Novel inhibitors of cytomegalovirus

Abstract

The present invention relates to novel inhibitors of cytomegalovirus (CMV) of formula (I), wherein Cy is an optionally substituted 1,4 diazepane group; Ar 1 is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O, and S; Ar 2 is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S, or a salt thereof. [Formula 1] JPEG2026505488000160.jpg34125

Description

[Technical Field]

[0001] The present invention relates to novel inhibitors of cytomegalovirus (CMV). [Background technology]

[0002] Cytomegalovirus (CMV) is a virus that belongs to the herpesvirus family. Because CMV is present worldwide and can affect anyone, CMV infection is very common. Generally, CMV infection does not cause any serious health problems. Once a person is infected with the virus, it remains in the body for the rest of the person's life. In fact, the virus remains latent for long periods of time, and the infection does not tend to recur unless the person's immune system is compromised. The majority of people infected with this virus who do not experience serious health problems generally do not exhibit any symptoms that would suggest they have CMV. Those who develop some symptoms may suffer from high fever, swollen lymph nodes, muscle pain, or fatigue. However, the virus is considered a major public health problem because it can cause severe illness in infants infected with the virus during pregnancy or birth, and in people with weakened immune systems.

[0003] The virus is often transmitted from person to person through direct contact with bodily fluids such as saliva, semen, blood, urine, and other secretions. The virus can also be transmitted 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. If a woman becomes infected during pregnancy, there is a high risk of transmitting the virus to the fetus. In this case, the infant is said to have congenital cytomegalovirus. 90% of infants infected with the virus before birth are born without any symptoms of the virus. However, the remaining 10% develop disabilities such as deafness, blindness, physical and mental disabilities, or even death. Furthermore, approximately another 10% of infected children who are asymptomatic at birth will develop sequelae at a later date. Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide novel inhibitors of human cytomegalovirus (HCMV). [Brief explanation of the drawings]

[0005] [Figure 1] Figure 1 shows the activity of HCMV inhibitors (dose-response curves), with inhibitor concentration on the X-axis and GFP expression on the Y-axis. DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention provides compounds of formula (I): [ka] wherein Cy is an optionally substituted 1,4 diazepane group; Ar 1 is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O, and S; Ar 2 is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S; or a salt thereof. Preferably, Cy is unsubstituted or substituted with one or two substituents independently selected from -F, -CH3, -OH, -COOH, -CONH2 and =O. More preferably, Cy is unsubstituted or is -F, C 1-4 Substituted with 1 or 2 substituents independently selected from alkyl, -OH, -COOH, -CONH2 and =O.

[0007] More preferably, Cy is unsubstituted or substituted with one or two substituents independently selected from -F, -CH3 and -CH(CH3)2. More preferably, Cy is selected from the following groups: [ka]

[0008] More preferred is a compound of formula (II) or a salt thereof. [ka] More preferably, Ar 1 is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O, and S. More preferably, Ar 1 is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S. More preferably, Ar 1 is an optionally substituted phenyl group. More preferably, Ar 1 is an optionally substituted pyridyl group.

[0009] More preferably, Ar 1 is an optionally substituted heteroaryl group containing 9 ring atoms selected from C, N, O and S. More preferably, Ar 1 is non-substituted. More preferably, Ar 1 is a halogen atom, CN group, OH group, N3 group, SF5 group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Heteroalkyl groups, C 3-7cycloalkyl groups, phenyl groups, optionally substituted heterocycloalkyl groups containing 3 to 7 ring atoms independently selected from C, N, O and S, where the optional substituents are preferably halogen, C 1-6 Alkyl group or C 1-6 The aryl group is substituted with a heteroaryl group (e.g., a heteroaryl group), ... or a heteroarylcycloaryl group. More preferably, Ar 1 is a halogen atom, a CN group, a SF5 group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 1-6 Heteroalkyl groups, C 3-7 It is substituted with a cycloalkyl group, a phenyl group, or a heterocycloalkyl group containing 3 to 7 ring atoms independently selected from C, N, O, and S.

[0010] More preferably, Ar 1 is substituted with a halogen atom (e.g., F, Cl, Br), a CN group, an N group, an OH group, an SF group, a methyl group, a CF group, an OCF 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, a COOCH3 group, a methoxy group, a -C(Cl)=CH2 group, a -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-oxetanyl group, a group of formula -OCH2-O-, a group of formula -OCF2-O-, a phenyl group or a group of formula: [ka] More preferably, Ar 1is substituted with a halogen atom (e.g., F, Cl, Br), a CN group, a SF group, a methyl group, a CF 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, a COOCH3 group, a methoxy group, a -C(Cl)=CH2 group, a -SCF3 group, an ethoxy group, a cyclopropyl group, or a phenyl group.

[0011] More preferably, Ar 1 is substituted by a halogen atom, an N3 group, an 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(Cl)=CH2 group, a -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-oxetanyl 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: [ka] More preferably, Ar 1 is selected from the following groups: [ka]

[0012] More preferably, Ar 1 is selected from the following groups: [ka]

[0013] More preferably, Ar 2 is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S. More preferably, Ar 2is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, O and S. More preferably, Ar 2 is substituted with one or two substituents independently selected from the following groups: -NH2, -NHMe, -NMe2, -NHAc, -OH, -OCH3, and -CN.

[0014] More preferably, Ar 2 is selected from the following groups: [ka]

[0015] More preferably, Ar 2 is selected from the following groups: [ka]

[0016] More preferred are compounds of formula (III). [ka] In the formula, R 2 is selected from the following groups: -NH2, -OH, NHMe, -NMe2, -NHAc, -OCH3, and -CN; or a salt thereof. More preferably, R 2 is NH2. The most preferred compounds of the present invention are the compounds disclosed in the Examples or salts thereof. It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., Ar 1 Any embodiment of Ar 2 (This may be combined with any of the embodiments of the previous paragraphs.)

[0017] According to one embodiment of the present invention, the following compounds per se are excluded from the present invention: [ka]

[0018] According to another embodiment, the use of these compounds in the treatment or prevention of herpesvirus infections (particularly in the treatment or prevention of beta-herpesvirus infections, such as human cytomegalovirus (HCMV) infections) is encompassed by the present invention.

[0019] According to a further embodiment of the present invention, the following compounds per se are excluded from the present invention: [ka] According to another embodiment, the use of these compounds in the treatment or prevention of herpesvirus infections (particularly in the treatment or prevention of beta-herpesvirus infections, such as human cytomegalovirus (HCMV) infections) is encompassed by the present invention.

[0020] The term alkyl refers to saturated linear or branched hydrocarbon groups containing 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, in particular 1 to 10 (e.g. 1, 2, 3 or 4) carbon atoms, such as methyl (Me, CH), ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl groups. C 1-6 The term alkyl refers to saturated straight or branched hydrocarbon groups containing 1 to 6 carbon atoms. 1-4 The term alkyl refers to a saturated, straight-chain or branched hydrocarbon group containing 1 to 4 carbon atoms. Examples include methyl (Me), CF3, CD3, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups.

[0021] The terms alkenyl and alkynyl refer to at least partially unsaturated, linear or branched hydrocarbon groups containing 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, in particular 2 to 10 (e.g. 2, 3 or 4) carbon atoms, such as ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl, propynyl, butynyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl groups. Preferably, alkenyl groups have one or two (particularly preferably one) double bonds, and alkynyl groups have one or two (particularly preferably one) triple bonds. 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, 2,2,2-trichloroethyl, -C(Cl)=CH2, difluoromethyl, fluoromethyl or trifluoromethyl groups.

[0022] The term heteroalkyl refers to an alkyl, alkenyl or alkynyl group as defined above, in which one or more (preferably 1 to 8; particularly preferably 1, 2, 3 or 4) carbon atoms are replaced by oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atoms (preferably oxygen, sulfur or nitrogen atoms) or by an SO or SO group. The term heteroalkyl also refers to carboxylic acids or groups derived from carboxylic acids, such as acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms are replaced by halogen atoms (preferably F or Cl).

[0023] Preferably, the heteroalkyl group contains 1 to 12 carbon atoms and 1 to 8 heteroatoms selected from oxygen, nitrogen, and sulfur (especially oxygen and nitrogen). Particularly preferably, the heteroalkyl group contains 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 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 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).

[0024] More preferably, the term heteroalkyl refers to an alkyl group (linear or branched) as defined above, in which one or more (preferably 1 to 6, particularly preferably 1, 2, 3 or 4) carbon atoms are replaced by oxygen, sulfur or nitrogen atoms or a CO group. This group preferably contains 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; particularly preferably 1, 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH, ═NH, N, CN or NO groups.

[0025] Examples of heteroalkyl groups include those of the formula: R a -OY a -, R a -SY a -, R a -SO-Y a -, Ra -SO2-Y a -、R a -N(R b )-SO2-Y a -、R a -SO2-N(R b )-Y a -、R a -N(R b )-Y a -、R a -CO-Y a -、R a -C(=NR d )-Y a -、R a -O-WHAT-Y a -、R a -CO-OY a -、R a -CO-N(R b )-Y a -、R a -N(R b )-CO-Y a -、R a -N(R b )-C(=NR d )-Y a -、R a -O-CO-N(R b )-Y a -、R a -N(R b )-CO-OY a -、R a -N(R b )-CO-N(R c )-Y a -、R a -O-CO-OY 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-OY a -、R a -CS-N(R b )-Y a -、R a -N(Rb )-CS-Y a -, R a -O-CS-N(R b )-Y a -, R a -N(R b )-CS-OY a -, R a -N(R b )-CS-N(R c )-Y a -, R a -O-CS-OY a -, R a -S-CO-Y a -, R a -CO-SY a -, R a -S-CO-N(R b )-Y a -, R a -N(R b )-CO-SY a -, R a -S-CO-OY a -, R a -O-CO-SY a -, R a -S-CO-SY a -, R a -S-CS-Y a -, R a -CS-SY a -, R a -S-CS-N(R b )-Y a -, R a -N(R b )-CS-SY a -, R a -S-CS-OY a -, R a -O-CS-SY a -:In formula, R a is a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl group; R b is a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl group; R c is a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl group; R dis a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl group, and Y a is a bond, a C-C alkylene, a C-C alkenylene, or a C-C alkynylene group, each heteroalkyl group containing at least one carbon atom, and one or more hydrogen atoms in the above groups may be replaced by a fluorine or chlorine atom.

[0026] Illustrative examples of heteroalkyl groups include methoxy, trifluoromethoxy, -OCD, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CHCHOH, -CHOH, -SOMe, -NHAc, -CONH, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino, propionylamino, carboxymethyl, carboxyethyl, carboxypropyl, N-ethyl-N-methylcarbamoyl, and N-methylcarbamoyl. Further examples of heteroalkyl groups include nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate, and alkylnitrile groups.

[0027] The term cycloalkyl refers to saturated or partially unsaturated (e.g., cycloalkenyl) cyclic groups containing one or more rings (preferably one or two) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6, or 7) ring carbon atoms. The term cycloalkyl also refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine, or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N, or NO groups, thus, for example, cyclic ketones, such as cyclohexanone, 2-cyclohexenone, or cyclopentanone. Further specific examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl groups.

[0028] The term 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 oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atoms (preferably oxygen, sulfur or nitrogen atoms) or by an SO or SO group. Heterocycloalkyl groups preferably have one or two rings containing 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). The term heterocycloalkyl refers to groups which are further substituted by fluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH, ═NH, N or NO groups. Examples include piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g., —N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, or 2 pyrazolinyl groups, as well as lactams, lactones, cyclic imides, and cyclic anhydrides.

[0029] The expression alkylcycloalkyl refers to groups containing both cycloalkyl and alkyl, alkenyl or alkynyl groups in accordance with the above definitions, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. Alkylcycloalkyl groups preferably contain one or two rings with 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) with 1 or 2 to 6 carbon atoms. The term heteroalkylcycloalkyl refers to an alkylcycloalkyl group as defined above in which one or more (preferably 1, 2, or 3) carbon atoms have been replaced by oxygen, nitrogen, silicon, boron, selenium, phosphorus, or sulfur atoms (preferably oxygen, sulfur, or nitrogen atoms) or by an SO or SO group. Heteroalkylcycloalkyl groups preferably contain one or two rings with 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) with 1 or 2 to 6 carbon atoms. Examples of such groups include alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl, and heteroalkylheterocycloalkenyl, where the cyclic groups are saturated or mono-, di-, or tri-unsaturated.

[0030] The term aryl refers to an aromatic group containing one or more rings containing 6 to 14 ring carbon atoms, preferably 6 to 10 (especially 6) ring carbon atoms. The term aryl also refers to groups substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH, N or NO groups. Examples include phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups. The term heteroaryl refers to an aromatic group containing one or more rings containing 5 to 14 ring atoms, preferably 5 to 10 (especially 5, 6, 9 or 10) ring atoms, including one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The term heteroaryl refers to groups which are further substituted by fluorine, chlorine, bromine or iodine atoms, or by OH, SH, N, NH or NO groups. Examples include 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.

[0031] The term "aralkyl" refers to groups containing both aryl and alkyl, alkenyl, alkynyl, and / or cycloalkyl groups according to the above definitions, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl, and alkylarylcycloalkenyl groups. Specific examples of aralkyls include toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene, and indane. The aralkyl group preferably contains one or two aromatic ring systems (especially one or two rings), each containing 6 to 10 carbon atoms and one or two alkyl, alkenyl, and / or alkynyl groups containing 1 or 2 to 6 carbon atoms, and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0032] The term heteroaralkyl refers to a group containing both aryl and / or heteroaryl groups and alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups, in accordance with the above definitions. Heteroaralkyl groups contain at least one heteroatom, preferably selected from N, O and S. Heteroaralkyl groups preferably contain one or two aromatic ring systems (especially one or two rings) each containing 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 and including 1, 2, 3 or 4 oxygen, sulphur or nitrogen atoms.

[0033] Examples include 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, wherein the cyclic groups are saturated or mono-, di-, or tri-unsaturated. Specific examples include tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3-, or 4-methoxyphenyl, 4-ethoxyphenyl, and 2-, 3-, or 4-carboxyphenylalkyl groups.

[0034] As already mentioned above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups which are substituted by a fluorine, chlorine, bromine or iodine atom or by an OH, ═O, SH, ═S, NH, ═NH, N or NO group.

