably, Ar¹ is an optionally substituted pyridyl group.

Moreover preferably, Ar¹ is an optionally substituted heteroaryl group containing 9 ring atoms selected from C, N, O and S.

Further preferably, Ar¹ is unsubstituted.

Moreover preferably, Ar¹ is substituted by a halogen atom, a CN group, an OH group, a N3 group, a SFs group, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, O and S (wherein the optional substituents are preferably selected from halogen or a C1-6 alkyl group or a C1-6 heteroalkyl group), a heteroaralkyl group (e.g., a benzyloxy group), or a heteroalkylcycloalkyl group.

Further preferably, Ar¹ is substituted by a halogen atom, a CN group, a SFs group, a C1- 6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, or a heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, O and S.

Moreover preferably, Ar¹ is 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-propyl 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: Further preferably, Ar¹ is 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.

Moreover preferably, Ar¹ is substituted by a halogen atom, a N3 group, a SF5 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-tetra hydropyranyl 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:

Further preferably, Ar¹ is selected from the following groups:

Moreover preferably, Ar¹ is selected from the following groups: Further preferably, Ar² is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S.

Moreover preferably, Ar² is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, O and S.

Further preferably, Ar² is substituted by one or two substituents which are independently selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc -OH, -OCH3 and -CN.

Moreover preferably, Ar² is selected from the following groups:

Further preferably, Ar² is selected from the following groups: Further preferred are compounds of formula (III): wherein R² is selected from the following groups: -NH2, -OH, NHMe, -NMe2, -NHAc - OCH3 and -CN; or a salt thereof.

Moreover preferably, R² is NH2.

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

It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment of Ar¹ may be combined with any embodiment of Ar²).

According to one embodiment of the present invention, the following compounds as such are excluded from the present invention:

According to another embodiment, the use of these compounds in the treatment or prevention of a herpesvirus infection (especially in the treatment or prevention of a beta- herpesvirus infection; e.g., a Human Cytomegalovirus (HCMV) infection) is encompassed by the present invention.

According to a further embodiment of the present invention, the following compounds as such are excluded from the present invention:

According to another embodiment, the use of these compounds in the treatment or prevention of a herpesvirus infection (especially in the treatment or prevention of a beta- herpesvirus infection; e.g., a Human Cytomegalovirus (HCMV) infection) is encompassed by the present invention. 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, CHs), ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

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.

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).

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.

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).

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 C1-C6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and/or N (especially O and/or N). 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 O, S and/or N (especially O 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 O, S and/or N (especially O and/or N).

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.

Examples of heteroalkyl groups are groups of formulae: R^a-0-Y^a-, R^a-S-Y^a-, R^a-S0-Y^a-, R^a-S0₂-Y^a-, R^a-N(R^b)-S0₂-Y^a-, R^a-SO₂-N(R^b)-Y^a-, R^a-N(R^b)-Y^a-, R^a-C0-Y^a-,

R^a-C(=NR^d)-Y^a-, R^a-0-C0-Y^a-, R^a-C0-0-Y^a-, R^a-C0-N(R^b)-Y^a-, R^a-N(R^b)-C0-Y^a-, R^a-N(R^b)-C(=NR^d)-Y^a-, R^a-0-C0-N(R^b)-Y^a-, R^a-N(R^b)-CO-O-Y^a-, R^a-N(R^b)-CO-N(R^c)-Y^a-, R^a-0-C0-0-Y^a-, R^a-N(R^b)-C(=NR^d)-N(R^c)-Y^a-, R^a-CS-Y^a-, R^a-O-CS-Y^a-, R^a-CS-O-Y^a- R^a-CS-N(R^b)-Y^a-, R^a-N(R^b)-CS-Y^a-, R^a-O-CS-N(R^b)-Y^a-, R^a-N(R^b)-CS-O-Y^a-, R^a-N(R^b)-CS-N(R^c)-Y^a-, R^a-O-CS-O-Y^a-, R^a-S-CO-Y^a~, R^a-CO-S-Y^a-, R^a-S-CO-N(R^b)-Y^a-, R^a-N(R^b)-CO-S-Y^a-, R^a-S-C0-0-Y^a-, R^a-O-CO-S-Y^a-, R^a-S-CO-S-Y^a-, R^a-S-CS-Y^a-, R^a-CS-S-Y^a-, R^a-S-CS-N(R^b)-Y^a-, R^a-N(R^b)-CS-S-Y^a-, R^a-S-CS-O-Y^a-, R^a-O-CS-S-Y^a-, wherein R^a being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; R^b being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; R^c being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; R^d being a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group and Y^a being a bond, a C1-C6 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, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, -SCteMe, -NHAc, -CONH2, methoxyethyl, 1- methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, /V-ethyl-A/-methyl- carbamoyl or A/-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile (- CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

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. 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, O, 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.

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.

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 tri- unsaturated. 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.

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.

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. The expression heteroaralkyl refers to groups containing both aryl and/or heteroaryl groups and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or hetero- cycloalkyl groups in accordance with the above definitions. A heteroaralkyl group contains at least one heteroatom which is preferably selected from N, O and S. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, O and S) and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and N and/or one or two cycloalkyl groups each containing 5 or 6 ring carbon atoms and/or one or two heterocycloalkyl groups, each containing 5 or 6 ring atoms comprising 1 , 2, 3 or 4 oxygen, sulfur or nitrogen atoms.

Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl- heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl- alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkyl- cycloalkenyl and 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.

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.

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

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.

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.

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, -N₃ and -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-Cis aryl, C1-C17 heteroaryl, C7-C20 aralkyl and C1-C19 heteroaralkyl groups; especially C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl and C1-C11 heteroaralkyl groups, further preferably C1-C6 alkyl and C1-C6 heteroalkyl groups.

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.

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.

It should be appreciated that certain compounds of formula (I), (II) or (Illi) 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 of formula (I), (II) or (Illi) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.

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 of formula (I), (II) or (Illi). The term hydrogen also encompasses deuterium.

The therapeutic use of compounds according to formula (I), (II) or (Illi), 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.

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

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

The present invention moreover provides the use of a compound or a pharmaceutical composition as described herein for the preparation of a medicament for use in the treatment or prevention of a herpesvirus infection. 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 of formula (I), (II) or (Illi), or a salt thereof.

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 of formula (I), (II) or (Illi), or a salt thereof.

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.

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

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 of formula (I), (II) or (Illi). 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.

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.

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

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.

EXAMPLES

I. Synthesis of the compounds of the present invention

Abbreviations and Acronyms

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

Ar argon

Boc tert-Butyloxycarbonyl br. broad CDCI₃ deuterated chloroform CD₃OD deuterated methanol cHex cyclohexane cone, Concentrated d doublet DCM dichloromethane

DIPEA Diisopropylethylamine

DMSO dimethylsulfoxide DMSO-de deuterated dimethylsulfoxide ESI electrospray EtOAc ethyl acetate

EtOH ethanol h hour hept heptet HCI hydrochloric acid

HPLC high performance liquid chromatography

H₂O water

H2SO4 sulfuric acid m multiplet

MeCN acetonitrile

MeOH methanol min minutes MS mass spectrometry NaHCOs sodium hydrogencarbonate

NaCI sodium chloride NaOH sodium hydroxide Na2SO4 sodium sulfate NMR nuclear magnetic resonance

Ns 2-nosyl, 2-nitrobenzenesulfonyl q quartet quint quintet r. t. room temperature s singlet sat. saturated t triplet

TFA trifluoroacetic acid

UPLC Ultra Performance Liquid Chromatography wt weight

1. Methods of making the compounds of the present invention

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.

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

2. Experimental procedures

LC-MS method

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.

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

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

Flash chromatography method

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.

Preparative HPLC method

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

Column: Luna® Prep C18 5 pm, 21.2 x 250 mm

Flow: 10 mL/min

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

Accurate Mass method

High resolution masses were obtained using Maxis II TM HD mass spectrometer (Bruker).

NMR methods

Proton (¹H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker Avance III (500MHz) or a Bruker Avance III (700MHz) spectrometer with residual protonated solvent (CHCI3 5 7.26; MeOH 6 3.30; DMSO 5 2.49) as standard. The NMR data of the synthesized examples are in agreement with their corresponding structural assignments.

2.1 Experimental Examples of the Invention

2.1.1 Synthetic methods

Synthesis of HCMV Inhibitors (Scheme 1)

General Procedure 1 (GP1). Isocyanate synthesis. triphosgene, Et₃N

A solution of an aniline derivative (0.6 mmol, 1.0 eq.) in dry DCM (3 mL) was treated with triphosgene (89 mg, 0.3 mmol, 0.5 eq.) followed by the dropwise addition of EtsN (97 μL, 0.66 mmol, 1.1 eq.). The reaction was stirred for 3 h at r. t.. The solvent was removed under reduced pressure to yield a solid, which was directly used in the next step.

General Procedure 2 (GP2). Synthesis of tert-Butyl 4-(arylcarbamoyl)-1,4- diazepane-1 -carboxylate

To the solution of an isocyanate (0.6 mmol, 1.0 eq.) in dry toluene (5 mL) was added a solution of fert-butyl 1 ,4-diazepane-1 -carboxylate (1) (0.6 mmol, 1.0 eq.) in dry THF (5 mL). The reaction mixture stirred overnight at r.t.. The reaction was quenched by the addition of water (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered and the solvent is removed under reduced pressure to yield the product (2), which was directly used in the next step.

General Procedure 3 (GP3). Synthesis of N-Aryl-1,4-diazepane-1 -carboxamide

TFA (5 mL) was added dropwise to the solution of crude tert-butyl 4-(arylcarbamoyl)-1,4- diazepane-1 -carboxylate (2) (0.6 mmol) in DCM (5 mL). The reaction mixture was stirred for 3 h at r.t.. The solvent was removed under reduced pressure to give the product (3) that was used for the next step without further purification.

General Procedure 4 (GP4). Amide Coupling

To the solution of crude A/-aryl-1 ,4-diazepane-1 -carboxamide (3) (0.6 mmol, 1 eq.) in DMF (2 mL ) 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (77 mg, 0.6 mmol, 1 eq.), HATU (274 mg, 0.72 mmol, 1.2 eq.) in DMF (3 mL) and DIPEA (430 μL, 3 mmol, 5 eq.) were added. The resulting mixture was stirred overnight at room temperature. EtOAc (100 mL) was added. The reaction mixture was washed with saturated NH4CI (2 x 100 mL), 1M NaOH (2 x 100 mL) and brine (100 mL). The organic phase was dried over Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by HPLC (C18, MeCN/water 0.1 % HCOOH). The product containing fractions were lyophilized to dryness yielding the desired product.

Pentafluoro(4-isocyanatophenyl)-A⁶-sulfane (6)

To a solution of 4-aminophenylsulfurpentafluoride (200 mg, 0.91 mmol) in DCM (2 mL) a solution of triphosgene (270 mg, 0.91 mmol) in DCM (2 mL) was added followed by the dropwise addition of EtsN (0.38 mL, 2.74 mmol) in DCM (1 mL). The reaction was stirred for 18 h at r. t.. Toluene (10 mL) and triphosgene (135 mg, 0.46 mmol) were added and the reaction was stirred for 18 h at 70 °C. After completion of the reaction pentane (1 mL) was added that immediately resulted in the formation of a white precipitate. The suspension was filtered and the filtrate was concentrated under reduced pressure to yield an orange oil. The product was directly used in the next step. t-Butyl 4-((4-(pentafluoro-A⁶-sulfaneyl)phenyl)carbamoyl)-1 ,4-diazepane-1 - carboxylate (7) f-Buty I 4-((4-(pentafluoro-A6-sulfaneyl)phenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (7) was prepared according to GP2 starting from the solution of crude 6 (0.91 mmol) in toluene (5 mL) and the solution of ferf-butyl 1 ,4-diazepane-1 -carboxylate (1) (183 mg, 0.91 mmol) in dry THF (5 mL). The product was directly used in the next step.

N -(4-(pentafluoro-A⁶-sulfaney l)pheny l)-1 ,4-diazepane-1 -carboxamide (8)

N -(4-(pentafluoro-A⁶-sulfaneyl)phenyl)-1 ,4-diazepane-1 -carboxamide (8) was prepared according to GP3 starting from crude 7 (0.91 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step.

4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N -(4-(pentafluoro-A⁶-sulfaneyl)phenyl)- 1,4-diazepane-1 -carboxamide (3TO 025)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-(pentafluoro-A⁶-sulfaneyl)phenyl)-1 ,4- diazepane-1 -carboxamide (3TO 025) was prepared according to the general procedure GP4 starting from crude 8 (0.91 mmol) in DMF (5 mL), 4-amino-1 ,2,5-oxadiazole-3- carboxylic acid (4) (133 mg, 1.0 mmol), HATU (468 mg, 1.2 mmol), HOBt (173 mg, 1.3 mmol) and DIPEA (0.9 mL, 5.1 mmol). Yield: 165.0 mg (0.362 mmol, 32 %). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (700 MHz, DMSO-d6) δ [ppm] = 8.82 (s, 0.5H), 8.78 (s, 0.5H), 7.75 (d, J = 9.2 Hz, 1 H), 7.74 (d, J = 9.2 Hz, 1 H), 7.70 (d, J = 9.2 Hz, 1 H), 7.66 (d, J = 9.2 Hz, 1 H), 6.36 (s, 1 H), 6.33 (s, 1 H), 3.85 - 3.79 (m, 2H), 3.74 - 3.70 (m, 1 H), 3.69 - 3.65 (m, 3H), 3.63 - 3.58 (m, 2H), 1.91 - 1 .80 (m, 2H).

¹³C NMR (176 MHz, DMSO-d6) δ [ppm] = 158.48, 158.36, 156.18, 156.08, 154.25, 154.20, 144.00, 143.92, 141.37, 141.33, 126.21 , 126.19, 118.89, 118.83, 49.02, 47.67, 47.55, 46.33, 45.95, 45.64, 45.14, 45.06, 28.28, 25.84.

¹⁹F NMR (471 MHz, DMSO-d6) δ [ppm] = 89.54 (p, J = 150 Hz, 1 F), 65.18 (d, J = 150 Hz, 4F).

HRMS (ESI) calcd. for C15H18F5N6O3S ([M+H]⁺): m/z = 457.1081 , exp.: 457.1091.

4-Cyclopropylphenyl isocyanate (9)

4-Cyclopropylphenyl isocyanate (9) was prepared according to GP1 starting from 4-cyclopropylaniline hydrochloride (100 mg, 0.59 mmol), triphosgene (87 mg, 0.3 mmol) and EtsN (1.23 mL, 8.84 mmol) in DCM (3 mL). The product was directly used for the next step. tert-Buty I 4-((4-cyclopropy Ipheny l)carbamoy l)-1 ,4-diazepane-1 -carboxylate (10) tert-Butyl 4-((4-cyclopropylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (10) was prepared according to the general procedure GP2 starting from the solution of crude 9 (0.59 mmol) in toluene (5 mL) and a solution of tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (118 mg, 0.59 mmol) in THF (5 mL). The product was directly used for the next step.

