HK1036797A - Anti-viral pyrimidine derivatives - Google Patents

Description

Antiviral pyrimidine derivatives

Related application

This application is a continuation of USSN 60/075, 005 (application date 1998, 2, 17), which is incorporated herein by reference in its entirety.

Statement regarding federally sponsored research in the United states

The invention disclosed herein is not made with the assistance of any federal government fund.

Technical Field

The present invention is in the field of novel substituted pyrimidine compounds and their use as pharmacologically active agents capable of inhibiting viruses, such as herpes viruses. The subject compounds and compositions are particularly useful for treating and inhibiting human cytomegalovirus.

Technical Field

Cytomegalovirus (CMV) is a member of the herpes family of viruses. Other known members of the herpes virus family include, for example, herpes simplex virus types I and II, EB virus and varicella zoster virus. These viruses are taxonomically related, but the clinical manifestations of each are distinct. For CMV, medical conditions resulting from natural infection with CMV include jaundice, respiratory distress, and spastic episodes, which can lead to mental retardation, neurological disability, or death. Adult infections are usually asymptomatic, but can manifest as, in particular, mononucleosis, hepatitis, pneumonia or retinitis in immunocompromised patients, such as AIDS patients, chemotherapy patients and organ transplant patients undergoing treatment for tissue rejection.

Various drugs, including naturally occurring proteins and synthetic nucleoside analogs, have been developed to treat herpes virus infections. For example, natural antiviral interferons have been used to treat herpes virus infections, such as the nucleoside analogs cytosine-arabinoside, adenine-arabinoside, iodohydroxyuridine (iodoxyuridine), and acyclovir are currently the drugs of choice for treating herpes simplex type II infections.

Unfortunately, drugs that have proven effective in treating certain herpes viruses, such as acyclovir, are not sufficiently effective in treating CMV. In addition, the drugs currently used to treat CMV infections, such as 9- ((1, 3-dihydroxy-2-propoxy) methyl) guanidine (ganciclovir, DHPG) and phosphonoformic acid (phosphonoformic acid), lack acceptable side effects and approved drug safety profiles for the treatment of other herpes viruses. In addition, such drugs are ineffective for the treatment of certain CMV that have acquired resistance. Thus, despite the development of anti-herpes virus drugs, there remains a need for therapeutic agents with increased safety margins that are effective in treating CMV infection. The present invention provides surprisingly effective such therapeutic agents, substituted pyrimidine compounds.

Summary of The Invention

The present invention provides novel substituted pyrimidine compounds. The compounds have the general formula I:wherein X represents-NR³R⁴、-OR³、-SR³Aryl, alkyl or aralkyl. The letter Y represents a covalent bond, -N (R)⁶) -, -O-, -S-, -C (= O) -or alkylene. R¹And R²Independently selected from hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl, -S-aryl, -NO₂、-NR⁷R⁸、-C(O)R⁹、-CO₂R¹⁰、-C(O)NR⁷R⁸-N(R⁷)C(O)R⁹、-N(R⁷)CO₂R¹¹、-N(R⁹)C(O)NR⁷R⁸、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen and-N (R)⁷)S(O)_mR¹¹. Radical R³And R⁴Independently selected from hydrogen, alkyl, aryl or arylalkyl, or, when X is-NR³R⁴When R is³And R⁴And the nitrogen atom to which it is attached, form a 5-, 6-or 7-membered aromatic or non-aromatic ring containing 1 to 3 heteroatoms in the ring. R⁵And R⁶Each is hydrogen, alkyl, aryl or arylalkyl. R⁷And R⁸Each independently hydrogen, alkyl, aryl or arylalkyl, or when attached to the same nitrogen atom may combine with the nitrogen atom to form a 4-, 5-, 6-, 7-or 8-membered ring containing 1-3 heteroatoms in the ring. R⁹And R¹⁰Independently selected from hydrogen, alkyl, aryl and arylalkyl. R¹¹Selected from alkyl, aryl and arylalkyl groups. Subscript m is an integer of 1 to 2 and subscript n is an integer of 1 to 3.