[0035] The term halogen refers to F, Cl, Br or I. The term "optionally substituted" refers to a group that is unsubstituted or substituted with one or more (especially 1, 2, or 3; preferably 1 or 2; particularly preferably 1) substituents. When a group includes two or more substituents, these substituents are independently selected, i.e., they can be the same or different. When a group is substituted with a cyclic group, such as a cycloalkyl group or a heterocycloalkyl group, the cyclic group may be attached to the group through a single or double bond, or the cyclic group may be cyclized or fused to the group.

[0036] Examples of substituents include fluorine, chlorine, bromine, and iodine, as well as OH, SH, NH, =O, -SOH, -SONH, -COOH, -COOMe, -COOEt, CHOH, -COMe(Ac), -NHSOMe, -SONMe, -CHNH, -NHAc, -SF, -NHMe, -O-CH-CH-O-, -NMe, -OCH, -SOMe, -CONH, -CN, -NHCONH, -NHC(NH)NH, -NOHCH, -N, and -NO groups. Further examples of substituents include C-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Heteroalkyl, C3-C 18 Cycloalkyl, C1-C 17 Heterocycloalkyl, C4-C 20 Alkylcycloalkyl, C1-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C1-C 17 Heteroaryl, C7-C 20 Aralkyl and C1-C 19 Heteroaralkyl groups; in particular C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C 3- C 10 Cycloalkyl, C1-C9 heterocycloalkyl, C 4- C 12 Alkylcycloalkyl, C1-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Aralkyl and C1-C 11 Heteroaralkyl groups are preferred, and C1-C6 alkyl and C1-C6 heteroalkyl groups are more preferred.

[0037] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl group contains more than one ring, the rings may be joined to each other via a single or double bond, or the rings may be cyclized. The rings of any cycloalkylaryl, heterocycloalkylaryl, cycloalkylheteroaryl, and heterocycloalkylheteroaryl group may be joined to each other through single or double bonds, or the rings may be cyclized.

[0038] It should be recognized that certain compounds of formula (I), (II), or (III) may have tautomeric forms, different geometric isomers (usually designated as cis / trans isomers or more commonly as (E) and (Z) isomers), of which only one may be specifically mentioned or illustrated in the following description, or different optical isomers (usually designated under the Cahn-Ingold-Prelog or R / S system) as a result of one or more chiral carbon atoms. All these tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers) and polymorphic forms are included in the present invention. Because compounds of formula (I), (II), or (III) may contain asymmetric C atoms, they may exist as either achiral compounds, mixtures of diastereomers, mixtures of enantiomers, or optically pure compounds. The present invention includes both all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any ratio.

[0039] 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 to its inherent pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces the formation of toxic metabolites, and / or increases the formation of desired active metabolites. Therefore, the present invention also encompasses partially and fully deuterated compounds of formula (I), (II), or (III). The term hydrogen also encompasses deuterium. Therapeutic uses of compounds of formula (I), (II) or (III), their salts (particularly their pharmacologically acceptable salts), solvates and hydrates, respectively, are within the scope of the present invention, along with formulations and pharmaceutical compositions.

[0040] The present invention further provides pharmaceutical compositions comprising one or more compounds as described herein or salts thereof (particularly pharmaceutically acceptable salts), solvates or hydrates thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants. The present invention further provides a compound or pharmaceutical composition as described herein for use in treating or preventing a herpes virus infection. The present invention further provides the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in the treatment or prevention of a herpes virus infection. According to a further preferred embodiment, the present invention provides a method for treating or preventing a herpes virus infection in a subject, comprising administering to the subject an effective amount of a compound of formula (I), (II) or (III) or a salt thereof.

[0041] According to a further preferred embodiment, the present invention provides a method for treating or preventing a herpes virus infection in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II) or (III) or a salt thereof. Preferred examples of herpesvirus include beta-herpesvirus.More preferred examples of herpesvirus include human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus-7 (HHV-7) and human cytomegalovirus (HCMV).Particularly preferably, the compound of the present invention can be used in the treatment or prevention of cytomegalovirus (CMV) infection, for example, human cytomegalovirus (HCMV) infection.

[0042] The present invention also relates to prodrugs consisting of a compound of formula (I), (II) or (III) and at least one pharmacologically acceptable protecting group which is cleaved under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g., pivaloyloxymethyl), a 2-alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylideneethyl group or an acyloxy group as defined herein, such as ethoxy, benzyloxy, acetyl or acetyloxy, or, in particular for compounds of formula (I), (II) or (III) bearing a hydroxy group (-OH), a sulfate ester, a phosphate ester (-OPO or -OCHOPO) or an ester of an amino acid. Preferably, the present invention also relates to prodrugs, biohydrolyzable esters, biohydrolyzable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biohydrolyzable carbamates, biohydrolyzable ethers, physiologically functional derivatives, atropisomers, or in vivo hydrolyzable precursors, diastereomers or mixtures of diastereomers, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of the compounds of Formula (I), (II) or (III).

[0043] Examples of salts (particularly pharmacologically acceptable salts) of sufficiently basic compounds include salts of physiologically acceptable mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid, and salicylic acid. Furthermore, sufficiently acidic compounds can form alkali or alkaline earth metal salts, such as sodium, potassium, lithium, calcium, or magnesium salts; ammonium salts; or organic base salts, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine, or arginine salts, all of which are further examples of salts of the compounds described herein.

[0044] The compounds described herein may be solvated, particularly hydrated. Hydration / hydration may occur during the production process or as a result of the hygroscopic nature of compounds that do not initially contain water. Solvates and / or hydrates may exist, for example, in solid or liquid form. In general, the compounds and pharmaceutical compositions described herein are administered using accepted methods known in the art.

[0045] For oral administration, such therapeutically useful agents can be administered by any of the following routes: orally, for example, as tablets, sugar-coated tablets, coated tablets, pills, semisolids, soft or hard capsules, for example, soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions, or syrups; parenterally, including intravenous, intramuscular, and subcutaneous injections, for example, as injectable solutions or suspensions; rectally as suppositories; by inhalation or insufflation, for example, as a powder formulation, as microcrystals, or as a spray (e.g., liquid aerosol); transdermally, for example, via a transdermal delivery system (TDS) containing a plaster containing the active ingredient; or intranasally. For the preparation of such tablets, pills, semisolids, coated tablets, sugar-coated tablets, and hard capsules such as gelatin, the therapeutically useful products may be mixed with pharmaceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dried skim milk, etc. For the preparation of soft capsules, excipients such as vegetable oils, petroleum oils, animal oils, synthetic oils, waxes, fats, and polyols may be used. For the preparation of solutions, emulsions, suspensions, or syrups, excipients such as water, alcohol, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum oils, animal oils, or synthetic oils may be used. Lipids are particularly preferred, and phospholipids (preferably of natural origin; particularly preferably having a particle size of 300-350 nm) in phosphate-buffered saline (pH = 7-8, preferably 7.4) are more preferred. For suppositories, excipients such as vegetable oils, petroleum oils, animal oils, synthetic oils, waxes, fats, and polyols may be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen, and carbon dioxide, may be used. Pharmaceutically useful agents may also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, flavoring agents, salts for varying osmotic pressure, buffers, coating additives, and antioxidants.

[0046] Generally, for oral or parenteral administration to an adult weighing approximately 80 kg, a daily dose of about 0.1 mg to about 10,000 mg, preferably about 1 mg to about 1,000 mg, is appropriate, although the upper limit may be exceeded if necessary. The daily dose can be administered as a single dose or divided doses, or, for parenteral administration, as continuous infusion or subcutaneous injection.

[0047] [Example]

[0048] I. Synthesis of Compounds of the Invention Abbreviations and Acronyms Abbreviations and acronyms used in the chemical descriptions and examples below are as follows: aq. water-based Ar Argon Boc tert-butyloxycarbonyl br. Wide line CDCl3 deuterated chloroform CD3OD Deuterated Methanol cHex cyclohexane conc. concentration d double line DCM dichloromethane DIPEA Diisopropylethylamine DMSO dimethyl sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide ESI electrospray EtOAc ethyl acetate EtOH ethanol h time hept septet HCl Hydrochloric acid HPLC High-Performance Liquid Chromatography H2O Water H2SO4 Sulfuric Acid m multiplet MeCN acetonitrile MeOH Methanol min MS mass spectrometry NaHCO3 Sodium bicarbonate NaCl Sodium chloride NaCl Sodium hydroxide Na2SO4 Sodium Sulfate NMR nuclear magnetic resonance Ns 2-nosyl, 2-nitrobenzenesulfonyl q quartet quint quintet rt room temperature s single line sat. saturation t triple line TFA trifluoroacetic acid UPLC Ultra High Performance Liquid Chromatography wt weight

[0049] 1. Method for producing the compound of the present invention In general, the compounds of the present invention can be prepared by standard techniques known in the art, by known processes similar thereto, and / or by the processes described herein, using starting materials that are commercially available or can be prepared according to conventional chemical methods. The specific process utilized in preparing the compounds of the present invention depends on the specific compound desired. Factors such as the type of substitution at various positions on the molecule and the commercial availability of starting materials will affect the route to be followed and the reaction conditions selected for the preparation of a specific compound of the present invention. These factors will be readily recognized by those skilled in the art.

[0050] The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention. 2. Experimental Procedure LC-MS method HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using an Agilent 6130 Single Quadrupole LC / MS System equipped with a 1260 Infinity II LC system. Column: Gemini® 3 μm NX-C18, LC column 50 × 2 mm Eluents: A: H2O with 0.1% formic acid, and B: MeCN with 0.1% formic acid. Flash Chromatography Flash chromatography was performed using a Pure C-850 FlashPrep system in flash mode. Reversed-phase (RP) separations were performed using Buchi FlashPure EcoFlex C cartridges with HO-MeCN eluent. Normal-phase separations were performed using Buchi FlashPure silica cartridges.

[0051] Preparative HPLC method Preparative HPLC was performed using a Pure C-850 FlashPrep system in HPLC mode. Column: Luna® Prep C18 5 μm, 21.2 × 250 mm Flow rate: 10mL / min Eluents: A: H2O with 0.1% formic acid, and B: MeCN with 0.1% formic acid. Exact Mass Method High resolution mass was obtained using a Maxis II™ HD mass spectrometer (Bruker). NMR method proton( 1 H) Nuclear magnetic resonance (NMR) spectra were measured on a Bruker Avance III (500 MHz) or Bruker Avance III (700 MHz) spectrometer using residual protonated solvents (CHCl δ 7.26; MEOH δ 3.30; DMSO δ 2.49) as standards. The NMR data for the synthesized examples are consistent with their corresponding structural assignments.

[0052] 2.1. Experimental Examples of the Present Invention 2.1.1.Synthesis method Synthesis of HCMV inhibitors (Scheme 1) [ka]

[0053] General Procedure 1 (GP1). Synthesis of isocyanates. [ka] A solution of the aniline derivative (0.6 mmol, 1.0 equiv) in dry DCM (3 mL) was treated with triphosgene (89 mg, 0.3 mmol, 0.5 equiv), followed by the dropwise addition of EtN (97 μL, 0.66 mmol, 1.1 equiv). The reaction was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give a solid, which was used directly in the next step.

[0054] General Procedure 2 (GP2). Synthesis of tert-butyl 4-(arylcarbamoyl)-1,4-diazepane-1-carboxylate [ka] To a solution of the isocyanate (0.6 mmol, 1.0 equiv.) in dry toluene (5 mL) was added a solution of tert-butyl 1,4-diazepane-1-carboxylate (1) (0.6 mmol, 1.0 equiv.) in dry THF (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction was quenched by adding water (5 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over NaSO, filtered, and the solvent was removed under reduced pressure to give the product (2), which was used directly in the next step.

[0055] General Procedure 3 (GP3). Synthesis of N-aryl-1,4-diazepane-1-carboxamides [ka] To a solution of crude tert-butyl 4-(arylcarbamoyl)-1,4-diazepane-1-carboxylate (2) (0.6 mmol) in DCM (5 mL) was added dropwise TFA (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give product (3), which was used in the next step without further purification.

[0056] General Procedure 4 (GP4): Amide Bond [ka] To a solution of crude N-aryl-1,4-diazepane-1-carboxamide (3) (0.6 mmol, 1 equiv.) in DMF (2 mL) was added 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (77 mg, 0.6 mmol, 1 equiv.), HATU (274 mg, 0.72 mmol, 1.2 equiv.) in DMF (3 mL), and DIPEA (430 μL, 3 mmol, 5 equiv.). The resulting mixture was stirred at room temperature overnight. EtOAc (100 mL) was added. The reaction mixture was washed with saturated NH4Cl (2 × 100 mL), 1 M NaOH (2 × 100 mL), and brine (100 mL). The organic phase was dried over Na2SO4. The 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 to give the desired product.

[0057] Pentafluoro(4-isocyanatophenyl)-λ 6 -Sulfane (6) [ka] To a solution of 4-aminophenylsulfur pentafluoride (200 mg, 0.91 mmol) in DCM (2 mL) was added a solution of triphosgene (270 mg, 0.91 mmol) in DCM (2 mL), followed by the dropwise addition of EtN (0.38 mL, 2.74 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 hours. Toluene (10 mL) and triphosgene (135 mg, 0.46 mmol) were added, and the reaction was stirred at 70 °C for 18 hours. After completion of the reaction, pentane (1 mL) was added, and a white precipitate formed immediately. The suspension was filtered, and the filtrate was concentrated under reduced pressure to give an orange oil. The product was used directly in the next step.

[0058] t-Butyl 4-((4-(pentafluoro-λ 6 -sulfanayl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (7) [ka] Starting from a solution of crude 6 (0.91 mmol) in toluene (5 mL) and tert-butyl 1,4-diazepane-1-carboxylate 1 (183 mg, 0.91 mmol) in dry THF (5 mL), tert-butyl 4-((4-(pentafluoro-λ-sulfanayl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (7) was prepared according to GP2. The product was used directly in the next step.

[0059] N-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)-1,4-diazepane-1-carboxamide (8) [ka] Starting from crude 7 (0.91 mmol) in DCM (5 mL) and TFA (5 mL), N-(4-(pentafluoro-λ)-2-methyl-2-(2-methyl- ... 6 (-sulfanail)phenyl)-1,4-diazepane-1-carboxamide (8) was prepared and used directly in the next step.