N-(4-cyclopropy Ipheny l)-1 ,4-diazepane-1 -carboxamide (11 )

N -(4-cyclopropylphenyl)-1 ,4-diazepane-1 -carboxamide (11) was prepared according to GP3 starting from crude 10 (0.59 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step without further purification.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-cyclopropylphenyl)-1 ,4-diazepane-1 - carboxamide (3TO 026)

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(4-cyclopropylphenyl)-1 ,4-diazepane-1- carboxamide (3TO 026) was prepared according to GP4 starting from the solution of crude 11 (0.59 mmol) in DMF (5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (76 mg, 0.59 mmol), HATU (269 mg, 0.70 mmol) and DIPEA (0.5 mL, 2.9 mmol). Yield: 82.0 mg (0.22 mmol, 38 %). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (700 MHz, DMSO-d6) δ [ppm] = 8.25 (s, 0.5H), 8.21 (s, 0.5H), 7.31 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.41 - 6.27 (bs, 2H), 3.83 - 3.75 (m, 2H), 3.72 - 3.60 (m, 4H), 3.59 - 3.54 (m, 2H), 1.89 - 1.85 (m, 1 H), 1.84 - 1.77 (m, 2H), 0.90 - 0.84 (m, 2H), 0.60 - 0.55 (m, 2H).

¹³C NMR (176 MHz, DMSO-d6) δ [ppm] = 158.46, 158.34, 156.19, 156.07, 154.76, 154.69, 141.38, 141.36, 137.71, 137.58, 137.05, 136.98, 125.13, 125.10, 120.52, 120.35, 49.27, 47.67, 47.54, 46.54, 45.73, 45.59, 45.22, 44.94, 28.30, 25.88, 14.51, 8.84.

HRMS (ESI) calcd. for C18H23N6O3 ([M+H]⁺): m/z = 371.1832, exp.: 371.1827.

1 -Ethy ny l-4-isocyanatobenzene (12)

1 -Ethynyl-4-isocyanatobenzene (12) was obtained according to GP1 starting from 4-ethynylaniline (100 mg, 0.85 mmol), triphosgene (127 mg, 0.43 mmol) and EtsN (0.12 mL, 0.85 mmol) in toluene (10 mL). The product was directly used in the next step. fert-Butyl 4-((4-Ethynylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (13) tert- Butyl 4-((4-ethynylphenyl)carbamoyl)-1,4-diazepane-1 -carboxylate (13) was prepared according to the general procedure GP2 starting from the solution of crude 12 (0.85 mmol) in toluene (5 mL) and a solution of tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (171 mg, 0.85 mmol) in THF (5 mL). The product was directly used for the next step.

N-(4-(1-chlorovinyl)phenyl)-1,4-diazepane-1 -carboxamide (14)

To a solution of crude 13 (150 mg, 0.44 mmol) in 1 ,4-dioxane (3 mL) was added HCI (5 mL, 4 M in 1,4-dioxane). The reaction mixture was stirred for 18 h at r. t. and was concentrated under reduced pressure. The crude product 14 was used for the next step without further purification.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-(1 -chlorovinyl)phenyl)-1 ,4- diazepane-1 -carboxamide (3TO 064)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-(1-chlorovinyl)phenyl)-1 ,4-diazepane-1- carboxamide (3TO 064) was prepared according to GP4 starting from the solution of crude 14 (0.44 mmol) in DMF (5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (56 mg, 0.44 mmol), HATLI (199 mg, 0.52 mmol) and DIPEA (0.3 mL, 2.2 mmol). Yield: 60.0 mg (35%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.57 (s, 0.5H), 8.54 (s, 0.5H), 7.58 - 7.48 (m, 4H), 6.38 (s, 1 H), 6.35 (s, 1 H), 5.94 (d, J = 2.1 Hz, 1 H), 5.47 (dd, J = 2.1 , 0.9 Hz, 1 H), 3.85 - 3.77 (m, 2H), 3.73 - 3.63 (m, 4H), 3.63 - 3.56 (m, 2H), 1.91 - 1 .79 (m, 2H).

¹³C NMR (125 MHz, DMSO-d6) δ [ppm] = 158.51 , 158.38, 156.21 , 156.10, 154.47, 154.42, 141.69, 141.58, 141.42, 141.38, 138.50, 129.12, 129.08, 126.28, 126.24, 119.39, 119.27, 111.75, 49.18, 47.70, 47.59, 46.47, 45.89, 45.64, 45.20, 45.02, 28.35, 25.90. HRMS (ESI) calcd. for C17H20CIN6O3 ([M+H]⁺): m/z = 391.1285, exp.: 391.1284.

4-(Trifluoromethylthio)phenyl Isocyanate (15)

4-(Trifluoromethylthio)phenyl isocyanate (15) was obtained according to GP1 starting from 4-(trifluoromethylthio)aniline (100 mg, 0.52 mmol), triphosgene (77 mg, 0.26 mmol) and EtsN (70 μL, 0.52 mmol) in toluene (10 mL). The product was directly used in the next step. tert-Butyl 4-((4-((T rifluoromethyl)thio)phenyl)carbamoyl)-1 ,4-diazepane-1 - carboxylate (16)

tert-B uty I 4-((4-((trifluoromethyl)thio)phenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate

(16) was prepared according to the general procedure GP2 starting from the solution of crude 15 (0.52 mmol) in dry toluene (5 mL) and a solution of tert-butyl 1 ,4-diazepane-1- carboxylate (1) (104 mg, 0.52 mmol) in THF (5 mL). The product was directly used for the next step.

N -(4-((Trifluoromethyl)thio)phenyl)-1,4-diazepane-1 -carboxamide (17)

N -(4-((Trifluoromethyl)thio)phenyl)-1 ,4-diazepane-1 -carboxamide (17) was prepared according to GP3 starting from crude 16 (0.52 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step without further purification.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-((trifluoromethyl)thio)phenyl)-1,4- diazepane-1 -carboxamide (3TO 044)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/\/-(4-((trifluoromethyl)thio)phenyl)-1 ,4- diazepane-1 -carboxamide (3TO 044) was prepared according to GP4 starting from the solution of crude 17 (0.52 mmol) in DMF (5 ml_), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (67 mg, 0.52 mmol), HATU (236 mg, 0.62 mmol), HOBt (87 mg, 0.65 mmol) and DIPEA (0.44 mL, 2.6 mmol). Yield: 85.0 mg (38 %). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.70 (s, 0.5H), 8.66 (s, 0.5H), 7.65 (d, J = 8.8 Hz, 1 H), 7.61 (d, J = 8.8 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 6.36 (s, 1H), 6.34 (s, 1H), 3.85 - 3.77 (m, 2H), 3.74 - 3.69 (m, 1H), 3.69 - 3.64 (m, 3H), 3.63 - 3.58 (m, 2H), 1.91 - 1 .79 (m, 2H).

¹³C NMR (176 MHz, DMSO-d6) δ [ppm] = 158.48, 158.35, 156.19, 156.08, 154.33, 154.27, 143.80, 143.71 , 141.36, 141.32, 136.86, 136.82, 129.72 (q, J CF = 309 Hz), 120.48, 120.41 , 113.90, 113.86, 49.11 , 47.66, 47.61 , 46.38, 45.90, 45.67, 45.16, 45.03, 28.26, 25.82.

¹⁹F NMR (471 MHz, DMSO-d6) δ [ppm] = -43.09.

HRMS (ESI) calcd. for CieHisFsNeOsS ([M+H]⁺): m/z = 431.1113, exp.: 431.1117. tert-Butyl 4-((3-Chlorophenyl)carbarnoyl)-1 ,4-diazepane-1 -carboxylate (18)

terf-Butyl 4-((3-Chlorophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (18) was prepared according to the general procedure GP2 starting from the solution of crude 3- chlorophenyl isocyanate (120 mg, 0.78 mmol) in dry THF (2 mL) and a solution of tertbutyl 1 ,4-diazepane-1 -carboxylate (1) (157 mg, 0.78 mmol) in THF (3 mL). The product was directly used for the next step.

/V-(3-Chlorophenyl)-1,4-diazepane-1 -carboxamide (19)

N -(3-Chlorophenyl)-1 ,4-diazepane-1 -carboxamide (19) was prepared according to GP3 starting from crude tert-butyl 4-((3-chlorophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (18) (0.78 mmol) in DCM (5 mL) and TFA (5 mL). The product was directly used in the next step without further purification.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N -(3-chlorophenyl)-1,4-diazepane-1- carboxamide (3TO 031)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(3-chlorophenyl)-1 ,4-diazepane-1 - carboxamide (3TO 031) was prepared according to GP4 starting from the solution of crude 19 (0.78 mmol) in DMF (5 ml_), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (101 mg, 0.78 mmol), HATU (357 mg, 0.94 mmol) and DIPEA (0.66 mL, 3.9 mmol). Yield: 106.0 mg (37 %). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (700 MHz, DMSO-d6) δ [ppm] = 8.52 (s, 0.5H), 8.48 (s, 0.5H), 7.66 (t, J = 2.1 Hz, 0.5H), 7.61 (t, J = 2.1 Hz, 0.5H), 7.42 (ddd, J = 8.2, 2.1 , 1.0 Hz, 0.5H), 7.38 (ddd, J = 8.2, 2.1 , 1.0 Hz, 0.5H), 7.25 (t, J = 8.2 Hz, 0.5H), 7.24 (t, J = 8.2 Hz, 0.5H), 6.99 - 6.98 (m, 0.5H), 6.98 - 6.97 (m, 0.5H), 6.44 - 6.20 (br. s, 2H), 3.84 - 3.77 (m, 2H), 3.72 - 3.63 (m, 4H), 3.62 - 3.54 (m, 2H), 1.91 - 1.78 (m, 2H).

¹³C NMR (176 MHz, DMSO-d6) δ [ppm] = 158.49, 158.34, 156.18, 156.08, 154.37, 154.34, 142.03, 141.91 , 141.37, 141.34, 132.63, 132.59, 129.84, 129.78, 121.43, 121.38, 119.33, 119.20, 118.19, 118.08, 49.14, 47.66, 47.57, 46.42, 45.80, 45.63, 45.16, 44.98, 28.25, 25.79.

HRMS (ESI) calcd. for Ci₅Hi8CIN₆O3 ([M+H]⁺): m/z = 356.1129, exp.: 365.1126. tert-Butyl 4-((4-lsopropylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (20)

Boc terf-Butyl 4-((4-isopropylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (20) was prepared according to the general procedure GP2 starting from the solution of 4- isopropylphenyl isocyanate (684 mg, 4.2 mmol) in dry THF (15 mL) and a solution of tertbutyl 1 ,4-diazepane-1 -carboxylate (1) (850 mg, 4.2 mmol) in dry THF (15 mL). The product was directly used for the next step.

N-(4-lsopropylphenyl)-1,4-diazepane-1 -carboxamide (3TO 073)

N -(4-lsopropylphenyl)-1 ,4-diazepane-1 -carboxamide (3TO 073) was prepared according to GP3 starting from crude 20 (4.2 mmol) in DCM (20 mL) and TFA (5 mL). The product was directly used in the next step without further purification.

¹H NMR (700 MHz, DMSO-d6) δ [ppm] = 8.72 (s, 1 H), 7.37 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz , 2H), 3.72 - 3.67 (m, 2H), 3.58 - 3.55 (m, 1 H), 3.23 - 3.16 (m, 4H), 2.81 (hept, J = 6.9 Hz, 1 H), 2.02 - 1.97 (m, 2H), 1.17 (d, J = 6.9 Hz, 6H).

¹³C NMR (176 MHz, DMSO-d₆) 5 [ppm] = 154.94, 142.04, 137.97, 125.91 , 120.30, 54.90, 46.21 , 44.81 , 44.66, 42.20, 32.75, 24.02.

HRMS (ESI) calcd. for C15H24N3O ([M+H]⁺): m/z = 262.1919, exp.: 262.1912.

4-(4-Amino-'1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropy Ipheny l)-1 ,4-diazepane-1 - carboxamide (SK-C11)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-1 ,4-diazepane-1 - carboxamide (SK-C11) was prepared according to GP4 starting from the solution of crude 3TO 073 (0.42 mmol) in DMF (0.5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 92 mg (25%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.26 (s, 0.5H), 8.23 (s, 0.5H), 7.35 (d, J = 8.5 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1 H), 6.36 (s, 1 H), 6.34 (s, 1 H), 3.82 - 3.77 (m, 2H), 3.70 - 3.61 (m, 4H), 3.59 - 3.55 (m, 2H), 2.80 (hept, J = 6.9 Hz, 1 H), 1.90 - 1.79 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H).

¹³C NMR (126 MHz, DMSO-d6) δ [ppm] = 158.57, 158.33, 156.18, 156.07, 154.80, 154.74, 142.01 , 141.94, 141.39, 141.38, 138.02, 137.91 , 125.89, 125.86, 120.52, 120.34, 49.29, 47.67, 47.58, 46.53, 45.71 , 45.62, 45.22, 44.95, 32.76, 28.29, 25.88, 24.03.

MS (ESI) calcd. for C18H25N6O3 ([M+H]⁺): m/z = 373, exp.: 373.

4-(4-Amino-1,2,5-thiadiazole-3-carbonyl)-N -(4-isopropylphenyl)-1,4-diazepane-1- carboxamide (3TO 077)

4-(4-Amino-1 ,2,5-thiadiazole-3-carbonyl)-/V-(4-isopropylphenyl)-1 ,4-diazepane-1- carboxamide (3TO 077) was prepared according to GP4 starting from the solution of crude 3TO 073 (75 mg, 0.29 mmol) in DMF (4 mL), 4-amino-1 ,2,5-thiadiazole-3- carboxylic acid (42 mg, 0.29 mmol), HATU (131 mg, 0.34 mmol) and EtsN (0.4 mL, 2.9 mmol). Yield: 48.0 mg (43%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.27 (s, 0.5H), 8.23 (s, 0.5H), 7.35 (d, J = 8.6 Hz, 1 H), 7.30 (d, J = 8.6 Hz, 1 H), 7.08 (d, J = 8.6 Hz, 1 H), 7.07 (d, J = 8.6 Hz, 1 H), 3.88 (t, J = 5.4 Hz, 1 H), 3.81 - 3.75 (m, 1 H), 3.72 (t, J = 5.9 Hz, 1 H), 3.68 - 3.61 (m, 3H), 3.60 - 3.53 (m, 2H), 2.80 (hept, J = 6.9 Hz, 1 H), 1.92 - 1.81 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H). ¹³C NMR (126 MHz, DMSO-d6) δ [ppm] = 161.92, 161.64, 161.28, 161.08, 154.84, 154.81 , 141.97, 141.93, 140.85, 140.69, 138.11 , 138.02, 125.94, 125.91 , 120.47, 120.36, 49.62, 48.05, 47.85, 46.94, 45.82, 45.70, 45.48, 44.96, 32.82, 28.42, 25.88, 24.10.

HRMS (ESI) calcd. for C18H25N6O2S ([M+H]⁺): m/z = 389.1760, exp.: 389.1755. tert-Butyl 4-((4-Butylpheny l)carbamoyl)-1 ,4-diazepane-1 -carboxylate (21 ) tert-Butyl 4-((4-butylphenyl)carbamoyl)-1,4-diazepane-1 -carboxylate (21) was prepared according to the general procedure GP2 starting from 4-butylphenyl isocyanate (1.2 mmol) and tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (250 mg, 1.2 mmol) in dry THF (2.5 mL). The product was directly used for the next step. Yield: 400 mg (86%).

N -(4-Butylphenyl)-1 ,4-diazepane-1 -carboxamide (22)

To the solution of tert-butyl 4-((4-butylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (21) (250 mg, 0.69 mmol) in DCM (2.5 mL) was added HCI (4 M in dioxane, 0.5 mL) and the mixture was stirred overnight at rt. Volatiles were removed under reduced pressure to give the desired product 22 (223 mg, 94%) as a white solid. The crude product was used further without any purification.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-butylphenyl)-1 ,4-diazepane-1 - carboxamide (SK-C14)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-butylphenyl)-1 ,4-diazepane-1- carboxamide (SK-C14) was prepared according to GP4 starting from the solution of crude 22 (0.42 mmol) in DMF (0.5 mL), 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 92 mg (24%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.26 (s, 0.5H), 8.22 (s, 0.5H), 7.34 (d, J = 8.5 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 6.36 (s, 1 H), 6.34 (s, 1H), 3.82 - 3.77 (m, 2H), 3.70 - 3.61 (m, 4H), 3.59 - 3.55 (m, 2H), 1.91 - 1.77 (m, 2H), 1.55 - 1.46 (m, 2H), 1.32 - 1.22 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H).

MS (ESI) calcd. for C19H27N6O3 ([M+H]⁺): m/z = 387, exp.: 387. tert-Butyl 4-((4-tert-Butylphenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (23) tert-Butyl 4-((4-tert-butylphenyl)carbamoyl)-1 ,4-diazepane-1-carboxylate (23) was prepared according to the general procedure GP2 starting from 4-tenf-butylphenyl isocyanate (200 μL, 1.2 mmol) and terf-butyl 1 ,4-diazepane-1 -carboxylate (1) (250 mg, 1.2 mmol) in dry THF (2.5 mL). The product was directly used for the next step.

/V-(4-tert-Butylphenyl)-1 ,4-diazepane-1 -carboxamide (24)

To the solution of tert-butyl 4-((4-tert-butylphenyl)carbamoyl)-1 ,4-diazepane-1- carboxylate (23) (250 mg, 0.69 mmol) in DCM (2.5 mL) was added HCI (4 M in dioxane, 0.5 mL ) and the mixture was stirred overnight at rt. Volatiles were removed under reduced pressure to give the desired product (24) (239 mg, 96%) as a white solid. The crude product was used further without any purification.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-(tert-butyl)phenyl)-1 ,4-diazepane-1 - carboxamide (SK-C12)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-(tert-butyl)phenyl)-1 ,4-diazepane-1- carboxamide (SK-C12) was prepared according to GP4 starting from the solution of crude 24 (0.42 mmol) in DMF (0.5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 60 mg (16%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.27 (s, 0.5H), 8.24 (s, 0.5H), 7.36 (d, J = 8.7 Hz, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 7.23 (d, J = 8.7 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 6.36 (s, 1 H), 6.34 (s, 1 H), 3.82 - 3.77 (m, 2H), 3.70 - 3.61 (m, 4H), 3.59 - 3.55 (m, 2H), 1 .91 - 1.77 (m, 2H), 1.24 (s, 9H). tert-Butyl 4-((4-(T rifluoromethyl)pheny l)carbamoyl)-1 ,4-diazepane-1 -carboxylate (25)

te/t-Butyl 4-((4-(trifluoromethyl)phenyl)carbamoyl)-1 ,4-diazepane-1-carboxylate (25) was prepared according to the general procedure GP2 starting from 4-(trifluoromethyl)phenyl isocyanate (180 μL, 1.2 mmol) and tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (250 mg, 1.2 mmol) in dry THF (2.5 mL). The product was directly used for the next step.

/V-(4-(T rifluoromethyl)phenyl)-1 ,4-diazepane-1 -carboxamide (26)

To the solution of terf-butyl 4-((4-(trifluoromethyl)phenyl)carbamoyl)-1 ,4-diazepane-1- carboxylate (25) (250 mg, 0.64 mmol) in DCM (5 mL) was added HCI (4 M in dioxane, 0.8 mL) and the mixture was stirred overnight at rt. Volatiles were removed under reduced pressure to give the desired product (26) (220 mg, 95%) as a white solid. The crude product was used further without any purification.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(4-(trifluoromethyl)phenyl)-1,4- diazepane-1 -carboxamide (SK-C24)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-(trifluoromethyl)phenyl)-1,4-diazepane-1- carboxamide (SK-C24) was prepared according to GP4 starting from the solution of crude 26 (0.42 mmol) in DMF (0.5 ml_), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 20 mg (5%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.73 (s, 0.5H), 8.69 (s, 0.5H), 7.70 (d, J = 8.5 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.58 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 6.36 (s, 1 H), 6.33 (s, 1 H), 3.85 - 3.78 (m, 2H), 3.74 - 3.70 (m, 1 H), 3.70 - 3.65 (m, 3H), 3.64 - 3.58 (m, 2H), 1.90 - 1 .80 (m, 2H).

MS (ESI) calcd. for C16H18 F₃N₆O₂ ([M+H]⁺): m/z = 399, exp.: 399. tert-Butyl 4-( [1 ,T-Biphenyl]-4-ylcarbamoyl)-1 ,4-diazepane-1 -carboxylate (27) terf-Butyl 4-([1 ,1'-biphenyl]-4-ylcarbamoyl)-1 ,4-diazepane-1 -carboxylate (27) was prepared according to the general procedure GP2 starting from 4-biphenylyl isocyanate (244 mg, 1.2 mmol) and ferf-butyl 1 ,4-diazepane-1 -carboxylate (1) (250 mg, 1.2 mmol) in dry THF (2.5 mL). The product was directly used for the next step. /V-([1,1'-Biphenyl]-4-yl)-1,4-diazepane-1 -carboxamide (28)

To the solution of 27 (250 mg, 0.63 mmol) in DCM (5 mL) was added HCI (4 M in dioxane, 850 pL) and the mixture was stirred overnight at rt. Volatiles were removed under reduced pressure to give the desired product 28 (220 mg, 97%) as a white solid. The crude product was used further without any purification.

W-([1,1’-Biphenyl]-4-yl)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1- carboxamide (SK-C25)

N -([ 1 , 1 '-Biphenyl]-4-yl)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamide (SK-C25) was prepared according to GP4 starting from the solution of crude 28 (0.42 mmol) in DMF (0.5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 37 mg (9%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.46 (s, 0.5H), 8.43 (s, 0.5H), 7.62 (d, J = 7.2 Hz, 2H), 7.58 - 7.52 (m, 4H), 7.45 - 7.39 (m, 2H), 7.33 - 7.28 (m, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.86 - 3.79 (m, 2H), 3.74 - 3.65 (m, 4H), 3.63 - 3.58 (m, 2H), 1.93 - 1.80 (m, 2H).

MS (ESI) calcd. for C21H23N6O3 ([M+H]⁺): m/z = 407, exp.: 407. tert-Butyl 4-((4-Bromophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (29) tert-Butyl 4-((4-bromophenyl)carbamoyl)-1,4-diazepane-1 -carboxylate (29) was prepared according to the general procedure GP2 starting from 4-bromophenyl isocyanate (193 mg, 1.0 mmol) and tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (200 mg, 1.0 mmol) in dry THF (2.5 mL). The product was directly used for the next step.

N -(4-Bromophenyl)-1 ,4-diazepane-1 -carboxamide (30)

N -(4-Bromophenyl)-1,4-diazepane-1 -carboxamide (30) was prepared according to GP3 starting from crude 29 (220 mg, 0.55 mmol) in DCM (2.5 mL) and TFA (2.5 mL). The product 30 was directly used in the next step without further purification.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbony l)-N-(4-bromopheny l)-1 ,4-diazepane-1 - carboxamide (SK-C37)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-bromophenyl)-1 ,4-diazepane-1 - carboxamide (SK-C37) was prepared according to GP4 starting from the solution of crude 30 (140 mg, 0.42 mmol) in DMF (0.5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 80 mg (46%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.48 (s, 0.5H), 8.44 (s, 0.5H), 7.51 (d, J = 9.0 Hz, 1 H), 7.46 (d, J = 9.0 Hz, 1 H), 7.28 (d, J = 9.0 Hz, 1 H), 7.27 (d, J = 9.0 Hz, 1 H), 6.37 (s, 1 H), 6.34 (s, 1 H), 3.84 - 3.77 (m, 2H), 3.72 - 3.63 (m, 4H), 3.62 - 3.55 (m, 2H), 1.91 - 1.77 (m, 2H). tert-Buty I 4-((4-lodophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (31 ) tert- Butyl 4-((4-iodophenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (31) was prepared according to the general procedure GP2 starting from 4-iodophenyl isocyanate (242 mg, 1.0 mmol) and terf-butyl 1 ,4-diazepane-1 -carboxylate (1) (200 mg, 1.0 mmol) in dry THF (2.5 mL). The product was directly used for the next step. Yield: 430 mg (98%). N -(4-lodopheny I )-1 ,4-diazepane-1 -carboxamide (32)

N -(4-lodophenyl)-1 ,4-diazepane-1 -carboxamide (32) was prepared according to GP3 starting from crude 31 (220 mg, 0.49 mmol) in DCM (2.5 mL) and TFA (2.5 mL). The product 32 was directly used in the next step without further purification.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N -(4-iodophenyl)-1,4-diazepane-1- carboxamide (SK-C36)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-iodophenyl)-1 ,4-diazepane-1- carboxamide (SK-C36) was prepared according to GP4 starting from the solution of crude 32 (114 mg, 0.42 mmol) in DMF (0.5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (50 mg, 0.38 mmol), HATU (176 mg, 0.47 mmol) and DIPEA (0.33 mL). Yield: 60 mg (17%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.25 (s, 0.5H), 8.22 (s, 0.5H), 7.33 (d, J = 8.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 6.36 (s, 1 H), 6.34 (s, 1 H), 3.82 - 3.77 (m, 2H), 3.70 - 3.61 (m, 4H), 3.59 - 3.55 (m, 2H), 1.90 - 1.78 (m, 2H). MS (ESI) calcd. for C15H18IN6O3 ([M+H]⁺): m/z = 457, exp.: 457.

4-((tert-Butoxycarbonyl)amino)thiazole-5-carboxylic acid (33)

To a solution of methyl 4-amino-5-thiazolecarboxylate (400 mg, 2.5 mmol) and EtsN (710 p, 512 mg, 5.1 mmol) in dry DCM (30 mL) under Ar was added BOC2O (1100 mg, 5.1 mmol) and DMAP (62 mg, 0.5 mmol). The reaction mixture was stirred at r. t. for 18 h. Volatiles were removed under reduced pressure. The residue was dissolved in EtOH (20 mL) and THF (10 mL). Aq. NaOH (30 mL, 1 M) was added and the reaction mixture was stirred for 3 h at 70 °C. The mixture was allowed to cool down to r. t. and the pH was adjusted to 4-5 by adding cone. HCL The mixture was extracted with EtOAc (3x). Combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography (RP, C18, MeCN : H2O) yielding 337 mg (55%) of the desired compound 33.

4-(4-Aminothiazole-5-carbonyl)-/V-(4-isopropylphenyl)-1,4-diazepane-1- carboxamide (AR753)

To the solution of the crude compound 3TO 073 (107 mg, 0.40 mmol) in DMF (8 mL), the compound 33 (77 mg, 0.6 mmol, 1 eq.), HATU (187 mg, 0.49 mmol) and DIPEA (357 μL, 2.1 mmol) were added. The resulting mixture was stirred overnight at r. t. H2O was added and the mixture was extracted with EtOAc (3x). The combined organic phases were dried over NasSCU. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography (C18, MeCN/water). Solvents were evaporated under reduced pressure yielding the Boc-protected product.

The Boc-protected product (50.7 mg, 0.1 mmol) was dissolved in DCM (2 ml_). TFA (0.2 mL) was added and the reaction mixture was stirred for 2 h at r.t. Volatiles were removed under reduced pressure and the residue was purified by HPLC (C18, MeCN/water 0.1 % HCOOH). Yield: 23.9 mg (59%).

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.90 (s, 1 H), 8.23 (s, 1 H), 7.31 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.95 - 6.71 (br s, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.68 - 3.60 (m, 4H), 3.51 (t, J = 5.9 Hz, 2H), 2.79 (h, J = 6.9 Hz, 1H), 1.86 - 1.79 (m, 2H), 1.15 (d, J = 6.9 Hz, 6H).

¹³C NMR (126 MHz, DMSO-d6) δ [ppm] = 164.61 , 163.62, 154.99, 154.72, 141.92, 138.07, 125.92, 120.40, 91.74, 48.02, 46.91 , 46.42, 45.60, 32.81 , 27.90, 24.10.

MS (ESI) calcd. for C19H26N5O2S ([M+H]⁺): m/z = 388, exp.: 388.

Synthesis of HCMV inhibitors (Scheme 2) tert-Butyl 4-(4-amino-1 ,2,5-oxadiazole-3-carbony l)-1 ,4-diazepane-1 -carboxylate (34)

1 Boc 34

To the solution of tenf-butyl 1 ,4-diazepane-1 -carboxylate (1) (2.6 g, 13.0 mmol) in DMF (150 mL) 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (1.68 g, 13.0 mmol), HATU (5.92 g, 15.6 mmol) in DMF (50 mL) and EtsN (9 mL, 64.9 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction was then mixed with EtOAc (500 mL). The reaction mixture was washed with saturated NH4CI (2 x 300 mL), 1 M NaOH (2 x 300 mL) and brine (300 mL), then dried over Na2SO4. The solvent is removed under reduced pressure to yield a brownish solid, which was directly used in the next step. Yield: 4.00 g (12.8 mmol, 99 %).

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 6.41 - 6.31 (m, 1 H), 3.78 (dt, J = 28.1 , 5.8 Hz, 1 H), 3.73 (dd, J = 9.5, 5.4 Hz, 1 H), 3.68 - 3.59 (m, 2H), 3.57 - 3.45 (m, 2H), 3.42 - 3.34 (m, 2H), 1.84 - 1.70 (m, 2H), 1.37 (s, 6H), 1.27 (s, 3H).

¹³C NMR (176 MHz, DMSO-d6) δ [ppm] = 158.5, 158.4, 158.3, 156.4, 156.3, 156.1 , 154.3, 154.3, 154.1 , 153.9, 141.3, 141.1 , 78.8, 78.8, 78.7, 48.7, 48.2, 48.1 , 47.8, 47.1 ,

46.6, 46.2, 46.1 , 45.9, 45.8, 45.5, 45.3, 45.3, 45.2, 44.9, 28.0, 28.0, 27.9, 27.8, 25.8,

25.7.

General Procedure 5 (GP5). Monoamidation of Diazepan To a solution of 1 ,4-diazepane (200 mg, 2 mmol) in DMF (15 mL) was added 4-amino- 1 ,2,5-oxadiazole-3-carboxylic acid (4) (258 mg, 2 mmol), DIPEA (1 mL, 744 mg, 6 mmol) and HATU (911 mg, 2.4 mmol) under Ar. The reaction mixture was stirred for 18 h at r. t. Water 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 (RP, C18; MeCN : H2O) yielding 133 mg (32%) of the desired product (35). A product of double amidation (37) (83 mg, 13%) was also obtained.