[0060] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)-1,4-diazepane-1-carboxamide (3TO 025) [ka] Starting from crude 8 (0.91 mmol), 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) in DMF (5 mL), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(pentafluoro-λ)-2-methyl-2-propanol)-2-methyl-2-propanol was prepared according to general procedure GP4. 6(-sulfanail)phenyl)-1,4-diazepane-1-carboxamide (3TO 025) was prepared. The yield was 165.0 mg (0.362 mmol, 32%). This compound exists as an approximately 1:1 mixture of two conformers. 1 H NMR(700MHz,DMSO-d6):δ[ppm]=8.82(s,0.5H),8.78(s,0.5H),7.75(d,J=9.2Hz,1H),7.74(d,J=9.2Hz,1H),7.70(d,J=9.2Hz,1H),7.66( d,J=9.2Hz,1H),6.36(s,1H),6.33(s,1H),3.85-3.79(m,2H),3.74-3.70(m,1H),3.69-3.65(m,3H),3.63-3.58(m,2H),1.91-1.80(m,2H). 13 C NMR(176MHz,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. 19 F NMR(471MHz,DMSO-d6)δ[ppm]=89.54(p,J=150Hz,1F),65.18(d,J=150Hz,4F). HRMS(ESI)calcd.forC 15 H 18 F5N6O3S([M+H] + ):m / z=457.1081,exp.:457.1091.

[0061] 4-Cyclopropylphenylisocyanate (9) [ka] 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 EtN (1.23 mL, 8.84 mmol) in DCM (3 mL). The product was used directly in the next step.

[0062] tert-Butyl 4-((4-cyclopropylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (10) [ka] Starting from a 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), tert-butyl 4-((4-cyclopropylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (10) was prepared according to general procedure GP2. The product was used directly in the next step.

[0063] N-(4-cyclopropylphenyl)-1,4-diazepane-1-carboxamide (11) [ka] Starting from crude 10 (0.59 mmol) in DCM (5 mL) and TFA (5 mL), N-(4-cyclopropylphenyl)-1,4-diazepane-1-carboxamide (11) was prepared according to GP3. The product was used directly in the next step without further purification.

[0064] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-cyclopropylphenyl)-1,4-diazepane-1-carboxamide (3TO 026) [ka] Starting with crude 11 (0.59 mmol) in 5 mL of DMF, 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-cyclopropylphenyl)-1,4-diazepane-1-carboxamide (3TO 026) was prepared according to GP4. The yield was 82.0 mg (0.22 mmol, 38%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (700MHz, DMSO-d6): δ[ppm]=8.25(s,0.5H),8.21(s,0.5H),7.31(d,J=8. 6Hz,1H),7.27(d,J=8.6Hz,1H),6.93(d,J=8.6Hz,1H),6.92(d,J=8.6Hz,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,1H),1.84-1.77(m,2H),0.90-0.84(m,2H),0.60-0.55(m,2H). 13 C NMR(176MHz,DMSO-d6)δ[ppm]=158.46,158.34,156.19,156.07,154.76,154.69,141.38,141.36,137.71,137.58,137.05,1 36.98,125.13,125.10,120.52,120.35,49.27,47.67,47.54,46.54,45.73,45.59,45.22,44.94,28.30,25.88,14.51,8.84. HRMS(ESI)calcd.forC 18 H 23 N6O3([M+H] + ):m / z=371.1832,exp.:371.1827.

[0065] 1-ethynyl-4-isocyanatobenzene(12) [ka] Starting from 4-ethynylaniline (100 mg, 0.85 mmol), triphosgene (127 mg, 0.43 mmol), and EtN (0.12 mL, 0.85 mmol) in toluene (10 mL), 1-ethynyl-4-isocyanatobenzene (12) was obtained according to GP1, which was used directly in the next step.

[0066] tert-Butyl 4-((4-ethynylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (13) [ka] Starting from a 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), tert-butyl 4-((4-ethynylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (13) was prepared according to general procedure GP2. The product was used directly in the next step.

[0067] N-(4-(1-chlorovinyl)phenyl)-1,4-diazepane-1-carboxamide (14) [ka] To a solution of crude 13 (150 mg, 0.44 mmol) in 1,4-dioxane (3 mL) was added HCl (5 mL, 4 M in 1,4-dioxane). The reaction mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. The crude product 14 was used in the next step without further purification.

[0068] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(1-chlorovinyl)phenyl)-1,4-diazepane-1-carboxamide (3TO 064) [ka] Starting from a 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), HATU (199 mg, 0.52 mmol), and DIPEA (0.3 mL, 2.2 mmol), 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. The yield was 60.0 mg (35%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.57(s,0.5H),8.54(s,0.5H),7.58-7.48(m,4H),6.38(s,1H),6.35(s,1H),5.94(d,J =2.1Hz,1H),5.47(dd,J=2.1,0.9Hz,1H),3.85-3.77(m,2H),3.73-3.63(m,4H),3.63-3.56(m,2H),1.91-1.79(m,2H). 13 C NMR(125MHz,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.forC 17 H 20 ClNO([M+H] + ):m / z=391.1285,exp.:391.1284.

[0069] 4-(Trifluoromethylthio)phenyl isocyanate (15) [ka] Starting from 4-(trifluoromethylthio)aniline (100 mg, 0.52 mmol), triphosgene (77 mg, 0.26 mmol), and EtN (70 μL, 0.52 mmol) in toluene (10 mL), 4-(trifluoromethylthio)phenyl isocyanate (15) was obtained according to GP1, which was used directly in the next step.

[0070] tert-Butyl 4-((4-((trifluoromethyl)thio)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (16) [ka] Starting from a 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), tert-butyl 4-((4-((trifluoromethyl)thio)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (16) was prepared according to general procedure GP2. The product was used directly in the next step.

[0071] N-(4-((trifluoromethyl)thio)phenyl)-1,4-diazepane-1-carboxamide (17) [ka] Starting from crude 16 (0.52 mmol) in DCM (5 mL) and TFA (5 mL), N-(4-((trifluoromethyl)thio)phenyl)-1,4-diazepane-1-carboxamide (17) was prepared according to GP3. The product was used directly in the next step without further purification.

[0072] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-((trifluoromethyl)thio)phenyl)-1,4-diazepane-1-carboxamide (3TO 044) [ka] Starting from a 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-((trifluoromethyl)thio)phenyl)-1,4-diazepane-1-carboxamide (3TO 044) was prepared according to GP4. The yield was 85.0 mg (38%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.70(s,0.5H),8.66(s,0.5H),7.65(d,J=8.8Hz,1H),7.61(d,J=8.8Hz,1H),7.57(d,J=8.8Hz,1H),7.56( d,J=8.8Hz,1H),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). 13 C NMR(176MHz,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= 309Hz),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. 19 F NMR(471MHz,DMSO-d6)δ[ppm]=-43.09. HRMS(ESI)calcd.forC 16 H 18 F3N6O3S([M+H] + ):m / z=431.1113,exp.:431.1117.

[0073] tert-Butyl 4-((3-chlorophenyl)carbamoyl)-1,4-diazepane-1-carboxylate (18) [ka]

[0074] Starting from a solution of crude 3-chlorophenyl isocyanate (120 mg, 0.78 mmol) in dry THF (2 mL) and a solution of tert-butyl 1,4-diazepane-1-carboxylate 1 (157 mg, 0.78 mmol) in THF (3 mL), tert-butyl 4-((3-chlorophenyl)carbamoyl)-1,4-diazepane-1-carboxylate (18) was prepared according to general procedure GP2. The product was used directly in the next step.

[0075] N-(3-chlorophenyl)-1,4-diazepane-1-carboxamide (19) [ka] 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), N-(3-chlorophenyl)-1,4-diazepane-1-carboxamide (19) was prepared according to GP3. The product was used directly in the next step without further purification.

[0076] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(3-chlorophenyl)-1,4-diazepane-1-carboxamide (3TO 031) [ka] Starting with 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(3-chlorophenyl)-1,4-diazepane-1-carboxamide (3TO 031) was prepared according to GP4. The yield was 106.0 mg (37%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(700MHz,DMSO-d6):δ[ppm]=8.52(s,0.5H),8.48(s,0.5H),7.66(t,J=2.1Hz,0.5H),7.61( t,J=2.1Hz,0.5H),7.42(ddd,J=8.2,2.1,1.0Hz,0.5H),7.38(ddd,J=8.2,2.1,1.0Hz,0.5H),7. 25(t,J=8.2Hz,0.5H),7.24(t,J=8.2Hz,0.5H),6.99-6.98(m,0.5H),6.98-6.97(m,0.5H),6.4 4-6.20(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). 13 C NMR(176MHz,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.forC 15 H 18 ClNO([M+H] + ):m / z=356.1129,exp.:365.1126.

[0077] tert-Butyl 4-((4-isopropylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (20) [ka] Starting from a solution of 4-isopropylphenyl isocyanate (684 mg, 4.2 mmol) in dry THF (15 mL) and a solution of tert-butyl 1,4-diazepane-1-carboxylate 1 (850 mg, 4.2 mmol) in dry THF (15 mL), tert-butyl 4-((4-isopropylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (20) was prepared according to general procedure GP2. The product was used directly in the next step.

[0078] N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (3TO 073) [ka] N-(4-isopropylphenyl)-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 used directly in the next step without further purification. 1 H NMR(700MHz,DMSO-d6):δ[ppm]=8.72(s,1H),7.37(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),3.72-3.67(m,2H ),3.58-3.55(m,1H),3.23-3.16(m,4H),2.81(hept,J=6.9Hz,1H),2.02-1.97(m,2H),1.17(d,J=6.9Hz,6H). 13 C NMR(176MHz,DMSO-d6)δ[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.forC 15 H 24 NO([M+H] + ):m / z=262.1919,exp.:262.1912.

[0079] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (SK-C11) [ka] Starting with 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (SK-C11) was prepared according to GP4. The yield was 92 mg (25%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.26(s,0.5H),8.23(s,0.5H),7.35(d,J=8. 5Hz,1H),7.30(d,J=8.5Hz,1H),7.09(d,J=8.5Hz,1H),7.07(d,J=8.5Hz,1H) ,6.36(s,1H),6.34(s,1H),3.82-3.77(m,2H),3.70-3.61(m,4H),3.59-3.55 (m,2H),2.80(hept,J=6.9Hz,1H),1.90-1.79(m,2H),1.16(d,J=6.9Hz,6H). 13C NMR(126MHz,DMSO-d6)δ[ppm]=58.57,158.33,156.18,156.07,154.80,154.74,142.01,141.94,141.39,141.38,138.02,13 7.91,125.89,125.86,120.52,120.34,49.29,47.67,47.58,46.53,45.71,45.62,45.22,44.95,32.76,28.29,25.88,24.03. MS(ESI)calcd.forC 18 H 25 N6O3([M+H] + ):m / z=373,exp.:373.

[0080] 4-(4-amino-1,2,5-thiadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (3TO 077) [ka] Starting with crude 3TO 073 (75 mg, 0.29 mmol) in 4 mL of DMF, 4-amino-1,2,5-thiadiazole-3-carboxylic acid (42 mg, 0.29 mmol), HATU (131 mg, 0.34 mmol), and EtN (0.4 mL, 2.9 mmol), 4-(4-amino-1,2,5-thiadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (3TO 077) was prepared according to GP4. The yield was 48.0 mg (43%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.27(s,0.5H),8.23(s,0.5H),7.35(d,J=8.6Hz, 1H),7.30(d,J=8.6Hz,1H),7.08(d,J=8.6Hz,1H),7.07(d,J=8.6Hz,1H),3.88(t, J=5.4Hz,1H),3.81-3.75(m,1H),3.72(t,J=5.9Hz,1H),3.68-3.61(m,3H),3.60- 3.53(m,2H),2.80(hept,J=6.9Hz,1H),1.92-1.81(m,2H),1.16(d,J=6.9Hz,6H). 13 C NMR(126MHz,DMSO-d6)δ[ppm]=161.92,161.64,161.28,161.08,154.84,154.81,141.97,141.93,140.85,140.69,138.11,13 8.02,125.94,125.91,120.47,120.36,49.62,48.05,47.85,46.94,45.82,45.70,45.48,44.96,32.82,28.42,25.88,24.10. HRMS(ESI)calcd.forC 18 H 25 N6O2S([M+H] + ):m / z=389.1760,exp.:389.1755.

[0081] tert-Butyl 4-((4-butylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (21) [ka] 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), tert-butyl 4-((4-butylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (21) was prepared according to general procedure GP2. The product was used directly in the next step. The yield was 400 mg (86%).

[0082] N-(4-butylphenyl)-1,4-diazepane-1-carboxamide (22) [ka] To a 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 HCl (4 M in dioxane, 0.5 mL), and the mixture was stirred at room temperature overnight. The 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 purification.

[0083] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-butylphenyl)-1,4-diazepane-1-carboxamide (SK-C14) [ka] Starting from a 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-butylphenyl)-1,4-diazepane-1-carboxamide (SK-C14) was prepared according to GP4. The yield was 92 mg (24%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.26(s,0.5H),8.22(s,0.5H),7.34(d,J=8.5H z,1H),7.29(d,J=8.5Hz,1H),7.03(d,J=8.5Hz,1H),7.02(d,J=8.5Hz,1H),6.36 (s,1H),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=7.3Hz,3H). MS(ESI)calcd.forC 19 H 27 N6O3([M+H] + ):m / z=387,exp.:387.

[0084] tert-Butyl 4-((4-tert-butylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (23) [ka] Starting from 4-tert-butylphenyl isocyanate (200 μL, 1.2 mmol) and tert-butyl 1,4-diazepane-1-carboxylate 1 (250 mg, 1.2 mmol) in dry THF (2.5 mL), tert-butyl 4-((4-tert-butylphenyl)carbamoyl)-1,4-diazepane-1-carboxylate (23) was prepared according to general procedure GP2. The product was used directly in the next step.

[0085] N-(4-butylphenyl)-1,4-diazepane-1-carboxamide (24) [ka] To a 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 HCl (4 M in dioxane, 0.5 mL) and the mixture was stirred at room temperature overnight. The 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 purification.

[0086] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(tert-butyl)phenyl)-1,4-diazepane-1-carboxamide (SK-C12) [ka] Starting from a 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), 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. The yield was 60 mg (16%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.27(s,0.5H),8.24(s,0.5H),7.36(d,J=8.7Hz,1H),7.32(d,J=8.7Hz,1H),7.23(d,J=8.7Hz,1H),7.2 2(d,J=8.7Hz,1H),6.36(s,1H),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),1.24(s,9H).

[0087] tert-Butyl 4-((4-(trifluoromethyl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (25) [ka] 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), tert-butyl 4-((4-(trifluoromethyl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (25) was prepared according to general procedure GP2. The product was used directly in the next step.

[0088] N-(4-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxamide (26) [ka] To a solution of tert-butyl 4-((4-(trifluoromethyl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (25) (250 mg, 0.64 mmol) in DCM (5 mL) was added HCl (4 M in dioxane, 0.8 mL) and the mixture was stirred at room temperature overnight. The 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 purification.

[0089] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(trifluoromethyl)phenyl)-1,4-diazepane-1-carboxamide (SK-C24) [ka] Starting from a 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), 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. The yield was 20 mg (5%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.73(s,0.5H),8.69(s,0.5H),7.70(d,J=8.5Hz,1H),7.66(d,J=8.7Hz,1H),7.58(d,J=8.7Hz,1H),7.57( d,J=8.7Hz,1H),6.36(s,1H),6.33(s,1H),3.85-3.78(m,2H),3.74-3.70(m,1H),3.70-3.65(m,3H),3.64-3.58(m,2H),1.90-1.80(m,2H). MS(ESI)calcd.forC 16 H 18 F3N6O2([M+H] + ):m / z=399,exp.:399.

[0090] tert-Butyl 4-([1,1'-biphenyl]-4-ylcarbamoyl)-1,4-diazepane-1-carboxylate (27) [ka] Starting from 4-biphenylyl isocyanate (244 mg, 1.2 mmol) and tert-butyl 1,4-diazepane-1-carboxylate 1 (250 mg, 1.2 mmol) in dry THF (2.5 mL), tert-butyl 4-([1,1'-biphenyl]-4-ylcarbamoyl)-1,4-diazepane-1-carboxylate (27) was prepared according to general procedure GP2. The product was used directly in the next step.

[0091] N-([1,1'-biphenyl]-4-yl)-1,4-diazepane-1-carboxamide (28) [ka] To a solution of 27 (250 mg, 0.63 mmol) in DCM (5 mL) was added HCl (4 M in dioxane, 850 μL), and the mixture was stirred at room temperature overnight. 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 purification.

[0092] N-([1,1'-biphenyl]-4-yl)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamide (SK-C25) [ka] Starting with 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), 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. The yield was 37 mg (9%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.46(s,0.5H),8.43(s,0.5H),7.62(d,J=7.2Hz,2H),7.58-7.52(m,4H),7.45-7.39(m,2H) ,7.33-7.28(m,1H),6.37(s,1H),6.35(s,1H),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.forC 21 H23 N6O3([M+H] + ):m / z=407,exp.:407.

[0093] tert-Butyl 4-((4-bromophenyl)carbamoyl)-1,4-diazepane-1-carboxylate (29) [ka] 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), tert-butyl 4-((4-bromophenyl)carbamoyl)-1,4-diazepane-1-carboxylate (29) was prepared according to general procedure GP2. The product was used directly in the next step.

[0094] N-(4-bromophenyl)-1,4-diazepane-1-carboxamide (30) [ka] 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 used directly in the next step without further purification.

[0095] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-bromophenyl)-1,4-diazepane-1-carboxamide (SK-C37) [ka] Starting from a 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-bromophenyl)-1,4-diazepane-1-carboxamide (SK-C37) was prepared according to GP4. The yield was 80 mg (46%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.48(s,0.5H),8.44(s,0.5H),7.51(d,J=9.0Hz,1H),7.46(d,J=9.0Hz,1H),7.28(d,J=9.0Hz,1 H),7.27(d,J=9.0Hz,1H),6.37(s,1H),6.34(s,1H),3.84-3.77(m,2H),3.72-3.63(m,4H),3.62-3.55(m,2H),1.91-1.77(m,2H).

[0096] tert-Butyl 4-((4-iodophenyl)carbamoyl)-1,4-diazepane-1-carboxylate (31) [ka] Starting from 4-iodophenyl isocyanate (242 mg, 1.0 mmol) and tert-butyl 1,4-diazepane-1-carboxylate 1 (200 mg, 1.0 mmol) in dry THF (2.5 mL), tert-butyl 4-((4-iodophenyl)carbamoyl)-1,4-diazepane-1-carboxylate (31) was prepared according to general procedure GP2. The product was used directly in the next step. The yield was 430 mg (98%).

[0097] N-(4-iodophenyl)-1,4-diazepane-1-carboxamide (32) [ka] Starting from crude 31 (220 mg, 0.49 mmol) in DCM (2.5 mL) and TFA (2.5 mL), N-(4-iodophenyl)-1,4-diazepane-1-carboxamide (32) was prepared according to GP3. The product 32 was used directly in the next step without further purification.

[0098] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-iodophenyl)-1,4-diazepane-1-carboxamide (SK-C36) [ka] Starting from a 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-iodophenyl)-1,4-diazepane-1-carboxamide (SK-C36) was prepared according to GP4. The yield was 60 mg (17%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.25(s,0.5H),8.22(s,0.5H),7.33(d,J=8.5Hz,1H),7.28(d,J=8.5Hz,1H),7.03(d,J=8.5Hz,1 H),7.02(d,J=8.5Hz,1H),6.36(s,1H),6.34(s,1H),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.forC 15 H 18 IN6O3([M+H] + ):m / z=457,exp.:457.

[0099] 4-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid (33) [ka] To a solution of methyl 4-amino-5-thiazolecarboxylate (400 mg, 2.5 mmol) and EtN (710 μg, 512 mg, 5.1 mmol) in dry DCM (30 mL) under argon, BocO (1100 mg, 5.1 mmol) and DMAP (62 mg, 0.5 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under reduced pressure. The residue was dissolved in EtOH (20 mL) and THF (10 mL). Aqueous NaOH (30 mL, 1 M) was added, and the reaction mixture was stirred at 70 °C for 3 h. The mixture was cooled to room temperature, and the pH was adjusted to 4-5 by adding concentrated HCl. The mixture was extracted with EtOAc (3×). The combined organic phases were dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and purified by flash chromatography (RP, C18, MeCN:H 2 O) to give 337 mg (55%) of the desired compound 33.

[0100] 4-(4-aminothiazole-5-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (AR753) [ka] To a solution of crude compound 3TO073 (107 mg, 0.40 mmol) in DMF (8 mL) was added compound 33 (77 mg, 0.6 mmol, 1 equiv.), HATU (187 mg, 0.49 mmol), and DIPEA (357 μL, 2.1 mmol). The resulting mixture was stirred overnight at room temperature. HO was added, and the mixture was extracted with EtOAc (3×). The combined organic phases were dried over NaSO. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (C18, MeCN / water). The solvent was evaporated under reduced pressure to give 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 at room temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was purified by HPLC (C18, MeCN / water 0.1% HCOOH). The yield was 23.9 mg (59%). 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.90(s,1H),8.23(s,1H),7.31(d,J=8.6Hz,2H),7.07(d,J=8.6Hz,2H),6.95-6.71(br s,2H),3.74(t,J=5.9Hz,2H),3.68-3.60(m,4H),3.51(t,J=5.9Hz,2H),2.79(h,J=6.9Hz,1H),1.86-1.79(m,2H),1.15(d,J=6.9Hz,6H). 13 C NMR(126MHz,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.forC 19 H 26 N5O2S([M+H] + ):m / z=388,exp.:388.

[0101] Synthesis of HCMV inhibitors (Scheme 2) [ka]

[0102] tert-Butyl 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxylate (34) [ka] To a solution of tert-butyl 1,4-diazepane-1-carboxylate (1) (2.6 g, 13.0 mmol) in DMF (150 mL) was added 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (1.68 g, 13.0 mmol) and HATU (5.92 g, 15.6 mmol) in DMF (50 mL) and EtN (9 mL, 64.9 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then mixed with EtOAc (500 mL). The reaction mixture was washed with saturated NH4Cl (2 × 300 mL), 1 M NaOH (2 × 300 mL), and brine (300 mL) and then dried over Na2SO4. The solvent was removed under reduced pressure to give a brownish solid, which was used directly in the next step. The yield was 4.00 g (12.8 mmol, 99%). 1 H NMR(500MHz,DMSO-d6):δ[ppm]=6.41-6.31(m,1H),3.78(dt,J=28.1,5.8Hz,1H),3.73(dd,J=9.5,5.4Hz,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). 13 C NMR(176MHz,DMSO-d6)δ[ppm]=158.5,158.4,158.3,156.4,156.3,156.1,154.3,154.3,154.1,153.9,141.3,141.1,78.8,78.8,7 8.7,48.7,48.2,48.1,47.8,47.1,46.6,46.2,46.1,45.9,45.8,45.5,45.3,45.3,45.2,44.9,28.0,28.0,27.9,27.8,25.8,25.7.

[0103] General Procedure 5 (GP5). Monoamidation of diazepanes [ka] 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 argon. The reaction mixture was stirred at room temperature for 18 h. Water was added, and the 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 (RP, C18; MeCN:HO) to give 133 mg (32%) of the desired product (35). The double amidation product (37) (83 mg, 13%) was also obtained.

[0104] General Procedure 6 (GP6) [ka] A solution of the isocyanate (0.3 mmol, 1.0 equiv.) in a mixture of dry THF (1.5 mL) and dry DMF (0.5 mL) was added to 35 (0.3 mmol, 1.0 equiv.) in a 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 adding water (5 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over NaSO and filtered. The solvent was removed under reduced pressure, and the residue was purified by HPLC (RP, C18; MeCN:water + 0.1% HCOOH). The product-containing fractions were lyophilized.

[0105] (4-Amino-1,2,5-oxadiazol-3-yl)(1,4-diazepan-1-yl)methanone (35) [ka] Step 1 Compound 34 (89 mg, 0.29 mmol) was dissolved in DCM (2 mL). TFA (0.5 mL) was added to the solution and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give product 35 as a brownish solid, which was used in the next step without further purification. Step 2 (4-Amino-1,2,5-oxadiazol-3-yl)(1,4-diazepan-1-yl)methanone (36) was synthesized under argon 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) according to GP5. The yield was 133 mg (32%). 1 H NMR(500MHz,DMSO-d6):8.66(s,1H),6.42(s,2H),3.95-3.91(m,1H),3.87-3.83(m,1H),3.75(t ,J=6.0Hz,1H),3.71(t,J=6.0Hz,1H),3.34-3.29(m,2H),3.26-3.22(m,2H),2.06-1.99(m,2H). MS(ESI)calcd.forC8H 14 NO2([M+H] + ):m / z=212,exp.:212.

[0106] (4-Amino-1,2,5-oxadiazol-3-yl)(6,6-difluoro-1,4-diazepan-1-yl)methanone (38) [ka] (4-Amino-1,2,5-oxadiazol-3-yl)(6,6-difluoro-1,4-diazepan-1-yl)methanone (38) was synthesized under argon 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). The yield was 169 mg (68%).

[0107] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (VK565) [ka] Starting with a solution of 4-isopropylphenyl isocyanate (42 mg, 0.25 mmol) in 5 mL of THF and 38 (78 mg, 0.32 mmol) in 5 mL of THF, 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. The yield was 61 mg (60%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6)δ[ppm]=8.48(s,0.5H),8.47(s,0.5H),7.36(d,J=8.6Hz,1H),7.33(d,J=8.6Hz,1H),7.12(d,J=8.6Hz,2H),6.43(s,2H),4.29 (t,J=12.0Hz,1H),4.18(t,J=12.0Hz,1H),4.15-4.08(m,2H),3.95-3.89( m,2H),3.83-3.77(m,2H),2.82(hept,J=6.9Hz,1H),1.17(d,J=6.9Hz,6H). 19 F NMR(471MHz,DMSO-d6)δ[ppm]=-98.99(p,J=12.3Hz,1F),-101.69(p,J=12.5Hz,1F). MS(ESI)calcd.forC 18 H 23 F2N6O3([M+H] + ):m / z=409,exp.:409.

[0108] 4-(2,2,2-trifluoroethyl)phenyl isocyanate (41) [ka] Starting from 4-(2,2,2-trifluoroethyl)aniline (50 mg, 0.28 mmol), triphosgene (42 mg, 0.14 mmol), and EtN (40 μL, 0.28 mmol) in DCM (3 mL), 4-(2,2,2-trifluoroethyl)phenyl isocyanate (39) was prepared according to GP1. The product was used in the next step without purification.

[0109] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(2,2,2-trifluoroethyl)phenyl)-1,4-diazepane-1-carboxamide (3TO 076) [ka] Starting from crude 41 (0.28 mmol) and 35 (60 mg, 0.29 mmol) obtained in the previous step in THF (4 mL), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(2,2,2-trifluoroethyl)phenyl)-1,4-diazepane-1-carboxamide (3TO 076) was prepared according to GP6. The yield was 42.0 mg (36%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.41(s,0.5H),8.38(s,0.5H),7.46(d,J=8.6Hz,1H),7.42(d,J=8.6Hz,1H),7.20(d,J=8.6 Hz,1H),7.19(d,J=8.6Hz,1H),6.37(s,1H),6.35(s,1H),3.85-3.76(m,2H),3.72-3.64(m,4H),3.61-3.57(m,2H),3.52(q,J H-F =11.6Hz,2H),1.89-1.78(m,2H). 13 C NMR(126MHz,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 =273Hz),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,J C-F =29Hz), 28.31, 25.87. 19 F NMR(471MHz,DMSO-d6)δ[ppm]=-64.69(t,J H-F =11.6Hz,1.5F),-64.71(t,J H-F =11.6Hz,1.5F). HRMS(ESI)calcd.forC 17 H 20 F3N6O3([M+H] + ):m / z=413.1549,exp.:413.1548.

[0110] General Procedure 7 (GP7). Synthesis of 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(hetero)aryl-1,4-diazepane-1-carboxamides [ka] 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 at room temperature for 2 h. The resulting solution was added to a solution of 35 (133 mg, 0.63 mmol) and DIPEA (1 mL) in DMF (3 mL), and the reaction mixture was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. Brine was added, and the mixture was extracted with EtOAc (3×). The combined organic phases were dried over Na SO and concentrated under reduced pressure. The residue was purified by column chromatography (RP; C18; MeCN:HO) followed by HPLC (HO:MeCN + 0.1% HCOOH).