General Procedure 6 (GP6)

To a solution of an isocyanate (0.3 mmol, 1.0 eq.) in a mixture of dry THF (1.5 mL) and dry DMF (0.5 mL) a solution of 35 (0.3 mmol, 1.0 eq.) was added in mixture of dry THF (1.5 mL) and dry DMF (0.5 mL) at 0 °C and stirred overnight at room temperature. The reaction was quenched by the addition of water (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2SO4 and filtered. The solvent is removed under reduced pressure and the residue was purified by HPLC (RP, C18; MeCN : water + 0.1 % HCOOH). Product containing fractions were lyophilized.

(4-Amino-1 ,2,5-oxadiazol-3-yl)(1 ,4-diazepan-1 -yl)methanone (35) Procedure 1.

The compound 34 (89 mg, 0.29 mmol) was dissolved in DCM (2 mL). TFA (0.5 mL) was added to the solution and stirred for 3 h at room temperature. The solvent was removed under reduced pressure to give the product 35 as brownish solid, which was used for the next step without further purification.

Procedure 2.

(4-Amino-1 ,2,5-oxadiazol-3-yl)(1 ,4-diazepan-1-yl)methanone (36) was synthesized according to GP5 from 1 ,4-diazepane (200 mg, 2 mmol), 4-amino-1 ,2,5-oxadiazole-3- carboxylic acid (4) (258 mg, 2 mmol), DIPEA (1 mL, 744 mg, 6 mmol) and HATU (911 mg, 2.4 mmol) in DMF (15 mL) under Ar. Yield: 133 mg (32%).

¹H NMR (500 MHz, DMSO-d₆): 8.66 (s, 1 H), 6.42 (s, 2H), 3.95 - 3.91 (m, 1H), 3.87 - 3.83 (m, 1 H), 3.75 (t, J = 6.0 Hz, 1 H), 3.71 (t, J = 6.0 Hz, 1 H), 3.34 - 3.29 (m, 2H), 3.26 - 3.22 (m, 2H), 2.06 - 1.99 (m, 2H).

MS (ESI) calcd. for C8H14N5O2 ([M+H]⁺): m/z = 212, exp.: 212.

(4-Amino-1 ,2,5-oxadiazol-3-yl)(6,6-difluoro-1 ,4-diazepan-1 -yl)methanone (38)

(4-Amino-1 ,2,5-oxadiazol-3-yl)(6,6-difluoro-1 ,4-diazepan-1 -yl)methanone (38) was synthesized according to GP5 from 6,6-difluoro-1 ,4-diazepane (37) (300 mg, 1 mmol), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (130 mg, 1 mmol), DIPEA (0.53 mL, 390 mg, 3 mmol) and HATU (459 mg, 1.2 mmol) in DMF (8 mL) under Ar. Yield: 169 mg (68%).

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N -(4-isopropylphenyl)-1,4- diazepane-1 -carboxamide (VK565)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N -(4-isopropylphenyl)-1 ,4- diazepane-1 -carboxamide (VK565) was prepared according to GP6 starting from the solution of 4-isopropylphenyl isocyanate (42 mg, 0.25 mmol) in THF (5 mL) and the solution of 38 (78 mg, 0.32 mmol) in THF (5 mL). Yield: 61 mg (60%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.48 (s, 0.5H), 8.47 (s, 0.5H), 7.36 (d, J = 8.6 Hz, 1 H), 7.33 (d, J = 8.6 Hz, 1 H), 7.12 (d, J = 8.6 Hz, 2H), 6.43 (s, 2H), 4.29 (t, J = 12.0 Hz, 1 H), 4.18 (t, J = 12.0 Hz, 1 H), 4.15 - 4.08 (m, 2H), 3.95 - 3.89 (m, 2H), 3.83 - 3.77 (m, 2H), 2.82 (hept, J = 6.9 Hz, 1 H), 1.17 (d, J = 6.9 Hz, 6H).

¹⁹F NMR (471 MHz, DMSO-d6) δ [ppm] = - 98.99 (p, J = 12.3 Hz, 1 F), -101 .69 (p, J = 12.5 Hz, 1 F).

MS (ESI) calcd. for C18H23F2N6O3 ([M+H]⁺): m/z = 409, exp.: 409.

4-(2,2,2-Trifluoroethyl)phenyl Isocyanate (41)

4-(2,2,2-Trifluoroethyl)phenyl isocyanate (39) was prepared according to GP1 starting from 4-(2,2,2-trifluoroethyl)aniline (50 mg, 0.28 mmol), triphosgene (42 mg, 0.14 mmol) and EtsN (40 μL, 0.28 mmol) in DCM (3 mL). The product was used for the next step without purification. 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(2,2,2-trifluoroethyl)phenyl)-1 ,4- diazepane-1 -carboxamide (3TO 076)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-(2,2,2-trifluoroethyl)phenyl)-1 ,4- diazepane-1 -carboxamide (3TO 076) was prepared according to GP6 starting from crude 41 (0.28 mmol) obtained in a previous step and 35 (60 mg, 0.29 mmol) in THF (4 mL). Yield: 42.0 mg (36%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.41 (s, 0.5H), 8.38 (s, 0.5H), 7.46 (d, J = 8.6 Hz, 1 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.20 (d, J = 8.6 Hz, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.85 - 3.76 (m, 2H), 3.72 - 3.64 (m, 4H), 3.61- 3.57 (m, 2H), 3.52 (q, JH-F = 11 .6 Hz, 2H), 1.89 - 1 .78 (m, 2H).

¹³C NMR (126 MHz, DMSO-d6) δ [ppm] = 158.48, 158.34, 156.19, 156.08, 154.65, 154.59, 141.41 , 141.39, 140.19, 140.06, 130.14, 130.10, 126.45 (q, JC-F = 273 Hz), 123.51 , 120.21 , 120.06, 49.27, 47.67, 47.61 , 46.51 , 45.74, 45.64, 45.21 , 44.96, 37.90 (q, JC-F = 29 Hz), 28.31 , 25.87.

¹⁹F NMR (471 MHz, DMSO-d₆) 6 [ppm] = -64.69 (t, JH-F = 11.6 Hz, 1.5F), -64.71 (t, JH-F = 11.6 Hz, 1.5F).

HRMS (ESI) calcd. for C17H20F3N6O3 ([M+H]⁺): m/z = 413.1549, exp.: 413.1548.

General Procedure 7 (GP7). Synthesis of 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)- N-(hetero)aryl-1 ,4-diazepane-1 -carboxamide

A solution of (hetero)arylamine (0.5 mmol) in DCM (5 mL) was slowly added to a solution of 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) in DCM (5 mL) at 0 °C. Pyridine (120 μL, 1 .5 mmol) was slowly added to the resulting suspension at 0 °C. The reaction mixture was stirred for 2 h at r. t. The obtained solution was added to the solution of 35 (133 mg, 0.63 mmol) and DIPEA (1 mL) in DMF (3 mL) 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 and concentrated under reduced pressure. The residue was purified by column chromatography (RP; C18; MeCN : H2O) and then HPLC (H2O : MeCN + 0.1% HCOOH)) .

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N -(6-isopropylpyridin-3-yl)-1,4- diazepane-1 -carboxamide (VK573)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(6-isopropylpyridin-3-yl)-1 ,4-diazepane-1- carboxamide (VK573) was synthesized according to GP7 starting from 6- isopropylpyridin-3-amine (68 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (133 mg, 0.63 mmol). Yield: 53 mg (28%). The compound exists as a ca. 1 : 1 mixture of two conformers. ¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.51 (d, J = 2.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.46 (d, J = 2.6 Hz, 0.5H), 8.43 (s, 0.5H), 7.77 (dd, J = 8.5, 2.6 Hz, 0.5H), 7.73 (dd, J = 8.5, 2.6 Hz, 0.5H), 7.14 (d, J = 8.5 Hz, 0.5H), 7.13 (d, J = 8.5 Hz, 0.5H), 6.38 (s, 1 H), 6.36 (s, 1 H), 3.83 - 3.77 (m, 2H), 3.72 - 3.63 (m, 4H), 3.61 - 3.55 (m, 2H), 2.93 (h, J = 6.9 Hz, 1 H), 1.91 - 1.78 (m, 2H), 1.19 (d, J = 6.9 Hz, 6H).

¹³C NMR (125 MHz, DMSO-d6) δ [ppm] = 163.13, 159.91 , 159.85, 158.52, 158.38, 156.18, 156.09, 154.74, 141.45, 141.25, 141.14, 134.69, 134.57, 128.30, 128.11 , 119.83, 119.80, 41.12, 47.72, 47.54, 46.44, 45.87, 45.64, 45.19, 45.01 , 34.87, 28.29, 25.88, 22.67.

MS (ESI) calcd. for C17H24N7O3 ([M+H]⁺): m/z = 374, exp.: 374.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-W-(5-isopropylpyridin-2-yl)-1,4- diazepane-1 -carboxamide (VK560)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(5-isopropylpyridin-2-yl)-1 ,4-diazepane-1- carboxamide (VK560)was synthesized according to GP7 starting from 5-isopropylpyridin- 3-amine (136 mg, 1 mmol), 4-nitrophenyl chloroformate (202 mg, 1 mmol) and 35 (274 mg, 1.3 mmol). Yield: 29 mg (8%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.92 (s, 1 H), 8.10 (dd, J = 6.6, 2.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 0.5H), 7.68 (d, J = 8.4 Hz, 0.5H), 7.58 (dd, J = 5.5, 2.4 Hz, 0.5H), 7.56 (dd, J = 5.5, 2.4 Hz, 0.5H), 6.37(s, 1 H), 6.34 (s, 1 H), 3.86 - 3.53 (m, 8H), 2.86 (h, J = 6.9 Hz, 1 H), 1.89 - 1.77 (m, 2H), 1.19 (d, J = 6.9 Hz, 6H).

¹³C NMR (125 MHz, DMSO-d6) δ [ppm] = 163.17, 158.51 , 158.36, 156.19, 156.07, 154.54, 154.42, 151.70, 151.65, 145.19, 145.14, 141.42, 141.38, 137.43, 137.41, 135.32, 135.28, 113.62, 113.56, 49.20, 47.66 (2x), 46.44, 45.91 , 45.66, 45.21 , 45.06, 30.41 , 28.20, 25.81 , 23.73. MS (ESI) calcd. for C17H24N7O3 ([M+H]⁺): m/z = 374, exp.: 374.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-JV-(1 H-indol-5-yl)-1 ,4-diazepane-1 - carboxamide (VK630)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(1 H-i nd ol-5-y I)- 1 ,4-diazepane-1 - carboxamide (VK630) was synthesized according to GP7 starting from 1H-indol-5-amine (66 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 27 mg (15%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 10.92 (s, 1 H), 8.17 (s, 0.5 H), 8.14 (s, 0.5 H), 7.54 (d, J = 2.0 Hz, 0.5 H), 7.48 (d, J = 2.0 Hz, 0.5 H), 7.28 - 7.21 (m, 2 H), 7.08 (dd, J = 8.6, 2.0 Hz, 0.5 H), 7.03 (dd, J = 8.6, 2.0 Hz, 0.5 H), 6.38 (s, 1 H), 6.36 (s, 1 H), 6.33 - 6.31 (m, 1 H), 3.84 - 3.78 (m, 2 H), 3.72 - 3.62 (m, 4 H), 3.61 - 3.55 (m, 2 H), 1.93 - 1.80 (m, 2 H).

HRMS (ESI) calcd. for C17H20N7O3 [M+H] 370.1628, found 370.1624.

4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N -(1H-indol-6-yl)-1,4-diazepane-1- carboxamide (VK631)

4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(1 H-indol-6-yl)-1 ,4-diazepane-1- carboxamide (VK631) was synthesized according to GP7 starting from 1/-/-indol-6-amine (66 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (NP; silica; cyclohexane : EtOAc = 100 : 0 to 20 : 80) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH).Yield: 9 mg (5%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 10.88 (s, 1 H), 8.23 (s, 0.5 H), 8.21 (s, 0.5 H), 7.61 (s, 0.5 H), 7.57 (s, 0.5 H), 7.36 (d, J = 3.1 Hz, 0.5 H), 7.34 (d, J = 3.1 Hz, 0.5 H), 7.21 - 7.18 (m, 1 H), 7.00 (dd, J = 8.5, 1.9 Hz, 0.5 H), 6.96 (dd, J = 8.5, 1.9 Hz, 0.5 H), 6.38 (s, 1 H), 6.36 (s, 1 H), 6.32 - 6.29 (m, 1 H), 3.84 - 3.77 (m, 2 H), 3.73 - 3.64 (m, 4 H), 3.62 - 3.56 (m, 2 H), 1 .94 - 1.80 (m, 2 H).

HRMS (ESI) calcd. for C17H20N7O3 [M+H] 370.1628, found 370.1624.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(benzofuran-5-yl)-1 ,4-diazepane-1 - carboxamide (VK628)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(benzofuran-5-yl)-1 ,4-diazepane-1- carboxamide (VK628) was synthesized according to GP7 starting from benzofuran-5- amine (67 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 63 mg (34%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.38 (s, 0.5 H), 8.34 (s, 0.5 H), 7.91 (d, J = 2.0 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 0.5 H), 7.68 (d, J = 2.0 Hz, 0.5 H), 7.45 (d, J = 8.9 Hz, 0.5 H), 7.44 (d, J = 8.9 Hz, 0.5 H), 7.31 (dd, J = 8.9, 2.0 Hz, 0.5 H), 7.26 (dd, J = 8.9, 2.0 Hz, 0.5 H), 6.89 (s, 1 H), 6.38 (s, 1 H), 6.36 (s, 1 H), 3.85 - 3.79 (m, 2 H), 3.73 - 3.64 (m, 4 H), 3.62 - 3.56 (m, 2 H), 1.93 - 1.81 (m, 2 H).

HRMS (ESI) calcd. for C17H19N6O4 [M+H] 371.1468, found 371.1465. tert-Butyl (4-(4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamido)benzyl)carbamate (VK632) tert-Butyl (4-(4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 -carboxamido) benzyl)carbamate (VK632) was synthesized according to GP7 starting from tert-butyl (4- aminobenzyl)carbamate (111 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN). Yield: 96 mg (42%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.32 (s, 0.5 H), 8.29 (s, 0.5 H), 7.38 (s, 0.5 H), 7.36 (s, 0.5 H), 7.35 - 7.28 (m, 2 H), 7.10 - 7.06 (m, 2 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 4.03 (d, J = 6.1 Hz, 2 H), 3.82 - 3.76 (m, 2 H), 3.70 - 3.62 (m, 4 H), 3.60 - 3.55 (m, 2 H), 1.90 - 1.79 (m, 2 H), 1.38 (s, 9 H).