[0111] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(6-isopropylpyridin-3-yl)-1,4-diazepane-1-carboxamide (VK573) [ka] 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), 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. The yield was 53 mg (28%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.51(d,J=2.6Hz,0.5H),8.48(s,0.5H),8.46(d,J=2.6Hz,0. 5H),8.43(s,0.5H),7.77(dd,J=8.5,2.6Hz,0.5H),7.73(dd,J=8.5,2.6Hz,0.5H),7.14(d,J= 8.5Hz,0.5H),7.13(d,J=8.5Hz,0.5H),6.38(s,1H),6.36(s,1H),3.83-3.77(m,2H),3.72-3. 63(m,4H),3.61-3.55(m,2H),2.93(h,J=6.9Hz,1H),1.91-1.78(m,2H),1.19(d,J=6.9Hz,6H). 13 C NMR(125MHz,DMSO-d6)δ[ppm]=163.13,159.91,159.85,158.52,158.38,156.18,156.09,154.74,141.45,141.25,141.14,134.6 9,134.57,128.30,128.11,119.83,119.80,41.12,47.72,47.54,46.44,45.87,45.64,45.19,45.01,34.87,28.29,25.88,22.67. MS(ESI)calcd.forC17 H 24 N7O3([M+H] + ):m / z=374,exp.:374.

[0112] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(5-isopropylpyridin-2-yl)-1,4-diazepane-1-carboxamide (VK560) [ka] Starting from 5-isopropylpyridin-3-amine (136 mg, 1 mmol), 4-nitrophenyl chloroformate (202 mg, 1 mmol), and 35 (274 mg, 1.3 mmol), 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. The yield was 29 mg (8%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.92(s,1H),8.10(dd,J=6.6,2.4Hz,1H),7.70(d,J=8.4Hz,0.5H),7.68(d,J=8.4Hz,0.5H),7.58(dd,J=5.5,2.4Hz, 0.5H),7.56(dd,J=5.5,2.4Hz,0.5H),6.37(s,1H),6.34(s,1H),3.86-3.5 3(m,8H),2.86(h,J=6.9Hz,1H),1.89-1.77(m,2H),1.19(d,J=6.9Hz,6H). 13C NMR(125MHz,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.forC 17 H 24 N7O3([M+H] + ):m / z=374,exp.:374.

[0113] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(1H-indol-5-yl)-1,4-diazepane-1-carboxamide (VK630) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(1H-indol-5-yl)-1,4-diazepane-1-carboxamide (VK630) was synthesized according to GP7. The product was purified by column chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 27 mg (15%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=10.92(s,1H),8.17(s,0.5H),8.14(s,0.5H),7.54 (d,J=2.0Hz,0.5H),7.48(d,J=2.0Hz,0.5H),7.28-7.21(m,2H),7.08(dd,J=8.6,2 .0Hz,0.5H),7.03(dd,J=8.6,2.0Hz,0.5H),6.38(s,1H),6.36(s,1H),6.33-6.31( m,1H),3.84-3.78(m,2H),3.72-3.62(m,4H),3.61-3.55(m,2H),1.93-1.80(m,2H). HRMS(ESI)calcd.forC 17 H 20 N7O3[M+H]370.1628,found370.1624.

[0114] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(1H-indol-6-yl)-1,4-diazepane-1-carboxamide (VK631) [ka] Starting from 1H-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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(1H-indol-6-yl)-1,4-diazepane-1-carboxamide (VK631) was synthesized according to GP7. The product was purified by column chromatography (NP; silica; cyclohexane: EtOAc = 100:0 to 20:80) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 9 mg (5%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=10.88(s,1H),8.23(s,0.5H),8.21(s,0.5H),7.61(s,0.5 H),7.57(s,0.5H),7.36(d,J=3.1Hz,0.5H),7.34(d,J=3.1Hz,0.5H),7.21-7.18(m,1H),7. 00(dd,J=8.5,1.9Hz,0.5H),6.96(dd,J=8.5,1.9Hz,0.5H),6.38(s,1H),6.36(s,1H),6.32 -6.29(m,1H),3.84-3.77(m,2H),3.73-3.64(m,4H),3.62-3.56(m,2H),1.94-1.80(m,2H). HRMS(ESI)calcd.forC 17 H 20 N7O3[M+H]370.1628,found370.1624.

[0115] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(benzofuran-5-yl)-1,4-diazepane-1-carboxamide (VK628) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(benzofuran-5-yl)-1,4-diazepane-1-carboxamide (VK628) was synthesized according to GP7. The product was purified by column chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 63 mg (34%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.38(s,0.5H),8.34(s,0.5H),7.91(d,J=2.0Hz,1H),7.74 (d,J=2.0Hz,0.5H),7.68(d,J=2.0Hz,0.5H),7.45(d,J=8.9Hz,0.5H),7.44(d,J=8.9Hz,0. 5H),7.31(dd,J=8.9,2.0Hz,0.5H),7.26(dd,J=8.9,2.0Hz,0.5H),6.89(s,1H),6.38(s,1H) ),6.36(s,1H),3.85-3.79(m,2H),3.73-3.64(m,4H),3.62-3.56(m,2H),1.93-1.81(m,2H). HRMS(ESI)calcd.forC 17 H 19 N6O4[M+H]371.1468,found371.1465.

[0116] tert-Butyl (4-(4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamido)benzyl)carbamate (VK632) [ka] 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)), 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. The product was purified by column chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN). The yield was 96 mg (42%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.32(s,0.5H),8.29(s,0.5H),7.38(s,0.5H),7.36(s,0.5H),7.35-7.28(m,2H),7.10-7.06(m,2H),6. 37(s,1H),6.35(s,1H),4.03(d,J=6.1Hz,2H),3.82-3.76(m,2H),3.70-3.62(m,4H),3.60-3.55(m,2H),1.90-1.79(m,2H),1.38(s,9H). HRMS(ESI)calcd.forC 21 H 29 N7NaO5[M+Na]482.2128,found482.2124.

[0117] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(1-methyl-1H-indol-5-yl)-1,4-diazepane-1-carboxamide (VK620) [ka] Starting from 1-methyl-1H-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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(1-methyl-1H-indol-5-yl)-1,4-diazepane-1-carboxamide (VK620) was synthesized according to GP7. The product was purified by column chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 30 mg (16%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.20(s,0.5H),8.17(s,0.5H),7.57(d,J=2.0Hz,0.5H), 7.51(d,J=2.0Hz,0.5H),7.30-7.26(m,1H),7.24(d,J=3.0Hz,1H),7.16(dd,J=8.7,2.0Hz ,0.5H),7.11(dd,J=8.7,2.0Hz,0.5H),6.38(s,1H),6.36(s,1H),6.31(d,J=3.0Hz,1H), 3.84-3.78(m,2H),3.74(s,3H),3.71-3.63(m,4H),3.61-3.55(m,2H),1.94-1.80(m,2H). HRMS(ESI)calcd.forC 18 H 22 N7O3[M+H]384.1784,found384.1780.

[0118] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-azidophenyl)-1,4-diazepane-1-carboxamide (VK627) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-azidophenyl)-1,4-diazepane-1-carboxamide (VK627) was synthesized according to GP7. The product was purified by column chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 39 mg (21%). This compound exists as a 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.44(s,0.5H),8.40(s,0.5H),7.51(d,J=9.0Hz,1H),7.46(d,J=9.0Hz,1H),7.00(d,J=9.0Hz,1 H),6.99(d,J=9.0Hz,1H),6.37(s,1H),6.34(s,1H),3.83-3.76(m,2H),3.71-3.62(m,4H),3.60-3.54(m,2H),1.90-1.78(m,2H). HRMS(ESI)calcd.forC 15 H 18 N9O3[M+H]372.1533,found372.1528.

[0119] tert-Butyl 4-((4-(trifluoromethoxy)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (42) [ka] Starting with a solution of 1-isocyanato-4-(trifluoromethoxy)benzene (203 mg, 1.0 mmol) in dry THF (5 mL) and tert-butyl 1,4-diazepane-1-carboxylate (1) (120 mg, 0.6 mmol) in dry THF (5 mL), tert-butyl 4-((4-(trifluoromethoxy)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (42) was prepared according to general procedure GP2. The product was purified by flash chromatography (cyclohexane: EtOAc = 75:25 to 50:50) to afford 190 mg (79%) of the desired product. This compound exists as a ca. 1:1 mixture of two conformers. 1H NMR(500MHz,DMSO-d6):δ[ppm]=8.47(s,0.5H),8.46(s,0.5H),7.59(d,J=8.6Hz,1H),7.56(d,J=8.6Hz,1H),7.22(d,J= 8.6Hz,2H),3.60-3.52(m,2H),3.50-3.40(m,4H),3.33-3.26(m,2H),1.79-1.66(m,2H),1.37(s,4.5H),1.31(s,4.5H).

[0120] N-(4-(trifluoromethoxy)phenyl)-1,4-diazepane-1-carboxamide (43) [ka] Starting from 42 (95 mg, 0.24 mmol) in DCM (5 mL) and TFA (2 mL), N-(4-(trifluoromethoxy)phenyl)-1,4-diazepane-1-carboxamide (43) was prepared according to GP3. The product was used directly in the next step without further purification.

[0121] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(trifluoromethoxy)phenyl)-1,4-diazepane-1-carboxamide (VK667) [ka] Starting with crude 43 (0.24 mmol) in 5 mL of DMF, 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(trifluoromethoxy)phenyl)-1,4-diazepane-1-carboxamide (VK667) was prepared according to GP4. The product was purified by flash chromatography (cyclohexane: EtOAc 80:20 to 0:100) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 44 mg (44%). The compound exists as an approximately 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.55(s,0.5H),8.51(s,0.5H),7.57(d,J=9.1Hz,1H),7.53(d,J=9.1Hz,1H),7.25- 7.20(m,2H),6.37(s,1H),6.35(s,1H),3.84-3.77(m,2H),3.72-3.63(m,4H),3.62-3.56(m,2H),1.91-1.79(m,2H). HRMS(ESI)calcd.forC 16 H 18 F3N6O4[M+H]415.1342,found415.1339.

[0122] 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) [ka] 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), 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. The product was purified by flash chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 41 mg (37%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.62(s,0.5H),8.61(s,0.5H),7.47(d,J=8.4Hz ,1H),7.45(d,J=8.4Hz,1H),7.23(d,J=8.4Hz,2H),6.45-6.40(m,2H),4.30(t,JH -F =12.0Hz,1H),4.23-4.08(m,3H),3.97-3.89(m,2H),3.85-3.77(m,2H),3.55(q,JH) -F =11.6Hz,2H). HRMS(ESI)calcd.forC 17 H 18 F5N6O3[M+H]449.1361,found449.1359.

[0123] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N-(1H-indol-5-yl)-1,4-diazepane-1-carboxamide (VK659) [ka] Starting from 1H-indol-5-amine (33 mg, 0.25 mmol), 4-nitrophenyl chloroformate (50 mg, 0.25 mmol), and 38 (71 mg, 0.29 mmol), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-6,6-difluoro-N-(1H-indol-5-yl)-1,4-diazepane-1-carboxamide (VK659) was synthesized according to GP7. The product was purified by flash chromatography (RP; C18; MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 22 mg (22%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=10.94(s,1H),8.39(s,0.5H),8.37(s,0.5H), 7.57(d,J=2.0Hz,0.5H),7.54(d,J=2.0Hz,0.5H),7.30-7.25(m,2H),7.11-7. 05(m,1H),6.46-6.40(m,2H),6.34(s,1H),4.30(t,JH-F=12.0Hz,1H),4.20(t ,JH-F=12.4Hz,1H),4.16-4.07(m,2H),3.97-3.90(m,2H),3.86-3.78(m,2H). HRMS(ESI)calcd.forC 17 H 18 F2N7O3[M+H]406.1439,found406.1434.

[0124] tert-Butyl (R)-4-((4-isopropylphenyl)carbamoyl)-3-methyl-1,4-diazepane-1-carboxylate (44) [ka] Starting from a solution of 4-isopropylphenyl isocyanate (38 mg, 0.23 mmol) in dry THF (1 mL) and a solution of tert-butyl (R)-3-methyl-1,4-diazepane-1-carboxylate (50 mg, 0.23 mmol) in dry THF (1 mL), tert-butyl (R)-4-((4-isopropylphenyl)carbamoyl)-3-methyl-1,4-diazepane-1-carboxylate (44) was prepared according to general procedure GP2. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0125] (R)-N-(4-isopropylphenyl)-2-methyl-1,4-diazepane-1-carboxamide (45) [ka] Starting from crude 44 (0.23 mmol) in CHCl (4 mL) and TFA (0.4 mL), (R)-N-(4-isopropylphenyl)-2-methyl-1,4-diazepane-1-carboxamide (45) was prepared according to GP3. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0126] (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-2-methyl-1,4-diazepane-1-carboxamide (AR843.1) [ka] Starting with 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), (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. The product was purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 37 mg (42%). This compound exists as a 3:2 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.16(s,0.4H),8.12(s,0.6H),7.34-7.27(m,2H),7.09-7.04(m,2H),6.35(s,0. 8H),6.30(s,1.2H),4.66-4.57(m,0.6H),4.55-4.45(m,0.4H),4.41-4.33(m,0.4H),4.32-4.22(m,1H),4.08-4.0 0(m,0.6H),3.96-3.84(m,1H),3.37-3.22(m,2H),3.14(dd,J=14.0,11.0Hz,0.6H),3.05-2.97(m,0.4H),2.79(s eptet,J=6.9Hz,1H),1.85-1.63(m,2H),1.16(d,J=6.9Hz,6H),1.09(d,J=6.4Hz,1.8H),1.01(d,J=6.4Hz,1.2H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2139.

[0127] tert-Butyl (R)-3-methyl-4-((4-(2,2,2-trifluoroethyl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (46) [ka] 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), tert-butyl (R)-3-methyl-4-((4-(2,2,2-trifluoroethyl)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (46) was synthesized according to GP7. The product was purified by flash chromatography (cyclohexane: EtOAc = 100:0 to 0:100) and used directly in the next step.

[0128] (R)-2-Methyl-N-(4-(2,2,2-trifluoroethyl)phenyl)-1,4-diazepane-1-carboxamide (47) [ka] Starting from crude 46 (0.47 mmol) in CHCl (4 mL) and TFA (1 mL), (R)-2-methyl-N-(4-(2,2,2-trifluoroethyl)phenyl)-1,4-diazepane-1-carboxamide (47) was prepared according to GP3. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0129] (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) [ka] Starting from a 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), (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. The product was purified by flash chromatography (silica, cyclohexane:EtOAc) and HPLC (C18; HO:MeCN with 0.1% HCOOH). The yield was 47 mg (23%). This compound exists as a ca. 3:2 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.30(s,0.4H),8.27(s,0.6H),7.46-7.39(m,2H),7.17(d,J=8.5Hz,2H) ,6.35(s,0.8H),6.30(s,1.2H),4.67-4.57(m,0.6H),4.56-4.45(m,0.4H),4.41-4.34(m,0.4H),4.32-4. 21(m,1H),4.08-3.99(m,0.6H),3.97-3.85(m,1H),3.52(q,JH-F=11.7Hz,2H),3.39-3.22(m,2H),3.19-3 .10(m,0.6H),3.06-2.96(m,0.4H),1.85-1.62(m,2H),1.10(d,J=6.4Hz,1.8H),1.02(d,J=6.4Hz,1.2H). HRMS(ESI)calcd.forC 18 H 22 F3N6O3[M+H]427.1705,found427.1702.