HRMS (ESI) calcd. for C2iH29N₇NaO₅ [M+Na] 482.2128, found 482.2124.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(1 -methyl-1 H-indol-5-yl)-1 ,4-diazepane- 1 -carboxamide (VK620)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(1 -methyl-1 H-i ndol-5-y I)- 1 ,4-diazepane-1 - carboxamide (VK620) was synthesized according to GP7 starting from 1-methyl-1 H- indol-5-amine (73 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 30 mg (16%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.20 (s, 0.5 H), 8.17 (s, 0.5 H), 7.57 (d, J = 2.0 Hz, 0.5 H), 7.51 (d, J = 2.0 Hz, 0.5 H), 7.30 - 7.26 (m, 1 H), 7.24 (d, J = 3.0 Hz, 1 H), 7.16 (dd, J = 8.7, 2.0 Hz, 0.5 H), 7.11 (dd, J = 8.7, 2.0 Hz, 0.5 H), 6.38 (s, 1 H), 6.36 (s, 1 H), 6.31 (d, J = 3.0 Hz, 1 H), 3.84 - 3.78 (m, 2 H), 3.74 (s, 3 H), 3.71 - 3.63 (m, 4 H), 3.61 - 3.55 (m, 2 H), 1 .94 - 1 .80 (m, 2 H).

HRMS (ESI) calcd. for C18H22N7O3 [M+H] 384.1784, found 384.1780.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-azidophenyl)-1 ,4-diazepane-1 - carboxamide (VK627)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-azidophenyl)-1 ,4-diazepane-1 - carboxamide (VK627) was synthesized according to GP7 starting from 4-azidoaniline hydrochloride (85 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35

(obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 39 mg (21%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.44 (s, 0.5 H), 8.40 (s, 0.5 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.46 (d, J = 9.0 Hz, 1 H), 7.00 (d, J = 9.0 Hz, 1 H), 6.99 (d, J = 9.0 Hz, 1 H), 6.37 (s, 1 H), 6.34 (s, 1 H), 3.83 - 3.76 (m, 2 H), 3.71 - 3.62 (m, 4 H), 3.60 - 3.54 (m, 2 H), 1.90 - 1.78 (m, 2 H).

HRMS (ESI) calcd. for C15H18N9O3 [M+H] 372.1533, found 372.1528. tert-Butyl 4-((4-(trifluoromethoxy)phenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (42) tert-Butyl 4-((4-(trifluoromethoxy)phenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (42) was prepared according to the general procedure GP2 starting from the solution of 1- isocyanato-4-(trifluoromethoxy)benzene (203 mg, 1.0 mmol) in dry THF (5 mL) and a solution of tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (120 mg, 0.6 mmol) in dry THF (5 mL). The product was purified by flash chromatography (cyclohexane : EtOAc = 75 : 25 to 50 : 50) yielding 190 mg (79%) of the desired product. The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.47 (s, 0.5 H), 8.46 (s, 0.5 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.22 (d, J = 8.6 Hz, 2 H), 3.60 - 3.52 (m, 2 H), 3.50 - 3.40 (m, 4 H), 3.33 - 3.26 (m, 2 H), 1.79 - 1.66 (m, 2 H), 1.37 (s, 4.5 H), 1.31 (s, 4.5 H).

/V-(4-(T rifluoromethoxy)pheny l)-1 ,4-diazepane-1 -carboxamide (43)

/V-(4-(trifluoromethoxy)phenyl)-1 ,4-diazepane-1 -carboxamide (43) was prepared according to GP3 starting from 42 (95 mg, 0.24 mmol) in DCM (5 mL) and TFA (2 mL). The product was directly used in the next step without further purification.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(trifluoromethoxy)phenyl)-1,4- diazepane-1 -carboxamide (VK667)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-(trifluoromethoxy)phenyl)-1 ,4-diazepane- 1 -carboxamide (VK667) was prepared according to GP4 starting from the solution of crude 43 (0.24 mmol) in DMF (5 mL), 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (45 mg, 0.35 mmol), HATU (133 mg, 0.35 mmol) and DIPEA (0.3 mL, 226 mg, 1.75 mmol). The product was purified by flash chromatography (cyclohexane : EtOAc 80 : 20 to 0 : 100) and after that by HPLC (C18; H₂O : MeCN + 0.1% HCOOH).Yield: 44 mg (44%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.55 (s, 0.5 H), 8.51 (s, 0.5 H), 7.57 (d, J = 9.1 Hz, 1 H), 7.53 (d, J = 9.1 Hz, 1 H), 7.25 - 7.20 (m, 2 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.84 - 3.77 (m, 2 H), 3.72 - 3.63 (m, 4 H), 3.62 - 3.56 (m, 2 H), 1.91 - 1.79 (m, 2 H).

HRMS (ESI) calcd. for C16H18F3N6O4 [M+H] 415.1342, found 415.1339.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N-(4-(2,2,2- trifluoroethyl)phenyl)-1 ,4-diazepane-1 -carboxamide (VK660)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N -(4-(2,2,2-trifluoroethyl)phenyl)- 1 ,4-diazepane-1 -carboxamide (VK660) was synthesized according to GP7 starting from 4-(2,2,2-trifluoroethyl)aniline (44 mg, 0.25 mmol), 4-nitrophenyl chloroformate (50 mg, 0.25 mmol) and 38 (71 mg, 0.29 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 41 mg (37%). The compound exists as a ca. 1 : 1 mixture of two conformers. ¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.62 (s, 0.5 H), 8.61 (s, 0.5 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 2 H), 6.45 - 6.40 (m, 2 H), 4.30 (t, J H-F = 12.0 Hz, 1 H), 4.23 - 4.08 (m, 3 H), 3.97 - 3.89 (m, 2 H), 3.85 - 3.77 (m, 2 H), 3.55 (q, J H-F = 11.6 Hz, 2 H).

HRMS (ESI) calcd. for C17H18F5N6O3 [M+H] 449.1361 , found 449.1359.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N-(1 H-indol-5-yl)-1 ,4- diazepane-1 -carboxamide (VK659)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N-(1 H-indol-5-yl)-1 ,4-diazepane-1- carboxamide (VK659) was synthesized according to GP7 starting from 1 H-indol-5-amine (33 mg, 0.25 mmol), 4-nitrophenyl chloroformate (50 mg, 0.25 mmol) and 38 (71 mg, 0.29 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 22 mg (22%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 10.94 (s, 1 H), 8.39 (s, 0.5 H), 8.37 (s, 0.5 H), 7.57 (d, J = 2.0 Hz, 0.5 H), 7.54 (d, J = 2.0 Hz, 0.5 H), 7.30 - 7.25 (m, 2 H), 7.11 - 7.05 (m, 1 H), 6.46 - 6.40 (m, 2 H), 6.34 (s, 1 H), 4.30 (t, J H - F = 12.0 Hz, 1 H), 4.20 (t, J H - F = 12.4 Hz, 1 H), 4.16 - 4.07 (m, 2 H), 3.97 - 3.90 (m, 2 H), 3.86 - 3.78 (m, 2 H).

HRMS (ESI) calcd. for C17H18F2N7O3 [M+H] 406.1439, found 406.1434. fert-Butyl (R)-4-((4-lsopropylphenyl)carbamoyl)-3-methyl-1 ,4-diazepane-1 - carboxylate (44) terf-Butyl (/?)-4-((4-lsopropylphenyl)carbamoyl)-3-methyl-1,4-diazepane-1-carboxylate (44) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (38 mg, 0.23 mmol) in dry THF (1 mL ) and a solution of tertbutyl (F?)-3-methyl-1 ,4-diazepane-1 -carboxylate (50 mg, 0.23 mmol) in dry THF (1 ml_). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

(/?)-N-(4-lsopropylphenyl)-2-methyl-1 ,4-diazepane-1 -carboxamide (45)

(R)-/V-(4-lsopropylphenyl)-2-methyl-1,4-diazepane-1-carboxamide (45) was prepared according to GP3 starting from crude 44 (0.23 mmol) in CH2CI2 (4 mL ) and TFA (0.4 ml_). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

(/?)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-2-methyl-1,4- diazepane-1 -carboxamide (AR843.1 ) (R)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-2-methyl-1 ,4- diazepane-1 -carboxamide (AR843.1) was prepared according to GP4 starting from the solution of crude 45 (0.23 mmol) in DMF (2 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (30 mg, 0.23 mmol), HATU (106 mg, 0.28 mmol) and DIPEA (0.12 mL). The product was purified by HPLC (C18; H₂O : MeCN + 0.1% HCOOH). Yield: 37 mg (42%). The compound exists as a ca. 3 : 2 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.16 (s, 0.4 H), 8.12 (s, 0.6 H), 7.34 - 7.27 (m, 2 H), 7.09 - 7.04 (m, 2 H), 6.35 (s, 0.8 H), 6.30 (s, 1.2 H), 4.66 - 4.57 (m, 0.6 H), 4.55 - 4.45 (m, 0.4 H), 4.41 - 4.33 (m, 0.4 H), 4.32 - 4.22 (m, 1 H), 4.08 - 4.00 (m, 0.6 H), 3.96 - 3.84 (m, 1 H), 3.37 - 3.22 (m, 2 H), 3.14 (dd, J = 14.0, 11.0 Hz, 0.6 H), 3.05 - 2.97 (m, 0.4 H), 2.79 (septet, J = 6.9 Hz, 1 H), 1.85 - 1.63 (m, 2 H), 1.16 (d, J = 6.9 Hz, 6 H), 1.09 (d, J = 6.4 Hz, 1.8 H), 1.01 (d, J = 6.4 Hz, 1.2 H).

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2139. fert-Butyl (R)-3-Methyl-4-((4-(2,2,2-trifluoroethyl)phenyl)carbamoyl)-1,4-diazepane- 1 -carboxylate (46) fert-Butyl (R)-3-methyl-4-((4-(2,2,2-trifluoroethyl)phenyl)carbamoyl)-1 ,4-diazepane-1 - carboxylate (46) was synthesized according to GP7 starting from 4-(2,2,2- trifluoroethyl)aniline (88 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and tert-butyl (R)-3-methyl-1 ,4-diazepane-1 -carboxylate (100 mg, 0.47 mmol). The product was purified by flash chromatography (cyclohexane : EtOAc = 100 : 0 to 0 : 100) and used directly for the next step.

(R)-2-methyl-/V-(4-(2,2,2-trifluoroethyl)phenyl)-1 ,4-diazepane-1 -carboxamide (47)

(/?)-2-methyl-/V-(4-(2,2 ,2-trifluoroethyl)phenyl)-1 ,4-diazepane-1 -carboxamide (47) was prepared according to GP3 starting from crude 46 (0.47 mmol) in CH2CI2 (4 mL ) and TFA (1 ml_). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

(R)-4-(4-Amino-1,2_J5-oxadiazole-3-carbonyl)-2-methyl-N -(4-(2,2,2- trifluoroethyl)phenyl)-1,4-diazepane-1 -carboxamide (VK710)

(R)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-2-methyl-N -(4-(2,2,2-trifluoroethyl)phenyl)- 1 ,4-diazepane-1 -carboxamide (VK710) was prepared according to GP4 starting from the solution of crude 47 (0.47 mmol) in DMF (5 ml_), 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (77 mg, 0.6 mmol), HATU (266 mg, 0.7 mmol) and DIPEA (0.4 ml_). The product was purified by flash chromatography (silica, cyclohexane : EtOAc) and HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 47 mg (23%). The compound exists as a ca. 3 : 2 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.30 (s, 0.4 H), 8.27 (s, 0.6 H), 7.46 - 7.39 (m, 2 H), 7.17 (d, J = 8.5 Hz, 2 H), 6.35 (s, 0.8 H), 6.30 (s, 1.2 H), 4.67 - 4.57 (m, 0.6 H), 4.56 - 4.45 (m, 0.4 H), 4.41 - 4.34 (m, 0.4 H), 4.32 - 4.21 (m, 1 H), 4.08 - 3.99 (m, 0.6 H), 3.97 - 3.85 (m, 1 H), 3.52 (q, J H - F = 11.7 Hz, 2 H), 3.39 - 3.22 (m, 2H), 3.19 - 3.10 (m, 0.6 H), 3.06 - 2.96 (m, 0.4 H), 1.85 - 1.62 (m, 2 H), 1.10 (d, J = 6.4 Hz, 1.8 H), 1.02 (d, J = 6.4 Hz, 1.2 H). HRMS (ESI) calcd. for C18H22F3N6O3 [M+H] 427.1705, found 427.1702. tert-Butyl (R)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-3-methyl-1 ,4-diazepane-1 - carboxylate (48) tert-B uty I (R)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-3-methyl-1 ,4-diazepane-1 - carboxylate (48) was prepared according to GP4 starting from the solution of tert-butyl (R)-3-methyl-1 ,4-diazepane-1 -carboxylate (50 mg, 0.23 mmol) in DMF (2 mL), 4-amino- 1 ,2,5-oxadiazole-3-carboxylic acid (4) (30 mg, 0.23 mmol), HATU (106 mg, 0.28 mmol) and DIPEA (0.12 mL, 0.7 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O). Yield: 67 mg (91%). The compound was used for the next step without further characterization.

(R)-(4-Amino-1 ,2,5-oxadiazol-3-yl)(2-methyl-1 ,4-diazepan-1 -yl)methanone (49)

(R)-(4-Amino-1 ,2,5-oxadiazol-3-yl)(2-methyl-1 ,4-diazepan-1 -yl)methanone (49) was prepared according to GP3 starting from 48 (67 mg, 0.21 mmol) in CH2CI2 (4 mL) and TFA (0.4 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

(R)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(4-isopropylphenyl)-3-methyl-1,4- diazepane-1 -carboxamide (AR845.1 )

(R)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-3-methyl-1 ,4- diazepane-1 -carboxamide (AR845.1) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (31 mg, 0.19 mmol) in a mixture of dry THF (1 mL) and dry DMF (0.3 mL) and a solution of crude 49 (0.21 mmol) in a mixture of dry THF (1 mL) and dry DMF (0.3 mL). The product was purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH) yielding 35 mg (48%) of the desired product. The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.26 (s, 0.5 H), 8.15 (s, 0.5 H), 7.31 (d, J = 8.5 Hz, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.31 (s, 1 H), 6.26 (s, 1 H), 4.89 - 4.80 (m, 0.5 H), 4.70 - 4.61 (m, 0.5 H), 4.20 - 4.06 (m, 2 H), 4.05 - 3.97 (m, 0.5 H), 3.91 - 3.83 (m, 0.5 H), 3.55 - 3.45 (m, 0.5 H), 3.31 - 3.23 (m, 0.5 H), 3.17 - 3.02 (m, 1 H), 2.98 - 2.87 (m, 1 H), 2.95 (septet, J = 6.9 Hz, 1 H), 1.92 - 1.79 (m, 1 H), 1.73 - 1.59 (m, 1 H), 1.18 (d, J = 6.5 Hz, 1.5 H), 1.16 (d, J = 6.9 Hz, 6 H), 1.11 (d, J = 6.5 Hz, 1.5 H).

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2142.

(S)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(4-isopropylphenyl)-3-methyl-1,4- diazepane-1 -carboxamide (AR851.1 ) (S)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-3-methyl-1 ,4- diazepane-1 -carboxamide (AR851.1) was synthesized in close analogy to its enantiomer (/?)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-3-methyl-1 ,4- diazepane-1 -carboxamide (AR845.1) starting from tert-butyl (S)-3-methyl-1 ,4-diazepane- 1-carboxylate (50 mg, 0.23 mmol). Yield: 31.8 mg (23%). The compound exists as a ca.