[0130] tert-Butyl (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-3-methyl-1,4-diazepane-1-carboxylate (48) [ka] Starting from a 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), tert-butyl (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-3-methyl-1,4-diazepane-1-carboxylate (48) was prepared according to GP4. The product was purified by flash chromatography (RP; C18; MeCN:HO). The yield was 67 mg (91%). The compound was used in the next step without further characterization.

[0131] (R)-(4-amino-1,2,5-oxadiazol-3-yl)(2-methyl-1,4-diazepan-1-yl)methanone (49) [ka] Starting from 48 (67 mg, 0.21 mmol) in CHCl (4 mL) and TFA (0.4 mL), (R)-(4-amino-1,2,5-oxadiazol-3-yl)(2-methyl-1,4-diazepan-1-yl)methanone (49) was prepared according to GP3. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0132] (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-3-methyl-1,4-diazepane-1-carboxamide (AR845.1) [ka] (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 general procedure GP2, starting with 4-isopropylphenyl isocyanate (31 mg, 0.19 mmol) dissolved in a mixture of dry THF (1 mL) and dry DMF (0.3 mL) and crude 49 (0.21 mmol) dissolved in a mixture of dry THF (1 mL) and dry DMF (0.3 mL). The product was purified by HPLC (C18; HO:MeCN + 0.1% HCOOH) to give 35 mg (48%) of the desired product. This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.26(s,0.5H),8.15(s,0.5H),7.31(d,J=8.5Hz,1H),7.15(d,J=8.5Hz,1H),7.08(d,J=8.5Hz, 1H),7.05(d,J=8.5Hz,1H),6.31(s,1H),6.26(s,1H),4.89-4.80(m,0.5H),4.70-4.61(m,0.5H),4.20-4.06(m,2H),4.05-3.97 (m,0.5H),3.91-3.83(m,0.5H),3.55-3.45(m,0.5H),3.31-3.23(m,0.5H),3.17-3.02(m,1H),2.98-2.87(m,1H),2.95(septet ,J=6.9Hz,1H),1.92-1.79(m,1H),1.73-1.59(m,1H),1.18(d,J=6.5Hz,1.5H),1.16(d,J=6.9Hz,6H),1.11(d,J=6.5Hz,1.5H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2142.

[0133] (S)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-3-methyl-1,4-diazepane-1-carboxamide (AR851.1) [ka] Starting from tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate (50 mg, 0.23 mmol), (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 much the same manner as its enantiomer, (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-3-methyl-1,4-diazepane-1-carboxamide (AR845.1). The yield was 31.8 mg (23%). This compound exists as an approximately 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.26(s,0.5H),8.15(s,0.5H),7.31(d,J=8.5Hz,1H),7.15(d,J=8.5Hz,1H),7.08(d,J=8.5Hz, 1H),7.05(d,J=8.5Hz,1H),6.31(s,1H),6.26(s,1H),4.89-4.79(m,0.5H),4.70-4.60(m,0.5H),4.20-4.06(m,2H),4.04-3.98 (m,0.5H),3.91-3.83(m,0.5H),3.55-3.45(m,0.5H),3.31-3.23(m,0.5H),3.18-3.01(m,1H),2.98-2.87(m,1H),2.95(septet ,J=6.9Hz,1H),1.92-1.78(m,1H),1.75-1.59(m,1H),1.18(d,J=6.5Hz,1.5H),1.16(d,J=6.9Hz,6H),1.11(d,J=6.5Hz,1.5H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2140.

[0134] (S)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-2-methyl-1,4-diazepane-1-carboxamide (AR850.1) [ka] Starting from tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate (50 mg, 0.23 mmol), (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 much the same manner as its enantiomer (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-2-methyl-1,4-diazepane-1-carboxamide (AR843.1). The yield was 45.8 mg (52%). 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.16(s,0.4H),8.13(s,0.6H),7.34-7.27(m,2H),7.09-7.03(m,2H),6.35(s,0. 8H),6.30(s,1.2H),4.66-4.56(m,0.6H),4.55-4.46(m,0.4H),4.40-4.34(m,0.4H),4.31-4.22(m,1H),4.07-4.0 0(m,0.6H),3.95-3.84(m,1H),3.37-3.22(m,2H),3.14(dd,J=14.0,11.0Hz,0.6H),3.06-2.96(m,0.4H),2.79(s eptet,J=6.9Hz,1H),1.85-1.62(m,2H),1.16(d,J=6.9Hz,6H),1.09(d,J=6.4Hz,1.8H),1.01(d,J=6.4Hz,1.2H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2142.

[0135] tert-Butyl 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-5-methyl-1,4-diazepane-1-carboxylate (50) [ka] Starting with a solution of tert-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), tert-butyl 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-5-methyl-1,4-diazepane-1-carboxylate (50) was prepared according to GP4. The product was purified by flash chromatography (RP; C18; MeCN:HO). The yield was 136 mg (72%). The compound was used in the next step without further characterization.

[0136] (4-amino-1,2,5-oxadiazol-3-yl)(7-methyl-1,4-diazepan-1-yl)methanone (51) [ka] Starting from 50 (136 mg, 0.42 mmol) in CHCl (6 mL) and TFA (0.6 mL), (4-amino-1,2,5-oxadiazol-3-yl)(7-methyl-1,4-diazepan-1-yl)methanone (51) was prepared according to GP3. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0137] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-5-methyl-1,4-diazepane-1-carboxamide (AR863.1) [ka] 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 general procedure GP2, starting with 4-isopropylphenyl isocyanate (67 mg, 0.42 mmol) dissolved in a mixture of dry THF (3 mL) and dry DMF (0.9 mL) and crude 51 (0.42 mmol) dissolved in a mixture of dry THF (3 mL) and dry DMF (0.9 mL). The product was purified by HPLC (C18; HO:MeCN + 0.1% HCOOH) to give 108.7 mg (67%) of the desired product. This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.37(s,1H),7.38-7.30(m,2H),7.12-7.05(m,2H),6.43 (s,1H),6.39(s,1H),4.62-4.52(m,0.5H),4.22-4.15(m,0.5H),4.11-3.91(m,3H),3.49 -3.41(m,0.5H),3.26-3.13(m,1.5H),3.11-3.04(m,0.5H),3.02-2.95(m,0.5H),2.84-2 .76(m,1H),2.20-2.10(m,1H),1.71-1.51(m,1H),1.22-1.18(m,3H),1.18-1.14(m,6H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2145.

[0138] tert-Butyl 4-((4-isopropylphenyl)carbamoyl)-5-methyl-1,4-diazepane-1-carboxylate (52) [ka] Starting from a solution of 4-isopropylphenyl isocyanate (94 mg, 0.58 mmol) in dry THF (2 mL) and racemic tert-butyl 5-methyl-1,4-diazepane-1-carboxylate (125 mg, 0.58 mmol) in dry THF (2 mL), tert-butyl 4-((4-isopropylphenyl)carbamoyl)-5-methyl-1,4-diazepane-1-carboxylate (52) was prepared according to general procedure GP2. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0139] N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (53) [ka] Starting from crude 52 (0.58 mmol) in CHCl (8 mL) and TFA (0.8 mL), N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (53) was prepared according to GP3. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0140] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (AR873.1) [ka] Starting with 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (AR873.1) was prepared according to GP4. The product was purified by flash chromatography (RP; C18; MeCN:HO) and then further purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 106.6 mg (48%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.25(s,0.5H),8.19(s,0.5H),7.37(d,J=8.6Hz,1H),7.34(d,J=8.6Hz,1H ),7.10(d,J=8.6Hz,1H),7.09(d,J=8.6Hz,1H),6.38(s,2H),4.39-4.28(m,1H),4.27-4.14(m,1H),4.04-3 .96(m,0.5H),3.93-3.85(m,0.5H),3.85-3.75(m,1H),3.52-3.44(m,0.5H),3.33-3.16(m,2H),3.09-3.01 (m,0.5H),2.85-2.76(m,1H),2.22-2.08(m,1H),1.69-1.58(m,1H),1.18-1.15(m,6H),1.13-1.10(m,3H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2142.

[0141] tert-Butyl (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-7-methyl-1,4-diazepane-1-carboxylate (54) [ka] Starting from a 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), 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. The product was purified by flash chromatography (silica; cyclohexane:EtOAc). The yield was 151 mg (98%). The compound was used in the next step without further characterization.

[0142] (R)-(4-amino-1,2,5-oxadiazol-3-yl)(5-methyl-1,4-diazepan-1-yl)methanone (55) [ka] Starting from 54 (151 mg, 0.46 mmol) in CHCl (5 mL) and TFA (1 mL), N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (55) was prepared according to GP3. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0143] (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (VK745) [ka] Starting with a solution of 4-isopropylphenyl isocyanate (64 mg, 0.4 mmol) in dry THF (3 mL) and crude 55 (0.46 mmol) dissolved in a mixture of dry THF (3 mL) and dry DMF (1 mL), (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 general procedure GP2. The product was purified by flash chromatography (RP; C18; MeCN:HO) and then further purified by HPLC (C18; HO:MeCN + 0.1% HCOOH) to afford 87 mg (49%) of the desired product. This compound exists as a ca. 1:1 mixture of two conformers. The NMR spectrum of this compound is identical to that of AR873.1. HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2143.

[0144] (S)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (VK775) [ka] Starting from tert-butyl (S)-7-methyl-1,4-diazepane-1-carboxylate (100 mg, 0.47 mmol), (S)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (VK775) was synthesized in essentially the same manner as its enantiomer (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-7-methyl-1,4-diazepane-1-carboxamide (VK745). The yield was 76.4 mg (42%). The NMR spectrum of this compound is identical to that of AR873.1. HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2142.

[0145] tert-Butyl 4-(4-acetamido-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxylate (56) [ka] Acetic anhydride (2 mL) was added to a 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 room temperature, followed by the addition of a catalytic amount of DMAP. The reaction mixture was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure, and the residue was purified by flash chromatography (C18; MeCN:HO). The yield was 300 mg (85%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=11.44(s,1H),3.68-3.64(m,1H),3.60-3.55(m,1H),3 .54-3.40(m,6H),2.10(s,1.5H),2.08(s,1.5H),1.86-1.67(m,2H),1.43-1.35(m,9H).

[0146] N-(4-(1,4-diazepane-1-carbonyl)-1,2,5-oxadiazol-3-yl)acetamide (57) [ka] 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 CHCl (10 mL) and TFA (1 mL). The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0147] 4-(4-acetamido-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (VK610) [ka] Starting with a solution of 4-isopropylphenyl isocyanate (145 mg, 0.9 mmol) in dry THF (3 mL) and crude 57 (0.85 mmol) dissolved in a mixture of dry THF (3 mL) and dry DMF (1 mL), 4-(4-acetamido-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (VK610) was prepared according to general procedure GP2. The product was purified by flash chromatography (RP; C18; MeCN:HO). The yield was 230 mg (56%). An analytical sample was further purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(700MHz,DMSO-d6):δ[ppm]=11.43(s,1H),8.26(s,0.5H),8.20(s,0.5H),7.36(d,J =8.6Hz,1H),7.35(d,J=8.6Hz,1H),7.09(d,J=8.6Hz,2H),3.74-3.71(m,1H),3.68-3.6 5(m,1H),3.64-3.59(m,4H),3.57-3.54(m,1H),3.50-3.47(m,1H),2.84-2.78(m,1H),2 .08(s,1.5H),2.07(s,1.5H),1.91-1.86(m,1H),1.82-1.78(m,1H),1.18-1.16(m,6H). HRMS(ESI)calcd.forC 20 H 27 N6O3[M+H]415.2094,found415.2090.

[0148] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-cyclohexylphenyl)-1,4-diazepane-1-carboxamide (AR865.1) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-cyclohexylphenyl)-1,4-diazepane-1-carboxamide (AR865.1) was synthesized according to GP7. The product was purified by column chromatography (silica; cyclohexane: EtOAc) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 53 mg (26%). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.26(s,0.5H),8.23(s,0.5H),7.33(d,J=8.6 Hz,1H),7.29(d,J=8.6Hz,1H),7.06(d,J=8.6Hz,1H),7.29(d,J=8.6Hz,1H),6. 37(s,1H),6.35(s,1H),3.83-3.76(m,2H),3.70-3.60(m,4H),3.60-3.54(m,2H ),2.44-2.36(m,1H),1.90-1.65(m,8H),1.41-1.38(m,3H),1.26-1.15(m,1H). HRMS(ESI)calcd.forC 21 H 29 N6O3[M+H]413.2301,found413.2297.

[0149] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-morpholinophenyl)-1,4-diazepane-1-carboxamide (AR866.1) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-morpholinophenyl)-1,4-diazepane-1-carboxamide (AR866.1) was synthesized according to GP7. The product was purified by column chromatography (silica; cyclohexane: EtOAc 100:0 to 0:100) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 13.7 mg (7%). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.16(s,0.5H),8.12(s,0.5H),7.29(d,J=9.0Hz,1H),7.24(d,J=9.0Hz,1H),6.83(d,J=9.0Hz,1H),6.82(d,J=9.0H) z,1H),6.37(s,1H),6.35(s,1H),3.82-3.76(m,2H),3.74-3.70(m,4H),3. 69-3.60(m,4H),3.58-3.52(m,2H),3.03-2.98(m,4H),1.90-1.78(m,2H). HRMS(ESI)calcd.forC 19 H 26 N7O4[M+H]416.2046,found416.2042.

[0150] tert-Butyl 4-(4-(4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamido)phenyl)piperazine-1-carboxylate (AR868.1) [ka] 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)), tert-butyl 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. The product was purified by column chromatography (silica; cyclohexane: EtOAc 100:0 to 0:100). The yield was 185 mg (72%). 50 mg of this product was purified by HPLC (C18; HO: MeCN). This compound exists as a 1:1 mixture of two conformers. 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.17(s,0.5H),8.14(s,0.5H),7.29(d,J=9. 0Hz,1H),7.24(d,J=9.0Hz,1H),6.85(d,J=9.0Hz,1H),6.84(d,J=9.0Hz,1H), 6.37(s,1H),6.35(s,1H),3.82-3.75(m,2H),3.70-3.60(m,4H),3.58-3.52( m,2H),3.47-3.40(m,4H),3.01-2.95(m,4H),1.90-1.77(m,2H),1.41(s,9H). HRMS(ESI)calcd.forC 24 H 35 N8O5[M+H]515.2730,found515.2730.

[0151] 4-(4-(4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamido)phenyl)piperazin-1-ium trifluoroacetate (AR870.1) [ka] Starting from AR868.1 (135 mg, 0.26 mmol) in CHCl (2 mL) and TFA (0.5 mL), 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. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by HPLC (C18; HO:MeCN+0.1% HCOOH). The yield was 63.5 mg (46%). 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.78(s,1H),8.22(s,0.5H),8.18(s,0.5H),7.33(d,J=9.1Hz,1H),7.28(d,J=9.1Hz,1H),6.89(d,J=9.1Hz,1 H),6.88(d,J=9.1Hz,1H),6.37(s,1H),6.35(s,1H),3.82-3.76(m,2H) ,3.70-3.61(m,4H),3.58-3.53(m,2H),3.23(s,8H),1.89-1.77(m,2H). HRMS(ESI)calcd.forC 19 H 27 N8O3[M+H]415.2206,found415.2231.

[0152] N-(4-nitrobenzyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (58) [ka] 1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (308 mg, 2 mmol) was added to a 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 reaction mixture was stirred at room temperature for 16 h. H2O was added. The resulting 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). The yield was 387 mg (67%). 1 H NMR (500MHz, DMSO-d6): δ[ppm]=8.53(t,J=5.8Hz,1H),8.20(d,J=8.8Hz,2H),7. 48(d,J=8.8Hz,2H),4.40(d,J=5.8Hz,2H),1.38-1.32(m,2H),1.29-1.24(m,2H).

[0153] N-(4-aminobenzyl)-1-(trifluoromethyl)cyclopropane-1-carboxamide (59) [ka] SnCl 2H O (1.8 g, 6.7 mmol) was added to a 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 aqueous NaOH, and the product was extracted with ethyl acetate. The organic phase was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (C18:MeCN:H O). The yield was 150 mg (45%).

[0154] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-((1-(trifluoromethyl)cyclopropane-1-carboxamido)methyl)phenyl)-1,4-diazepane-1-carboxamide (MH06) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-((1-(trifluoromethyl)cyclopropane-1-carboxamido)methyl)phenyl)-1,4-diazepane-1-carboxamide (MH06) was synthesized according to GP7. The product was purified by flash chromatography (RP; C18; MeCN:HO) and then further by HPLC (C18; HO:MeCN+0.1% HCOOH). The yield was 28 mg (10%). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.35-8.27(m,2H),7.38(d,J=8.5Hz,1H),7. 33(d,J=8.5Hz,1H),7.08(d,J=8.5Hz,1H),7.07(d,J=8.5Hz,1H),6.37(s,1H) ),6.35(s,1H),4.20(d,J=5.9Hz,2H),3.83-3.76(m,2H),3.70-3.61(m,4H), 3.60-3.54(m,2H),1.90-1.78(m,2H),1.33-1.27(m,2H),1.24-1.19(m,2H). HRMS(ESI)calcd.forC 21 H 25 F3N7O4[M+H]496.1920,found496.1917.

[0155] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1,4-diazepane-1-carboxamide hydrochloride (AR869.1) [ka] 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)), 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. The product is soluble in water. It was purified by flash chromatography (C18:MeCN:HO) followed by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 11 mg (5%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=9.70(s,1H),8.21(s,0.5H),8.17(s,0.5H),7.3 3(d,J=9.1Hz,1H),7.28(d,J=9.1Hz,1H),6.90(d,J=9.1Hz,1H),6.89(d,J=9.1H z,1H),6.37(s,1H),6.35(s,1H),3.82-3.76(m,2H),3.76-3.61(m,6H),3.59-3. 53(m,2H),3.44-3.31(m,4H),3.21-3.08(m,2H),2.86(s,3H),1.89-1.77(m,2H). HRMS(ESI)calcd.forC 20 H 29 N8O3[M+H]429.2363,found429.2360.

[0156] tert-Butyl 4-((4-(benzyloxy)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (60) [ka] Starting from a 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), tert-butyl 4-((4-(benzyloxy)phenyl)carbamoyl)-1,4-diazepane-1-carboxylate (60) was prepared according to general procedure GP2. The product was used directly in the next step.

[0157] N-(4-(benzyloxy)phenyl)-1,4-diazepane-1-carboxamide (61) [ka] N-(4-(benzyloxy)phenyl)-1,4-diazepane-1-carboxamide (61) was prepared according to GP3 starting from 60 (109 mg, 0.26 mmol) in CHCl (4 mL) and TFA (0.4 mL). The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0158] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(benzyloxy)phenyl)-1,4-diazepane-1-carboxamide (AR876.1) [ka] Starting from a 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), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(benzyloxy)phenyl)-1,4-diazepane-1-carboxamide (AR876.1) was prepared according to GP4. The product was purified by flash chromatography (RP; C18; MeCN:HO). The yield was 63.2 mg (56%). An analytical sample was further purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). The compound exists as an approximately 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.21(s,0.5H),8.17(s,0.5H),7.45-7.4 1(m,2H),7.40-7.36(m,2H),7.34-7.30(m,2H),7.29-7.26(m,1H),6.91-6 .87(m,2H),6.36(s,1H),6.33(s,1H),5.05(s,2H),3.82-3.76(m,2H),3. 69-3.61(m,4H),3.59-3.53(m,2H),1.89-1.84(m,1H),1.84-1.79(m,1H). HRMS(ESI)calcd.forC 22 H 25 N6O4[M+H]437.1937,found437.1938.

[0159] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(benzo[d][1,3]dioxol-5-yl)-1,4-diazepane-1-carboxamide (AR880.1) [ka] 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)), 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. The product was purified by column chromatography (silica; cyclohexane: EtOAc) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 53 mg (28%). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.25(s,0.5H),8.21(s,0.5H),7.11(d,J=2.0Hz,0.5H),7.06(t,J=1.1Hz,0.5H),6.82(dd,J=8.4,2.0Hz,0.5 H),6.79-6.76(m,1.5H),6.38(s,1H),6.35(s,1H),5.94(s,2H),3.82- 3.75(m,2H),3.69-3.60(m,4H),3.58-3.52(m,2H),1.90-1.77(m,2H). HRMS(ESI)calcd.forC 16 H 19 N6O5[M+H]375.1417,found375.1416.

[0160] 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) [ka] 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)), 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. The product was purified by column chromatography (silica; cyclohexane: EtOAc) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 64.3 mg (31%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.56(s,0.5H),8.51(s,0.5H),7.60(d,J=2.0Hz, 0.5H),7.54(d,J=2.0Hz,0.5H),7.27(d,J=6.1Hz,0.5H),7.25(d,J=6.1Hz,0.5H) ,7.18(d,J=8.8,2.0Hz,0.5H),7.13(d,J=8.8,2.0Hz,0.5H),6.37(s,1H),6.34(s ,1H),3.83-3.77(m,2H),3.71-3.61(m,4H),3.60-3.55(m,2H),1.90-1.78(m,2H). HRMS(ESI)calcd.forC 16 H 17 F2N6O5[M+H]411.1228,found411.1225.

[0161] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,4-diazepane-1-carboxamide (AR883.1) [ka] 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)), 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,4-diazepane-1-carboxamide (AR883.1) was synthesized according to GP7. The product was purified by column chromatography (silica; cyclohexane: EtOAc) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 66.6 mg (32%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.30(s,0.5H),8.26(s,0.5H),7.37(d,J=8.6Hz,1 H),7.32(d,J=8.6Hz,1H),7.10(d,J=8.6Hz,1H),7.09(d,J=8.6Hz,1H),6.37(s,1H) ,6.35(s,1H),3.96-3.89(m,2H),3.83-3.75(m,2H),3.71-3.61(m,4H),3.60-3.54( m,2H),3.45-3.37(m,2H),2.72-2.62(m,1H),1.91-1.78(m,2H),1.69-1.56(m,4H). HRMS(ESI)calcd.forC 20 H 27 N6O4[M+H]415.2094,found415.2089.

[0162] 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-N-(4-(oxetan-3-yl)phenyl)-1,4-diazepane-1-carboxamide (AR885.1) [ka] 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), 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. The product was purified by flash chromatography (silica; cyclohexane: EtOAc) followed by HPLC (C18; HO: MeCN + 0.1% HCOOH). The yield was 67.9 mg (52%). This compound exists as a 1:1 mixture of two conformers. 1 H NMR(700MHz,DMSO-d6):δ[ppm]=8.35(s,0.5H),8.32(s,0.5H),7.45(d,J=8.6 Hz,1H),7.41(d,J=8.6Hz,1H),7.26(d,J=8.6Hz,1H),7.25(d,J=8.6Hz,1H),6. 36(s,1H),6.34(s,1H),4.93-4.87(m,2H),4.59-4.56(m,2H),4.19-4.14(m,1H ),4.83-4.77(m,2H),3.70-3.63(m,4H),3.60-3.55(m,2H),1.90-1.80(m,2H). HRMS(ESI)calcd.forC 18 H 23 N6O4[M+H]387.1781,found387.1777. [ka]

[0163] Benzyl 4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxylate (62) [ka] To a solution of benzyl 1,4-diazepane-1-carboxylate (908 mg, 3.9 mmol) in DMF (15 mL) were added 4-amino-1,2,5-oxadiazole-3-carboxylic acid (4) (500 mg, 3.9 mmol), HATU (1.77 g, 4.6 mmol), and DIPEA (2 mL, 11.6 mmol). The resulting mixture was stirred at room temperature overnight. HO was added, and the mixture was extracted with EtOAc (3 times). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (C18; MeCN:HO) to give 1 g (74%) of the desired product. The compound exists as a mixture of three conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=7.41-7.21(m,5H),6.40-6.35(m,2H),5.09(s,0.5H),5.07(s,1 H),5.01(s,0.5H),3.80-3.74(m,2H),3.70-3.55(m,4H),3.52-3.45(m,2H),1.83-1.72(m,2H).

[0164] Benzyl 4-(4-chloro-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxylate (63) [ka] To a solution of 62 (200 mg, 0.58 mmol) in MeCN (2.6 mL) and concentrated AcOH (2.6 mL) were added concentrated HCl (1.5 mL) and LiCl (74 mg, 1.74 mmol). The mixture was cooled to 0 °C, and a solution of NaNO (60 mg, 0.87 mmol) in HO (0.15 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 45 min. Saturated aqueous NH Cl was added, and the resulting mixture was extracted with EtOAc (3 times). The combined organic phases were dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (C18; MeCN:HO) to give 111 mg (53%) of the desired product. 1H NMR (500MHz, DMSO-d6): δ[ppm]=7.41-7.26(m,5H),5.12-5.02(m,2H),3.83-3.77(m,1H),3.74-3.45(m,7H),1.85-1.69(m,2H).

[0165] Benzyl 4-(4-(methylamino)-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxylate (64) [ka] To a solution of 63 (100 mg, 0.27 mmol) in dioxane (1.5 mL) were added methylammonium chloride (186 mg, 2.78 mmol) and DIPEA (0.95 mL, 5.46 mmol). The reaction mixture was stirred in a microwave at 140 °C for 5 h (controlled by LC-MS). Methylammonium chloride (186 mg, 2.78 mmol) and DIPEA (0.95 mL, 5.46 mmol) were added again, and the reaction mixture was stirred in a microwave at 140 °C for 5 h. Methylammonium chloride (186 mg, 2.78 mmol) and DIPEA (0.95 mL, 5.46 mmol) were added a third time, and the reaction mixture was stirred in a microwave at 140 °C for 5 h. The product was purified by flash chromatography (silica; cyclohexane: EtOAc) to give 30 mg (31%) of the desired product.

[0166] (1,4-Diazepan-1-yl)(4-(methylamino)-1,2,5-oxadiazol-3-yl)methanone (65) [ka] Compound 64 (30 mg, 0.08 mmol) was added to a solution of HBr in HOAc (32%) (1 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (C18; MeCN:HO) to give 15.6 mg (87%) of the desired product, which was used directly in the next step.

[0167] N-(4-isopropylphenyl)-4-(4-(methylamino)-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamide (AR844.1) [ka] N-(4-isopropylphenyl)-4-(4-(methylamino)-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamide (AR844.1) was prepared according to general procedure GP2, starting with a solution of 4-isopropylphenyl isocyanate (11 mg, 0.07 mmol) in dry THF (0.5 mL) and 65 (15.6 mg, 0.07 mmol) dissolved in a mixture of dry THF (0.5 mL) and dry DMF (0.3 mL). The product was purified by HPLC (C18; HO:MeCN + 0.1% HCOOH) to give 3.1 mg (11%) of the desired product. This compound exists as an approximately 1:1 mixture of two conformers. 1 H NMR(500MHz,CD3OD):δ[ppm]=7.24(d,J=8.5Hz,1H),7.19(d,J=8.5Hz,1H),7.16-7.11(m,2H),4.12-4.06(m,1H),3.98-3.90(m,2H) ,3.82-3.73(m,3H),3.69-3.62(m,2H),2.90(s,1.5H),2.85(s,1.5H),2.90-2.80(m,1H),2.06-1.96(m,2H),1.22(d,J=6.9Hz,6H). HRMS(ESI)calcd.forC 19 H 27 N6O3[M+H]387.2145,found387.2141.

[0168] (4-Chloro-1,2,5-oxadiazol-3-yl)(1,4-diazepan-1-yl)methanone (66) [ka] Compound 63 (216 mg, 0.59 mmol) was added to a solution of HBr in HOAc (32%) (1 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (C18; MeCN:HO) to give the desired product, which was used directly in the next step.