1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.26 (s, 0.5 H), 8.15 (s, 0.5 H), 7.31 (d, J = 8.5 Hz, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.31 (s, 1 H), 6.26 (s, 1 H), 4.89 - 4.79 (m, 0.5 H), 4.70 - 4.60 (m, 0.5 H), 4.20 - 4.06 (m,

2 H), 4.04 - 3.98 (m, 0.5 H), 3.91 - 3.83 (m, 0.5 H), 3.55 - 3.45 (m, 0.5 H), 3.31 - 3.23 (m, 0.5 H), 3.18 - 3.01 (m, 1 H), 2.98 - 2.87 (m, 1 H), 2.95 (septet, J = 6.9 Hz, 1 H), 1.92 - 1.78 (m, 1 H), 1.75 - 1.59 (m, 1 H), 1.18 (d, J = 6.5 Hz, 1.5 H), 1.16 (d, J = 6.9 Hz, 6 H), 1.11 (d, J = 6.5 Hz, 1.5 H).

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2140.

(S)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-2-methyl-1,4- diazepane-1 -carboxamide (AR850.1 )

(S)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-2-methyl-1 ,4- diazepane-1 -carboxamide (AR850.1) was synthesized in close analogy to its enantiomer (R)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-2-methyl-1 ,4- diazepane-1 -carboxamide (AR843.1) starting from tert-butyl (S)-3-methyl-1 ,4-diazepane- 1-carboxylate (50 mg, 0.23 mmol). Yield: 45.8 mg (52%).

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.16 (s, 0.4 H), 8.13 (s, 0.6 H), 7.34 - 7.27 (m, 2 H), 7.09 - 7.03 (m, 2 H), 6.35 (s, 0.8 H), 6.30 (s, 1 .2 H), 4.66 - 4.56 (m, 0.6 H), 4.55 - 4.46 (m, 0.4 H), 4.40 - 4.34 (m, 0.4 H), 4.31 - 4.22 (m, 1 H), 4.07 - 4.00 (m, 0.6 H), 3.95 - 3.84 (m, 1 H), 3.37 - 3.22 (m, 2 H), 3.14 (dd, J = 14.0, 11 .0 Hz, 0.6 H), 3.06 - 2.96 (m, 0.4 H), 2.79 (septet, J = 6.9 Hz, 1 H), 1.85 - 1.62 (m, 2 H), 1.16 (d, J = 6.9 Hz, 6 H), 1.09 (d, J = 6.4 Hz, 1.8 H), 1 .01 (d, J = 6.4 Hz, 1.2 H).

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2142. tert-Butyl 4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-5-methyl-1,4-diazepane-1- carboxylate (50) ferf-Butyl 4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-5-methyl-1 ,4-diazepane-1 - carboxylate (50) was prepared according to GP4 starting from the solution of terf-butyl 5-methyl-1 ,4-diazepane-1 -carboxylate (125 mg, 0.58 mmol) in DMF (4 ml_), 4-amino- 1 ,2,5-oxadiazole-3-carboxylic acid (4) (75 mg, 0.58 mmol), HATU (266 mg, 0.7 mmol) and DIPEA (0.3 mL, 1 .8 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O). Yield: 136 mg (72%). The compound was used for the next step without further characterization.

(4-Amino-1 ,2,5-oxadiazol-3-yl)(7-methyl-1 ,4-diazepan-1 -yl)methanone (51 )

(4-Amino-1 ,2,5-oxadiazol-3-yl)(7-methyl-1 ,4-diazepan-1 -yl)methanone (51 ) was prepared according to GP3 starting from 50 (136 mg, 0.42 mmol) in CH2CI2 (6 mL ) and TFA (0.6 ml_). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-5-methyl-1,4- diazepane-1 -carboxamide (AR863.1 )

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-5-methyl-1 ,4- diazepane-1 -carboxamide (AR863.1) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (67 mg, 0.42 mmol) in a mixture of dry THF (3 mL) and dry DMF (0.9 mL ) and a solution of crude 51 (0.42 mmol) in a mixture of dry THF (3 mL) and dry DMF (0.9 mL). The product was purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH) yielding 108.7 mg (67%) of the desired product. The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.37 (s, 1 H), 7.38 - 7.30 (m, 2 H), 7.12 - 7.05 (m, 2 H), 6.43 (s, 1 H), 6.39 (s, 1 H), 4.62 - 4.52 (m, 0.5 H), 4.22 - 4.15 (m, 0.5 H), 4.11 - 3.91 (m, 3 H), 3.49 - 3.41 (m, 0.5 H), 3.26 - 3.13 (m, 1.5 H), 3.11 - 3.04 (m, 0.5 H), 3.02 - 2.95 (m, 0.5 H), 2.84 - 2.76 (m, 1 H), 2.20 - 2.10 (m, 1 H), 1.71 - 1.51 (m, 1 H), 1.22 - 1.18 (m, 3 H), 1.18 - 1.14 (m, 6 H).

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2145. tert-Butyl 4-((4-lsopropylphenyl)carbamoyl)-5-methyl-1 ,4-diazepane-1 -carboxylate (52) terf-Butyl 4-((4-lsopropylphenyl)carbamoyl)-5-methyl-1 ,4-diazepane-1 -carboxylate (52) was prepared according to the general procedure GP2 starting from the solution of 4- isopropylphenyl isocyanate (94 mg, 0.58 mmol) in dry THF (2 mL) and a solution of racemic tert-butyl 5-methyl-1 ,4-diazepane-1 -carboxylate (125 mg, 0.58 mmol) in dry THF (2 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

N -(4-lsopropylphenyl)-7-methyl-1 ,4-diazepane-1 -carboxamide (53)

N -(4-lsopropylphenyl)-7-methyl-1 ,4-diazepane-1 -carboxamide (53) was prepared according to GP3 starting from the crude 52 (0.58 mmol) in CH2CI2 (8 mL) and TFA (0.8 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(4-isopropylphenyl)-7-methyl-1,4- diazepane-1 -carboxamide (AR873.1 )

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-isopropylphenyl)-7-methyl-1 ,4- diazepane-1 -carboxamide (AR873.1) was prepared according to GP4 starting from the solution of crude 53 (0.58 mmol) in DMF (4 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (75 mg, 0.58 mmol), HATU (266 mg, 0.67 mmol) and DIPEA (0.31 mL, 1.75 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O) and then additionally by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 106.6 mg (48%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.25 (s, 0.5 H), 8.19 (s, 0.5 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 6.38 (s, 2 H), 4.39 - 4.28 (m, 1 H), 4.27 - 4.14 (m, 1 H), 4.04 - 3.96 (m, 0.5 H), 3.93 - 3.85 (m, 0.5 H), 3.85 - 3.75 (m, 1 H), 3.52 - 3.44 (m, 0.5 H), 3.33 - 3.16 (m, 2 H), 3.09 - 3.01 (m, 0.5 H), 2.85 - 2.76 (m, 1 H), 2.22 - 2.08 (m, 1 H), 1.69 - 1.58 (m, 1 H), 1.18 - 1.15 (m, 6 H), 1.13 - 1.10 (m, 3 H).

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2142. fert-Butyl (R)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-7-methyl-1 ,4-diazepane-1 - carboxylate (54) tert- Butyl (R)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-7-methyl-1 ,4-diazepane-1- carboxylate (54) was prepared according to GP4 starting from the solution of tert-butyl (R)-7-methyl-1 ,4-diazepane-1 -carboxylate (100 mg, 0.47 mmol) in DMF (5 mL), 4-amino- 1 ,2,5-oxadiazole-3-carboxylic acid (4) (90 mg, 0.7 mmol), HATU (266 mg, 0.7 mmol) and DIPEA (0.2 mL, 1.4 mmol). The product was purified by flash chromatography (silica; cyclohexane : EtOAc). Yield: 151 mg (98%). The compound was used for the next step without further characterization.

(R)-(4-Amino-1 ,2,5-oxadiazol-3-yl)(5-methyl-1 ,4-diazepan-1 -y l)methanone (55)

N -(4-lsopropylphenyl)-7-methyl-1 ,4-diazepane-1 -carboxamide (55) was prepared according to GP3 starting from 54 (151 mg, 0.46 mmol) in CH2CI2 (5 mL) and TFA (1 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step. (R)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-7-methyl-1,4- diazepane-1 -carboxamide (VK745)

(R)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-7-methyl-1 ,4- diazepane-1 -carboxamide (VK745) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (64 mg, 0.4 mmol) in dry THF (3 mL ) and the solution of crude 55 (0.46 mmol) in a mixture of dry THF (3 mL) and dry DMF (1 mL). The product was purified by flash chromatography (RP; C18; MeCN : H₂O) and then additionally by HPLC (018; H2O : MeCN + 0.1% HCOOH) yielding 87 mg (49%) of the desired product. The compound exists as a ca. 1 : 1 mixture of two conformers.

NMR spectra of this compound are identical to those of AR873.1. HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2143.

(S)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4- diazepane-1 -carboxamide (VK775)

(S)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-7-methyl-1 ,4- diazepane-1 -carboxamide (VK775) was synthesized in close analogy to its enantiomer (R)-4-(4-amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-7-methyl-1 ,4- diazepane-1 -carboxamide (VK745) starting from tert- butyl (S)-7-methyl-1 ,4-diazepane-1- carboxylate (100 mg, 0.47 mmol). Yield: 76.4 mg (42%).

NMR spectra of this compound are identical to those of AR873.1.

HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2142. tert-Butyl 4-(4-Acetamido-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxylate (56)

Acetic anhydride (2 mL) was added to the solution of tert- butyl 4-(4-amino-1 ,2,5- oxadiazole-3-carbonyl)-1 ,4-diazepane-1 -carboxylate (34) (311 mg, 1 mmol) in pyridine (5 mL) at r. t. followed by the catalytic amount of DMAP. The reaction mixture was stirred for 16 h at r. t. Volatiles were removed under reduced pressure and the residue was purified by flash chromatography (C18; MeCN : H2O). Yield: 300 mg (85%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 11.44 (s, 1 H), 3.68 - 3.64 (m, 1 H), 3.60 - 3.55 (m, 1 H), 3.54 - 3.40 (m, 6 H), 2.10 (s, 1.5 H), 2.08 (s, 1.5 H), 1.86 - 1.67 (m, 2 H), 1.43 - 1.35 (m, 9 H).

N -(4-(1,4-diazepane-1-carbonyl)-1,2,5-oxadiazol-3-yl)acetamide (57)

N -(4-(1 ,4-diazepane-1-carbonyl)-1 ,2,5-oxadiazol-3-yl)acetamide (57) was prepared according to GP3 starting from 56 (300 mg, 0.85 mmol) in CH2CI2 (10 mL) and TFA (1 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

4-(4-Acetamido-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane- 1 -carboxamide (VK610)

4-(4-Acetamido-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-1 ,4-diazepane-1- carboxamide (VK610) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (145 mg, 0.9 mmol) in dry THF (3 mL) and the solution of crude 57 (0.85 mmol) in a mixture of dry THF (3 mL) and dry DMF (1 mL). The product was purified by flash chromatography (RP; C18; MeCN : H2O). Yield: 230 mg (56%). An analytical sample was additionally purified by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (700 MHz, DMSO-d6) δ [ppm] = 11.43 (s, 1 H), 8.26 (s, 0.5 H), 8.20 (s, 0.5 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 2 H), 3.74 - 3.71 (m, 1 H), 3.68 - 3.65 (m, 1 H), 3.64 - 3.59 (m, 4 H), 3.57 - 3.54 (m, 1 H), 3.50 - 3.47 (m, 1 H), 2.84 - 2.78 (m, 1 H), 2.08 (s, 1.5 H), 2.07 (s, 1.5 H), 1.91 - 1.86 (m, 1 H), 1.82 - 1.78 (m, 1 H), 1.18 - 1.16 (m, 6 H).

HRMS (ESI) calcd. for C20H27N6O3 [M+H] 415.2094, found 415.2090.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-cyclohexylphenyl)-1 ,4-diazepane-1 - carboxamide (AR865.1)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-cyclohexylphenyl)-1 ,4-diazepane-1 - carboxamide (AR865.1) was synthesized according to GP7 starting from 4- cyclohexylaniline (88 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 53 mg (26%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.26 (s, 0.5 H), 8.23 (s, 0.5 H), 7.33 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 7.06 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.83 - 3.76 (m, 2 H), 3.70 - 3.60 (m, 4 H), 3.60 - 3.54 (m, 2 H), 2.44 - 2.36 (m, 1 H), 1.90 - 1.65 (m, 8 H), 1.41 - 1.38 (m, 3 H), 1.26 - 1.15 (m, 1 H). HRMS (ESI) calcd. for C21H29N6O3 [M+H] 413.2301 , found 413.2297.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(4-morpholinophenyl)-1 ,4-diazepane-1 - carboxamide (AR866.1)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-morpholinophenyl)-1 ,4-diazepane-1- carboxamide (AR866.1) was synthesized according to GP7 starting from 4- morpholinoaniline (89 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (silica; cyclohexane : EtOAc 100 : 0 to 0 : 100) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 13.7 mg (7%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.16 (s, 0.5 H), 8.12 (s, 0.5 H), 7.29 (d, J = 9.0 Hz, 1 H), 7.24 (d, J = 9.0 Hz, 1 H), 6.83 (d, J = 9.0 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.82 - 3.76 (m, 2 H), 3.74 - 3.70 (m, 4 H), 3.69 - 3.60 (m, 4 H), 3.58 - 3.52 (m, 2 H), 3.03 - 2.98 (m, 4 H), 1.90 - 1 .78 (m, 2 H).

HRMS (ESI) calcd. for C19H26N7O4 [M+H] 416.2046, found 416.2042. tert-Butyl 4-(4-(4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamido)phenyl)piperazine-1 -carboxylate (AR868.1 ) tert- B uty I 4-(4-(4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamido)phenyl)piperazine-1 -carboxylate (AR868.1) was synthesized according to GP7 starting from tert-butyl 4-(4-aminophenyl)piperazine-1 -carboxylate (139 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (silica; cyclohexane : EtOAc 100 : 0 to 0 : 100). Yield: 185 mg (72%). 50 mg of this product was purified by HPLC (C18; H2O : MeCN). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.17 (s, 0.5 H), 8.14 (s, 0.5 H), 7.29 (d, J = 9.0 Hz, 1 H), 7.24 (d, J = 9.0 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 6.84 (d, J = 9.0 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.82 - 3.75 (m, 2 H), 3.70 - 3.60 (m, 4 H), 3.58 - 3.52 (m, 2 H), 3.47 - 3.40 (m, 4 H), 3.01 - 2.95 (m, 4 H), 1 .90 - 1.77 (m, 2 H), 1 .41 (s , 9 H).

HRMS (ESI) calcd. for C24H35N8O5 [M+H] 515.2730, found 515.2730.

4-(4-(4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamido)phenyl)piperazin-1-ium Trifluoroacetate (AR870.1) 4-(4-(4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1- carboxamido)phenyl)piperazin-1-ium trifluoroacetate (AR870.1) was prepared according to GP3 starting from AR868.1 (135 mg, 0.26 mmol) in CH2CI2 (2 mL) and TFA (0.5 ml_). The reaction mixture was concentrated under reduced pressure yielding the crude product that was purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 63.5 mg (46%).

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.78 (s, 1 H), 8.22 (s, 0.5 H), 8.18 (s, 0.5 H), 7.33 (d, J = 9.1 Hz, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 6.89 (d, J = 9.1 Hz, 1 H), 6.88 (d, J = 9.1 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.82 - 3.76 (m, 2 H), 3.70 - 3.61 (m, 4 H), 3.58 - 3.53 (m, 2 H), 3.23 (s, 8 H), 1.89 - 1.77 (m, 2 H).

HRMS (ESI) calcd. for C19H27N8O3 [M+H] 415.2206, found 415.2231.

N -(4-Nitrobenzyl)-1 -(trifluoromethyl)cyclopropane-l -carboxamide (58)

1-(Trifluoromethyl)cyclopropane-1 -carboxylic acid (308 mg, 2 mmol) was added to the solution of (4-nitrophenyl)methanamine hydrochloride (376 mg, 2 mmol) in DMF (5 mL) followed by DIPEA (1.7 mL) and HATU (912 mg, 2.4 mmol). The resulting mixture was stirred for 16 h at r. t. H2O was added. The obtained mixture was extracted with EtOAc (3x). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (cyclohexane : EtOAc). Yield: 387 mg (67%).

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.53 (t, J = 5.8 Hz, 1 H), 8.20 (d, J = 8.8 Hz, 2 H), 7.48 (d, J = 8.8 Hz, 2 H), 4.40 (d, J = 5.8 Hz, 2 H), 1.38 - 1.32 (m, 2 H), 1 .29 - 1 .24 (m, 2 H).

N-(4-aminobenzyl)-1 -(trifluoromethyl)cyclopropane-l -carboxamide (59) SnCl2*2H2O (1.8 g, 6.7 mmol) was added to the solution of 58 (387 mg, 1.3 mmol) in EtOAc (60 mL), and the reaction mixture was stirred at 60 °C for 6 h. The reaction was diluted with ethyl acetate, basified with 1 N aq. NaOH and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (C18: MeCN : H2O). Yield: 150 mg (45%).

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-((1 -(trifluoromethy l)cyclopropane-1 - carboxamido)methy l)phenyl)-1 ,4-diazepane-1 -carboxamide (MH06)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-((1 -(trifluoromethyl)cyclopropane-l - carboxamido)methyl)phenyl)-1 ,4-diazepane-1 -carboxamide (MH06) was synthesized according to GP7 starting from 59 (150 mg, 0.58 mmol), 4-nitrophenyl chloroformate (117 mg, 0.58 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified flash chromatography (RP; C18; MeCN : H2O) and then additionally by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 28 mg (10%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.35 - 8.27 (m, 2 H), 7.38 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.07 (d, J = 8.5 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 4.20 (d, J = 5.9 Hz, 2 H), 3.83 - 3.76 (m, 2 H), 3.70 - 3.61 (m, 4 H), 3.60 - 3.54 (m, 2 H), 1.90 - 1.78 (m, 2 H), 1.33 - 1.27 (m, 2 H), 1.24 - 1.19 (m, 2 H).

HRMS (ESI) calcd. for C21 H25F3N7O4 [M+H] 496.1920, found 496.1917.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-(4-methy lpiperazin-1 -yl)phenyl)-1 ,4- diazepane-1 -carboxamide hydrochloride (AR869.1)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-(4-methylpiperazin-1 -yl)phenyl)-1 ,4- diazepane-1 -carboxamide hydrochloride (AR869.1) was synthesized according to GP7 starting from 4-(4-methylpiperazin-1-yl)aniline (96 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product is soluble in water. It was purified by flash chromatography (C18: MeCN : H2O) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 11 mg (5%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 9.70 (s, 1 H), 8.21 (s, 0.5 H), 8.17 (s, 0.5 H), 7.33 (d, J = 9.1 Hz, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 6.90 (d, J = 9.1 Hz, 1 H), 6.89 (d, J = 9.1 Hz, 1 H), 6.37 (s , 1 H), 6.35 (s, 1 H), 3.82 - 3.76 (m, 2 H), 3.76 - 3.61 (m, 6 H), 3.59 - 3.53 (m, 2 H), 3.44 - 3.31 (m, 4 H), 3.21 - 3.08 (m, 2 H), 2.86 (s, 3 H), 1 .89 - 1.77 (m, 2 H).

HRMS (ESI) calcd. for C20H29N8O3 [M+H] 429.2363, found 429.2360. tert-Butyl 4-((4-(Benzyloxy)phenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (60) tert-Butyl 4-((4-(Benzyloxy)phenyl)carbamoyl)-1 ,4-diazepane-1 -carboxylate (60) was prepared according to the general procedure GP2 starting from the solution of 1- (benzyloxy)-4-isocyanatobenzene (500 mg, 2.22 mmol) in THF (6 mL) and a solution of tert-butyl 1 ,4-diazepane-1 -carboxylate (1) (445 mg, 2.22 mmol) in THF (6 mL). The product was directly used for the next step. N -(4-(Benzyloxy)phenyl)-1 ,4-diazepane-1 -carboxamide (61 )

N -(4-(Benzyloxy)phenyl)-1 ,4-diazepane-1 -carboxamide (61) was prepared according to GP3 starting from 60 (109 mg, 0.26 mmol) in CH2CI2 (4 mL) and TFA (0.4 mL). The reaction mixture was concentrated under reduced pressure yielding the crude product that was directly used for the next step.

4-(4-Amino-1 ,2,5-oxadiazole-3-carbony l)-/V-(4-(benzyloxy)phenyl)-1 ,4-diazepane-1 - carboxamide (AR876.1)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-(benzyloxy)phenyl)-1 ,4-diazepane-1- carboxamide (AR876.1) was prepared according to GP4 starting from the solution of crude 61 (0.26 mmol) in DMF (2 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (33 mg, 0.26 mmol), HATU (117 mg, 0.31 mmol) and DIPEA (0.13 mL, 0.77 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O). Yield: 63.2 mg (56%). An analytical sample was additionally purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.21 (s, 0.5 H), 8.17 (s, 0.5 H), 7.45 - 7.41 (m, 2 H), 7.40 - 7.36 (m, 2 H), 7.34 - 7.30 (m, 2 H), 7.29 - 7.26 (m, 1 H), 6.91 - 6.87 (m, 2 H), 6.36 (s, 1 H), 6.33 (s, 1 H), 5.05 (s, 2 H), 3.82 - 3.76 (m, 2 H), 3.69 - 3.61 (m, 4 H), .59 - 3.53 (m, 2 H), 1.89 - 1.84 (m, 1 H), 1.84 - 1.79 (m, 1 H).

HRMS (ESI) calcd. for C22H25N6O4 [M+H] 437.1937, found 437.1938. 4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(benzo[d][1 ,3]dioxol-5-yl)-1 ,4- diazepane-1 -carboxamide (AR880.1 )

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N-(benzo[d][1 ,3]dioxol-5-yl)-1 ,4-diazepane-1- carboxamide (AR880.1) was synthesized according to GP7 starting from benzo[d][1 ,3]dioxol-5-amine (69 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 53 mg (28%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.25 (s, 0.5 H), 8.21 (s, 0.5 H), 7.11 (d, J = 2.0 Hz, 0.5 H), 7.06 (t, J = 1.1 Hz, 0.5 H), 6.82 (dd, J = 8.4, 2.0 Hz, 0.5 H), 6.79 - 6.76 (m, 1.5 H), 6.38 (s, 1 H), 6.35 (s, 1 H), 5.94 (s, 2 H), 3.82 - 3.75 (m, 2 H), 3.69 - 3.60 (m, 4 H), 3.58 - 3.52 (m, 2 H), 1.90 - 1.77 (m, 2 H).

HRMS (ESI) calcd. for C16H19N6O5 [M+H] 375.1417, found 375.1416.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)- 1 ,4-diazepane-1 -carboxamide (AR882.1 ) 4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)-1 ,4- diazepane-1 -carboxamide (AR882.1) was synthesized according to GP7 starting from 2,2-difluorobenzo[d][1 ,3]dioxol-5-amine (87 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O : MeCN + 0.1 % HCOOH). Yield: 64.3 mg (31%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.56 (s, 0.5 H), 8.51 (s, 0.5 H), 7.60 (d, J = 2.0 Hz, 0.5 H), 7.54 (d, J = 2.0 Hz, 0.5 H), 7.27 (d, J = 6.1 Hz, 0.5 H), 7.25 (d, J = 6.1 Hz, 0.5 H), 7.18 (d, J = 8.8, 2.0 Hz, 0.5 H), 7.13 (d, J = 8.8, 2.0 Hz, 0.5 H), 6.37 (s , 1 H), 6.34 (s, 1 H), 3.83 - 3.77 (m, 2 H), 3.71 - 3.61 (m, 4 H), 3.60 - 3.55 (m, 2 H), 1.90 - 1.78 (m, 2 H).

HRMS (ESI) calcd. for C16H17F2N6O5 [M+H] 411.1228, found 411.1225.

4-(4-Amino-'l,2,5-oxadiazole-3-carbonyl)-/V-(4-(tetrahydro-2H-pyran-4-yl)phenyl)- 1 ,4-diazepane-1 -carboxamide (AR883.1 )

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-/V-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1 ,4- diazepane-1 -carboxamide (AR883.1) was synthesized according to GP7 starting from 4- (tetrahydro-2H-pyran-4-yl)aniline (89 mg, 0.5 mmol), 4-nitrophenyl chloroformate (101 mg, 0.5 mmol) and 35 (obtained from 34 (196 mg, 0.63 mmol)). The product was purified by column chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O : MeCN + 0.1% HCOOH). Yield: 66.6 mg (32%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.30 (s, 0.5 H), 8.26 (s, 0.5 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 6.37 (s, 1 H), 6.35 (s, 1 H), 3.96 - 3.89 (m, 2 H), 3.83 - 3.75 (m, 2 H), 3.71 - 3.61 (m, 4 H), 3.60 - 3.54 (m, 2 H), 3.45 - 3.37 (m, 2 H), 2.72 - 2.62 (m, 1 H), 1.91 - 1 .78 (m, 2 H), 1.69 - 1.56 (m, 4 H).

HRMS (ESI) calcd. for C20H27N6O4 [M+H] 415.2094, found 415.2089.

4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-/V-(4-(oxetan-3-yl)phenyl)-1 ,4-diazepane-

1 -carboxamide (AR885.1)

4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-N -(4-(oxetan-3-yl)phenyl)-1 ,4-diazepane-1 - carboxamide (AR885.1) was synthesized according to GP7 starting from 4-(oxetan-3- yl)aniline (50 mg, 0.34 mmol), 4-nitrophenyl chloroformate (68 mg, 0.34 mmol) and 35 (0.42 mmol). The product was purified by flash chromatography (silica; cyclohexane : EtOAc) and after that by HPLC (C18; H2O ; MeCN + 0.1% HCOOH). Yield: 67.9 mg (52%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (700 MHz, DMSO-d6) δ [ppm] = 8.35 (s, 0.5 H), 8.32 (s, 0.5 H), 7.45 (d, J = 8.6 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 1 H), 7.26 (d, J = 8.6 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 1 H), 6.36 (s, 1 H), 6.34 (s, 1 H), 4.93 - 4.87 (m, 2 H), 4.59 - 4.56 (m, 2 H), 4.19 - 4.14 (m, 1 H), 4.83 - 4.77 (m, 2 H), 3.70 - 3.63 (m, 4 H), 3.60 - 3.55 (m, 2 H), 1 .90 - 1 .80 (m, 2 H). HRMS (ESI) calcd. for C18H23N6O4 [M+H] 387.1781, found 387.1777.

62 63

Benzyl 4-(4-Amino-1 ,2,5-oxadiazole-3-carbony l)-1 ,4-diazepane-1 -carboxylate (62)

62

To the solution of benzyl 1 ,4-diazepane-1 -carboxylate (908 mg, 3.9 mmol) in DMF (15 mL) 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (500 mg, 3.9 mmol), HATLI (1.77 g, 4.6 mmol) and DIPEA (2 mL, 11.6 mmol) was added. The resulting mixture was stirred overnight at r. t. H2O was added and the mixture was extracted with EtOAc (3 times). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (C18; MeCN : H2O) yielding 1 g (74%) of the desired product. The compound exists as a mixture of three conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 7.41 - 7.21 (m, 5 H), 6.40 - 6.35 (m, 2 H), 5.09 (s, 0.5 H), 5.07 (s, 1 H), 5.01 (s, 0.5 H), 3.80 - 3.74 (m, 2 H), 3.70 - 3.55 (m, 4 H), 3.52 - 3.45 (m, 2 H), 1 .83 - 1.72 (m, 2 H).

Benzyl 4-(4-Chloro-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 -carboxylate (63)

To a solution of 62 (200 mg, 0.58 mmol) in MeCN (2.6 mL) and cone. AcOH (2.6 mL) was added cone. HCI (1.5 mL) and LiCI (74 mg, 1.74 mmol). The mixture was cooled to 0 °C and a solution of NaNC>2 (60 mg, 0.87 mmol) in H2O (0.15 mL) was added dropwise. The reaction mixture was stirred for 10 min at 0 °C, then for 45 min at r. t. Aq. sat. NH4CI was added and the resulting mixture was extracted with EtOAc (3 times). The combined organic phases were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (C18; MeCN : H2O) yielding 111 mg (53%) of the desired product.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 7.41 - 7.26 (m, 5 H), 5.12 - 5.02 (m, 2 H), 3.83 - 3.77 (m, 1 H), 3.74 - 3.45 (m, 7 H), 1.85 - 1 .69 (m, 2 H).

Benzyl 4-(4-(Methylamino)-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1- carboxylate (64)

To a solution of 63 (100 mg, 0.27 mmol) in dioxane (1.5 mL) was added methylammonium chloride (186 mg, 2.78 mmol) and DIPEA (0.95 mL, 5.46 mmol). The reaction mixture was stirred for 5 h at 140 °C in a microwave (control by LC-MS). Methylammonium chloride (186 mg, 2.78 mmol) and DIPEA (0.95 mL, 5.46 mmol) were added once more and the reaction mixture was stirred for 5 h at 140 °C in a microwave. Methylammonium chloride (186 mg, 2.78 mmol) and DIPEA (0.95 mL, 5.46 mmol) were added for the third time and the reaction mixture was stirred for 5 h at 140 °C in a microwave. The product was purified by flash chromatography (silica; cyclohexane : EtOAc) yielding 30 mg (31%) of the desired product. (1 ,4-Diazepan-1 -yl)(4-(methylamino)-1 ,2,5-oxadiazol-3-yl)methanone (65)

The compound 64 (30 mg, 0.08 mmol) was added to the solution of HBr in HOAc (32%) (1 mL). The reaction mixture was stirred for 18 h at r. t. It was concentrated under reduced pressure and purified by flash chromatography (C18; MeCN : H2O) yielding 15.6 mg (87%) of the desired product that was directly used for the next step.