[0169] 4-(4-chloro-1,2,5-oxadiazole-3-carbonyl)-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (67) [ka] 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 at room temperature for 3.5 h, and the 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 room temperature. HO was added, and the mixture was extracted with EtOAc (3 times). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (C18; MeCN:HO) to give 99.4 mg (43%). An analytical sample was further purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.29(s,0.5H),8.23(s,0.5H),7.35(d,J=8.5Hz,1H),7.32(d,J=8.5Hz,1H),7.09(d,J=8.5Hz, 2H),3.85-3.80(m,1H),3.73-3.54(m,7H),2.85-2.76(m,1H),1.91-1.76(m,2H),1.17(d,J=6.9Hz,3H),1.16(d,J=6.9Hz,3H). MS(ESI)calcd.forC 18 H33 ClNO3([M+H] + ):m / z=392,exp.:392.

[0170] N-(4-isopropylphenyl)-4-(4-methoxy-1,2,5-oxadiazole-3-carbonyl)-1,4-diazepane-1-carboxamide (AR858.1) [ka] Anhydrous MeOH (6.2 μL, 4.9 mg, 0.15 mmol) was added to a mixture of NaH (12 mg, 0.3 mmol, 60% dispersion in mineral oil) and anhydrous THF (0.35 mL). The mixture was stirred at room temperature for 5 min, and a solution of 67 (19.9 mg, 0.05 mmol) in anhydrous MeOH (20 μL) was added. The reaction mixture was stirred at 50 °C for 75 min, cooled to room temperature, filtered, and purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). The yield was 1.9 mg (10%). This compound exists as a ca. 1:1 mixture of two conformers. 1 H NMR(500MHz,CD3OD):δ[ppm]=7.28-7.23(m,2H),7.17-7.13(m,2H),4.10(s,1.5H),3.96-3.92(m,1H),3.94(s,1.5H),3.83-3.7 5(m,2H),3.74-3.69(m,2H),3.68-3.58(m,3H),2.90-2.82(m,1H),2.03-1.97(m,1H),1.93-1.87(m,1H),1.22(d,J=6.9Hz,6H). HRMS(ESI)calcd.forC 19 H 26 N5O4[M+H]388.1985,found388.1980. [ka]

[0171] (R)-N-(1-hydroxy-3-methylbutan-2-yl)-2-nitrobenzenesulfonamide (68) [ka] To a solution of D-valinol (1 g, 8.7 mmol) and NaHCO3 (1.1 g, 13.2 mmol) in HO (10 mL) was slowly added a solution of 2-NsCl (1.92 g, 8.7 mmol) in THF (10 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 15 h. The mixture was poured into HO and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The yield was 2.5 g (99%). 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.08-8.04(m,1H),7.93-7.90(m,1H),7.84-7.80(m,2H),7.73(s,1H),4.60(t,J=5.2 Hz,1H),3.29(t,J=5.5Hz,2H),3.09(q,J=5.7Hz,1H),1.88-1.80(m,1H),0.77(t,J=6.8Hz,3H),0.75(t,J=6.8Hz,3H).

[0172] (R)-N-(1-hydroxy-3-methylbutan-2-yl)-N-(3-hydroxypropyl)-2-nitrobenzenesulfonamide (69) [ka] A solution of 3-bromopropan-1-ol (1.8 g, 13 mmol) in dry DMF (5 mL) was added to a mixture of 68 (2.5 g, 8.7 mmol), KPO (3.69 g, 17.4 mmol), and BuNi (332 mg, 0.9 mmol) in dry DMF (15 mL) at 55 °C under argon. The reaction mixture was stirred at this temperature for 16 h, cooled to room temperature, and poured into brine. The mixture was extracted with EtOAc (3 times). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (C18:MeCN:HO). The yield was 1.2 g (40%). An analytical sample was further purified by HPLC (C18; HO:MeCN + 0.1% HCOOH). 1 H NMR(500MHz,CD3OD):δ[ppm]=8.19-8.16(m,1H),7.79-7.71(m,2H),7.68-7.65(m,1H),3.77-3.68(m,2H ),3.62-3.48(m,4H),3.39-3.32(m,1H),2.03-1.82(m,3H),0.99(d,J=6.6Hz,3H),0.85(d,J=6.6Hz,3H). MS(ESI)calcd.forC 14 H 23 N2O6S([M+H] + ):m / z=347,exp.:347. MS(ESI)calcd.forC 14 H 22 N2NaO6S([M+Na] + ): m / z=369, exp.:369

[0173] (R)-3-((N-(3-methyl-1-(tosyloxy)butan-2-yl)-2-nitrophenyl)sulfonamido)propyl 4-methylbenzenesulfonate (70) [ka] To a mixture of 69 (1.2 g, 3.5 mmol), DMAP (60 mg, 0.49 mmol), and EtN (1.5 mL, 10.4 mmol) in CHCl (8 mL) was added a solution of TosCl (1.4 g, 7.2 mmol) in CHCl (8 mL) at 0 °C. The reaction mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was separated by flash chromatography (cyclohexane: EtOAc). The yield was 430 mg (19%). 580 mg (33%) of the monotosyl derivative was also obtained. MS(ESI)calcd.forC 28 H 34 N2NaO 10 S3([M+Na] + ):m / z=677,exp.:677.

[0174] (R)-2-Isopropyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (71) [ka] To a solution of compound 70 (430 mg, 0.66 mmol) in MeCN (7 mL) was added aqueous NH (7 mL, 33%). The reaction mixture was stirred at 90 °C in a sealed vessel (microwave vial) for 16 h. The volatiles were evaporated under reduced pressure, and the residue was purified by flash chromatography (C18, MeCN:water). The yield was 175 mg (53%). MS(ESI)calcd.forC 14 H 22 N3O4S([M+H] + ):m / z=328,exp.:328.

[0175] (R)-(4-amino-1,2,5-oxadiazol-3-yl)(3-isopropyl-4-((4-nitrophenyl)sulfonyl)-1,4-diazepan-1-yl)methanone (72) [ka] Starting from a 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), (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. The product was purified by flash chromatography (RP; C18; MeCN:HO). The yield was 110 mg (47%). MS(ESI)calcd.forC 17 H 23 N6O6S([M+H] + ):m / z=439,exp.:439.

[0176] (R)-(4-amino-1,2,5-oxadiazol-3-yl)(3-isopropyl-1,4-diazepan-1-yl)methanone (73) [ka] 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 room temperature under argon. The reaction mixture was stirred at room temperature for 1 day. 4-(tert-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 room temperature for an additional 3 days. The insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C18; HO:MeCN). The yield was 29 mg (46%). MS(ESI)calcd.forC 11 H 20 NO2([M+H] + ):m / z=254,exp.:254.

[0177] (R)-4-(4-amino-1,2,5-oxadiazole-3-carbonyl)-2-isopropyl-N-(4-isopropylphenyl)-1,4-diazepane-1-carboxamide (VK765) [ka] (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 general procedure GP2, starting with a solution of 4-isopropylphenyl isocyanate (25 mg, 0.16 mmol) in dry THF (3 mL) and 73 (29 mg, 0.11 mmol) dissolved 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; HO:MeCN + 0.1% HCOOH) to give 35 mg (77%) of the desired product. This compound exists as a ca. 2:3 mixture of two conformers. 1 H NMR(500MHz,DMSO-d6):δ[ppm]=8.20(s,0.4H),8.14(s,0.6H),7.26(d,J=8.5Hz,2H),7.08-7.04(m,2H) ,6.33(s,0.8H),6.28(s,1.2H),4.63-4.51(m,0.4H),4.46-4.28(m,1.6H),4.07-3.90(m,1.6H),3.43-3. 31(m,1H),3.31-3.12(m,2H),3.08-2.94(m,0.4H),2.79(septet,J=6.9Hz,1H),1.89-1.70(m,2H),1.67- 1.55(m,1H),1.16(d,J=6.9Hz,6H),0.97(d,J=6.5Hz,1.8H),0.89-0.83(m,3H),0.79(d,J=6.5Hz,1.2H). HRMS(ESI)calcd.forC 21 H 31 N6O3[M+H]415.2458,found415.2454.

[0178] 3. Activity of compounds against HCMV infection To measure the activity of novel CMV inhibitors, the following assay was used. Normal human dermal fibroblasts (NHDF; obtained from Millipore, Darmstadt, Germany) were seeded in 96-well microtiter cell culture plates (10,000 cells / well) and grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% FCS, 100 U / ml penicillin, 100 μg / ml streptomycin, and 2 mM L-glutamine. The next day, cells were infected with a GFP-expressing HCMV strain (Borst and Messerle, 2000) at a low infectious dose (multiplicity of infection [MOI] of 0.05 PFU / ml).

[0179] Inhibitors were first dissolved in DMSO at a concentration of 10 mM (stock solution) and then further diluted with DMEM medium. Three hours after virus inoculation, the cell culture medium was replaced with DMEM containing the appropriate concentration of inhibitor (three wells per concentration [triplicate]). Depending on the activity of each inhibitor, the concentrations examined ranged from 10 μM to low nanomolar values, applying two-fold dilution steps. After 7 days of incubation, the GFP signal of infected cell cultures in individual wells was measured using a plate reader (Cytation3 Cell Imaging Multimode Reader; Biotek, VT, USA). In wells without inhibitors, the GFP-expressing virus underwent two rounds of infection during the 7-day incubation period, resulting in widespread viral infection in the majority of cells and strong GFP expression (corresponding to 100% infection). The GFP signal of inhibitor-treated cultures was calculated relative to that of untreated cultures (%). Exemplary dose-response curves are shown for several inhibitors (Figure 1). Maximum inhibition is measured by the GFP signal arising from cells infected in the first round, i.e., cells (approximately 1 in 20 cells) after inoculating the culture with the HCMV-GFP mutant [i.e., in the absence of further virus production and spread]. Figure 1 shows the activity of several 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 line). Means + / - SD are shown using GraphPad Prism software version 5.0. The concentration of inhibitors is shown on the X-axis. Results are representative of three experiments performed.

[0180] 4. Antiviral potency of novel HCMV inhibitors The half-maximal activity (effective concentration 50 [EC50]) of the inhibitors was calculated using CDD Vault software (Collaborative Drug Discovery, Inc.; Burlingame, CA; www.collaborativedrug.com). The EC50 values ​​as well as the structures of the inhibitor systems are listed in Table 1.

[0181] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Claims

1. Compounds of formula (I): 【Chemistry 1】 wherein Cy is an optionally substituted 1,4 diazepane group; Ar １ is an optionally substituted phenyl group; an optionally substituted naphthyl group, or an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O, and S; Ar ２ is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O and S, or a salt thereof.

2. Cy is unsubstituted or -F, C １－４ Alkyl, —OH, —COOH, —CONH ２ A compound of formula (I) substituted with 1 or 2 substituents independently selected from: and =O.

3. 2. The compound of claim 1, wherein Cy is selected from the following group: 【Chemistry 2】

4. The compound according to any one of claims 1 to 3, represented by formula (II) or a salt thereof: 【Transformation 3】

5. Ar １ The compound of any one of claims 1 to 4, wherein is an optionally substituted phenyl group.

6. Ar １ is an optionally substituted heteroaryl group containing 5 to 10 ring atoms selected from C, N, O and S.

7. Ar １ is unsubstituted or is a halogen atom, a CN group, an OH group, N ３ Base, SF ５ Group, C １－６ Alkyl group, C ２－６ Alkenyl group, C １－６ Heteroalkyl group, C ３－７ 7. The compound of any one of the preceding claims 1 to 6, substituted with a cycloalkyl group, a phenyl group, an optionally substituted heterocycloalkyl group, heteroaralkyl group, or heteroalkylcycloalkyl group containing 3 to 7 ring atoms independently selected from C, N, O, and S.

8. Ar １ is a halogen atom, N ３ Base, SF ５ group, methyl group, CF ３ Group, OCF ３ Group, CH ２ CF ３ group, i-propyl group, n-butyl group, t-butyl group, CH ２ NHCOOC (CH ３ ) ３ group, -C(Cl)=CH ２ group, -SCF ３ group, cyclopropyl group, cyclohexyl group, benzyloxy group, —N(CH ２ CH ２ ) ２ O group, —N(CH ２ CH ２ ) ２ NH group, -N(CH ２ CH ２ ) ２ NMe, group -N(CH ２ CH ２ ) ２ NCOOC (CH ３ ) ３ group, a 4-tetrahydropyranyl group, a 3-oxetanyl group, a group of the formula —O—CH ２ -O- group, the formula -O-CF ２ A compound according to any one of the preceding claims 1 to 6, substituted with a group of -O-, a phenyl group or a group of the formula: 【Chemistry 4】

9. Ar １ Br, CN group, SF ５ Group, CH ２ CF ３ group, i-propyl group, n-butyl group, t-butyl group, —C(Cl)═CH ２ group, -SCF ３ 7. A compound according to any one of the preceding claims 1 to 6, substituted with a group, a cyclopropyl group, or a phenyl group.

10. Ar １ A compound according to any one of the preceding claims 1 to 4, wherein is selected from the group: 【Transformation 6】

11. Ar １ A compound according to any one of the preceding claims 1 to 4, wherein is selected from the group: 【Transformation 7】

12. Ar ２ The compound of any one of claims 1 to 11, wherein is an optionally substituted heteroaryl group containing 5 ring atoms selected from C, N, O and S.

13. Ar ２ is selected from the group: -NH ２ , -NHMe, -NMe ２ , -NHAc, -OH, -OCH ３ 13. The compound of any one of claims 1 to 12, substituted with 1 or 2 substituents independently selected from -CN and -CN.

14. Ar ２ A compound according to any one of the preceding claims 1 to 11, wherein is selected from the group: 【Transformation 8】

15. Ar ２ A compound according to any one of the preceding claims 1 to 11, wherein is selected from the group: 【Chemistry 9】

16. of formula (III) A compound according to any one of claims 1 to 15. 【Chemistry 10】 In the formula, Ar １ is defined as in any one of claims 1 to 15; R ２ is the following group: -NH ２ , -NHMe, -NMe ２ , -NHAc, -OH, -OCH ３ and —CN; or salts thereof; in particular R ２ is NH ２ is.

17. The compound according to any one of claims 1 to 16, excluding the following compounds: 【Chemistry 11】

18. The compound according to any one of claims 1 to 17, excluding the following compounds: 【Chemistry 12】

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and optionally one or more carrier substances and / or one or more adjuvants.

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

21. A compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for use in the treatment or prevention of herpes virus infections, in particular for use in the treatment or prevention of cytomegalovirus (CMV) infections.

22. 20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for the manufacture of a medicament for the treatment or prevention of herpes virus infections, in particular for the treatment or prevention of cytomegalovirus (CMV) infections.

23. 1. A method for the treatment or prevention of herpes virus infection, particularly the treatment or prevention of cytomegalovirus (CMV) infection, comprising: A method 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.

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