N -(4-lsopropylphenyl)-4-(4-(methylamino)-1,2,5-oxadiazole-3-carbonyl)-1 ,4- diazepane-1 -carboxamide (AR844.1 )

N -(4-isopropylphenyl)-4-(4-(methylamino)-1,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-

1 -carboxamide (AR844.1) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (11 mg, 0.07 mmol) in dry THF (0.5 mL) and the solution of 65 (15.6 mg, 0.07 mmol) in a mixture of dry THF (0.5 mL) and dry DMF (0.3 mL). The product was purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH) yielding 3.1 mg (11%) of the desired product. The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, CD3OD ): δ [ppm] = 7.24 (d, J = 8.5 Hz, 1 H), 7.19 (d, J = 8.5 Hz, 1 H), 7.16 - 7.11 (m, 2 H), 4.12 - 4.06 (m, 1 H), 3.98 - 3.90 (m, 2 H), 3.82 - 3.73 (m, 3 H), 3.69 - 3.62 (m, 2 H), 2.90 (s, 1 .5 H), 2.85 (s, 1.5 H), 2.90 - 2.80 (m, 1 H), 2.06 - 1 .96 (m, 2 H), 1.22 (d, J = 6.9 Hz, 6 H). HRMS (ESI) calcd. for C19H27N6O3 [M+H] 387.2145, found 387.2141.

(4-Chloro-1,2,5-oxadiazol-3-yl)(1,4-diazepan-1-yl)methanone (66)

The compound 63 (216 mg, 0.59 mmol) was added to the solution of HBr in HOAc (32%) (1 mL). The reaction mixture was stirred for 18 h at r. t. It was concentrated under reduced pressure and purified by flash chromatography (C18; MeCN : H2O) yielding the desired product that was directly used for the next step.

4-(4-Chloro-1,2,5-oxadiazole-3-carbonyl)-N -(4-isopropylphenyl)-1,4-diazepane-1- carboxamide (67)

To a solution of 4-isopropylphenyl isocyanate (112 mg, 0.7 mmol) in THF (3 mL) and DMF (1 mL) was added a solution of 66 (0.59 mmol) in THF (3 mL) and DMF (1 mL). The reaction mixture was stirred for 3.5 h at r. t. and a next portion of 4-isopropylphenyl isocyanate (112 mg, 0.7 mmol) in THF (1 mL) and DMF (0.3 mL) was added. The reaction mixture was stirred overnight at r. t. H2O was added and the mixture was extracted with EtOAc (3 times). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (C18; MeCN : H2O) yielding 99.4 mg (43%). An analytical sample was additionally purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH). The compound exists as a ca. 1 : 1 mixture of two conformers. ¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.29 (s, 0.5 H), 8.23 (s, 0.5 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.32 (d, J = 8.5 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 2 H), 3.85 - 3.80 (m, 1 H), 3.73 - 3.54 (m, 7 H), 2.85 - 2.76 (m, 1 H), 1.91 - 1.76 (m, 2 H), 1.17(d, J = 6.9 Hz, 3 H), 1.16 (d, J = 6.9 Hz, 3 H).

MS (ESI) calcd. for C18H33CIN5O3 ([M+H]⁺): m/z = 392, exp.: 392.

N -(4-lsopropylphenyl)-4-(4-methoxy-1 ,2,5-oxadiazole-3-carbonyl)-1 ,4-diazepane-1 - carboxamide (AR858.1)

Absolute MeOH (6.2 μL, 4.9 mg, 0.15 mmol) was added to the mixture of NaH (12 mg, 0.3 mmol, 60% dispersion in mineral oil) and absolute THF (0.35 ml_). The mixture was stirred for 5 min at r. t. and a solution of 67 (19.9 mg, 0.05 mmol) in absolute MeOH (20 pL) was added. The reaction mixture was stirred for 75 min at 50 °C, cooled down to r. t., filtered and purified by HPLC (C18; H₂O : MeCN + 0.1% HCOOH). Yield: 1.9 mg (10%). The compound exists as a ca. 1 : 1 mixture of two conformers.

¹H NMR (500 MHz, CD3OD ): δ [ppm] = 7.28 - 7.23 (m, 2 H), 7.17 - 7.13 (m, 2 H), 4.10 (s, 1.5 H), 3.96 - 3.92 (m, 1 H), 3.94 (s, 1.5 H), 3.83 - 3.75 (m, 2 H), 3.74 - 3.69 (m, 2 H), 3.68 - 3.58 (m, 3 H), 2.90 - 2.82 (m, 1 H), 2.03 - 1 .97 (m, 1 H), 1 .93 - 1 .87 (m, 1 H), 1.22 (d, J = 6.9 Hz, 6 H).

HRMS (ESI) calcd. for C19H26N5O4 [M+H] 388.1985, found 388.1980.

(R)-N-(1-Hydroxy-3-methylbutan-2-yl)-2-nitrobenzenesulfonamide (68)

To a solution of D-valinol (1 g, 8.7 mmol) and NaHCO3 (1.1 g, 13.2 mmol) in H2O (10 mL) was gradually added a solution of 2-NsCI (1.92 g, 8.7 mmol) in THF (10 mL) at 0 °C. The reaction mixture was allowed to warm to r.t. and stirred for 15 h. The mixture was poured into H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Yield: 2.5 g (99%).

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.08 - 8.04 (m, 1 H), 7.93 - 7.90 (m, 1 H), 7.84 - 7.80 (m, 2 H), 7.73 (s, 1 H), 4.60 (t, J = 5.2 Hz, 1 H), 3.29 (t, J = 5.5 Hz, 2 H), 3.09 (q, J = 5.7 Hz, 1 H), 1 .88 - 1.80 (m, 1 H), 0.77 (t, J = 6.8 Hz, 3 H), 0.75 (t, J = 6.8 Hz, 3 H).

(R)-N-(1-hydroxy-3-methylbutan-2-yl)-N-(3-hydroxypropyl)-2- nitrobenzenesulfonamide (69)

A solution of 3-bromopropan-1-ol (1.8 g, 13 mmol) in dry DMF (5 mL ) was added to the mixture of 68 (2.5 g, 8.7 mmol), K3PO4 (3.69 g, 17.4 mmol), BU4NI (332 mg, 0.9 mmol) in dry DMF (15 mL ) at 55 °C under argon. The reaction mixture was stirred for 16 h at this temperature, cooled down to r. t. and poured into brine. The mixture was extracted with EtOAc (3 times). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (C18; MeCN : H2O). Yield: 1.2 g (40%). An analytical sample was additionally purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH).

¹H NMR (500 MHz, CD3OD ): δ [ppm] = 8.19 - 8.16 (m, 1 H), 7.79 - 7.71 (m, 2 H), 7.68 - 7.65 (m, 1 H), 3.77 - 3.68 (m, 2 H), 3.62 - 3.48 (m, 4 H), 3.39 - 3.32 (m, 1 H), 2.03 - 1.82 (m, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H).

MS (ESI) calcd. for C14H23N2O6S ([M+H]⁺): m/z = 347, exp.:347.

MS (ESI) calcd. for Ci4H22N₂NaO₆S ([M+Na]⁺): m/z = 369, exp.:369

(R)-3-((W-(3-Methyl-1-(tosyloxy)butan-2-yl)-2-nitrophenyl)sulfonamido)propyl 4-

Methylbenzenesulfonate (70)

To a mixture of 69 (1.2 g, 3.5 mmol), DMAP (60 mg, 0.49 mmol) and EtsN (1.5 mL, 10.4 mmol) in CH2CI2 (8 mL) was added a solution of TosCI (1.4 g, 7.2 mmol) in CH2CI2 (8 mL) at 0 °C. The reaction mixture was stirred for 18 h at r. t. and concentrated under reduced pressure. The residue was separated by flash chromatography (cyclohexane : EtOAc). Yield: 430 mg (19%). Also 580 mg (33%) of mono-Tosyl-derivatives were obtained.

MS (ESI) calcd. for C₂8H34N2NaOioS₃ ([M+Na]⁺): m/z = 677, exp.: 677. (R)-2-lsopropyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (71)

To a solution of the compound 70 (430 mg, 0.66 mmol) in MeCN (7 mL ) was added aq. NH3 (7 mL, 33%). The reaction mixture was stirred for 16 h at 90 °C in a closed vessel (microwave vial was used). Volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography (C18; MeCN : water). Yield: 175 mg (53%). MS (ESI) calcd. for C14H22N3O4S ([M+H]⁺): m/z = 328, exp.: 328.

(R)-(4-Amino-1,2,5-oxadiazol-3-yl)(3-isopropyl-4-((4-nitrophenyl)sulfonyl)-1,4- diazepan-1-yl)methanone (72)

(R)-(4-amino-1 ,2,5-oxadiazol-3-yl)(3-isopropyl-4-((4-nitrophenyl)sulfonyl)-1 ,4-diazepan- 1-yl)methanone (72) was prepared according to GP4 starting from the solution of 71 (175 mg, 0.53 mmol) in DMF (5 mL), 4-amino-1 ,2,5-oxadiazole-3-carboxylic acid (4) (90 mg, 0.7 mmol), HATU (266 mg, 0.7 mmol) and DIPEA (0.24 mL, 1.4 mmol). The product was purified by flash chromatography (RP; C18; MeCN : H2O). Yield: 110 mg (47%).

MS (ESI) calcd. for C17H23N6O6S ([M+H]⁺): m/z = 439, exp.: 439.

(/?)-(4-Amino-1,2,5-oxadiazol-3-yl)(3-isopropyl-1,4-diazepan-1-yl)metlianone (73)

To a mixture of 72 (110 mg, 0.25 mmol) and K2CO3 (69 mg, 0.5 mmol) in MeCN (5 mL) was added 4-(tert-butyl)benzenethiol (0.13 mL, 125 mg, 0.75 mmol) at r.t under argon. The reaction mixture was stirred at r.t. for 1 day. 4-(fert-Butyl)benzenethiol (0.13 ml_, 125 mg, 0.75 mmol), K2CO3 (69 mg, 0.5 mmol) and MeCN (5 mL) were added and the reaction mixture was stirred at r.t. for further 3 days. The insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C18; H2O : MeCN). Yield: 29 mg (46%).

MS (ESI) calcd. for C11H20N5O2 ([M+H]⁺): m/z = 254, exp.: 254.

(R)-4-(4-Amino-1,2,5-oxadiazole-3-carbonyl)-2-isopropyl-/V-(4-isopropylphenyl)-

1 ,4-diazepane-1 -carboxamide (VK765)

(R)-4-(4-Amino-1 ,2,5-oxadiazole-3-carbonyl)-2-isopropyl-N -(4-isopropylphenyl)-1 ,4- diazepane-1 -carboxamide (VK765) was prepared according to the general procedure GP2 starting from the solution of 4-isopropylphenyl isocyanate (25 mg, 0.16 mmol) in dry THF (3 mL) and the solution of 73 (29 mg, 0.11 mmol) in a mixture of dry THF (3 mL) and dry DMF (1 mL). Volatiles were removed under reduced pressure and the residue was purified by HPLC (C18; H2O : MeCN + 0.1% HCOOH) yielding 35 mg (77%) of the desired product. The compound exists as a ca. 2 : 3 mixture of two conformers.

¹H NMR (500 MHz, DMSO-d6) δ [ppm] = 8.20 (s , 0.4 H), 8.14 (s, 0.6 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.08 - 7.04 (m, 2 H), 6.33 (s, 0.8 H), 6.28 (s, 1.2 H), 4.63 - 4.51 (m, 0.4 H), 4.46 - 4.28 (m, 1.6 H), 4.07 - 3.90 (m, 1.6 H), 3.43 - 3.31 (m, 1 H), 3.31 - 3.12 (m, 2 H), 3.08 - 2.94 (m, 0.4 H), 2.79 (septet, J = 6.9 Hz, 1 H), 1.89 - 1.70 (m, 2 H), 1.67 - 1.55 (m, 1 H), 1 .16 (d, J = 6.9 Hz, 6 H), 0.97 (d, J = 6.5 Hz, 1 .8 H), 0.89 - 0.83 (m, 3 H), 0.79 (d, J = 6.5 Hz, 1.2 H).

HRMS (ESI) calcd. for C21H31N6O3 [M+H] 415.2458, found 415.2454.

3. Activity of the compounds against HCMV infection

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).

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].

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.

4. Antiviral potencies of the novel HCMV inhibitors

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

1. A compound of formula (I): wherein

Cy is an optionally substituted 1 ,4 diazepane group;

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, 0 and S; and

Ar² is 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 of Formula (I), wherein Cy is unsubstituted or substituted by one or two substituents that are independently selected from -F, C1-4 alkyl, -OH, -COOH, -CONH2, and =0.

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

4. A compound according to any one of the preceding claims of formula (II) or a salt thereof:

5. A compound according to any one of the preceding claims, wherein Ar¹ is an optionally substituted phenyl group.

6. A compound according to any one of the preceding claims, wherein Ar¹ is an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S.

7. A compound according to any one of the preceding claims 1 to 6, wherein Ar¹ is unsubstituted or substituted by a halogen atom, a CN group, an OH group, a N3 group, a SFs group, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 heteroalkyl group, a C3-7 cycloalkyl group, a phenyl group, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N, O and S, a heteroaralkyl group, or a heteroalkylcycloalkyl group.

8. A compound according to any one of the preceding claims 1 to 6, wherein Ar¹ is 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:

9. A compound according to any one of the preceding claims 1 to 6, wherein Ar¹ is substituted by Br, a CN group, a SFs group, a CH2CF3 group, an i-propyl group, an n-butyl group, a t-butyl group, a -C(CI)=CH2 group, an -SCF3 group, a cyclopropyl group, or a phenyl group.

10. A compound according to any one of the preceding claims 1 to 4, wherein Ar¹ is selected from the following groups:

11. A compound according to any one of the preceding claims 1 to 4, wherein Ar¹ is selected from the following groups:

12. A compound according to any one of the preceding claims, wherein Ar² is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, O and S.

13. A compound according to any one of the preceding claims, wherein Ar² is substituted by one or two substituents which are independently selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc, -OH, -OCH3 and -CN.

14. A compound according to any one of the preceding claims 1 to 11 , wherein Ar² is selected from the following groups:

15. A compound according to any one of the preceding claims 1 to 11 , wherein Ar² is selected from the following groups:

16. A compound according to any one of the preceding claims of formula (III): wherein

Ar¹ is defined as in any one of the preceding claims; and R² is selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc, -OH, - OCH3 and -CN; or a salt thereof; especially, wherein R² is NH2.

17. A compound according to any one of the preceding claims, wherein the following compounds are excluded:

18. A compound according to any one of the preceding claims, wherein the following compounds are excluded:

19. 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.

20. Compound according to any one of claims 1 to 18 or pharmaceutical composition according to claim 19 for use as a medicament.

21. Compound according to any one of claims 1 to 18 or pharmaceutical composition according to claim 19 for use in the treatment or prevention of a herpesvirus infection; especially for use in the treatment or prevention of a Cytomegalovirus (CMV) infection.

22. Use of a compound according to any one of claims 1 to 18 or of a pharmaceutical composition according to claim 19 for the manufacture of a medicament for the treatment or prevention of a herpesvirus infection; especially for the treatment or prevention of a Cytomegalovirus (CMV) infection.

23. A method for the treatment or prevention of a herpesvirus infection; especially for the treatment or prevention of a Cytomegalovirus (CMV) infection comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19.