In addition to the above-mentioned R¹To R¹¹In addition to the definitions of (a), the above formula also represents a number of compounds wherein the second ring is fused to a pyrimidine ring. For example, R¹Can be reacted with R²Is connected to R¹Can be reacted with R³Is connected to R³Can be reacted with N³(nitrogen atom at 3-position of pyrimidine ring) linkage, R⁵Can be reacted with N³Is connected to R⁵Can be reacted with N¹(nitrogen atom in 1-position of pyrimidine ring), or R²Can be reacted with N¹(nitrogen atom at 1-position of pyrimidine ring), or R²Can be reacted with N¹Joined to form a fused 5-, 6-, or 7-membered ring.

Finally, the molecular weight of the compounds of the present invention is typically about 150-750. The compounds provided by the above formula are meant to also include all pharmaceutically acceptable salts thereof.

The compounds of the invention are useful in therapy and prophylaxis as well as in diagnostics. Further, the compounds of the invention can be used to develop additional therapeutic agents as standards in various assay formats. Accordingly, the present invention provides compositions comprising the above compounds and a pharmaceutically or diagnostically acceptable excipient. The invention further provides methods of inhibiting certain viruses, and methods of treating individuals infected with such viruses, particularly CMV. In addition to treatment of existing diseases, the present invention also provides a method of prophylactic treatment to prevent infection by a virus in a patient undergoing organ transplantation.

Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.

Brief Description of Drawings

FIG. 1 provides the structure of an exemplary compound of formula IIa.

FIG. 2 provides the structure of an exemplary compound of formula IIb.

FIG. 3 provides the structure of exemplary compounds of formula IIc.

FIG. 4 provides the structure of exemplary compounds of formula Id.

FIG. 5 provides the structure of exemplary compounds of formula IIe.

FIGS. 6-14 provide synthetic schemes for exemplary compounds of formulas IIa-e, and also provide selective conversion of functional groups on the compounds.

Detailed Description

Abbreviations and Definitions

The term "alkyl" by itself or as part of another substituent, unless otherwise specified, denotes a straight or branched chain or cyclic hydrocarbon group, or combinations thereof, which may be fully saturated, mono-unsaturated or poly-unsaturated, including binary and polybasic groups, the number of carbon atoms of which is specified (i.e., C1-C1O denotes1-10 carbon atoms). Examples of saturated hydrocarbon groups include straight or branched chain groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, congeners or isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl and the like, and the like. Other saturated hydrocarbon groups include cyclopropylmethyl, cyclohexylmethyl and the like. Unsaturated alkyl is a group having one or more double or triple bonds. Examples of unsaturated alkyl groups include ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher congeners and isomers. The term "alkyl", unless otherwise specified, also includes the following heteroalkyl, alkylene, heteroalkylene, cycloalkyl, and heterocycloalkyl alkyl derivatives. Typically, alkyl groups have 1 to 24 carbon atoms, and preferably these groups have 10 or fewer carbon atoms. The term "alkylene" by itself or as part of another substituent denotes a divalent radical derived from an alkane, such as-CH₂CH₂CH₂CH₂-. "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having 8 or fewer carbon atoms. Unless otherwise specified, an alkyl group may be unsubstituted or substituted with the following substituents.

The term "heteroalkyl", by itself or in combination with another term, unless otherwise stated, denotes a stable straight or branched chain radical consisting of the stated number of carbon atoms and 1-3 heteroatoms selected from O, N, Si and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N and S may be in any position interposed between the heteroalkyl group. The heteroatom Si may be placed anywhere in the heteroalkyl group, including at the point where the alkyl group is attached to the remainder of the molecule. Examples include-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH=CH-O-CH₃、-Si(CH₃)3、-CH₂-CH=N=OCH₃and-CH = CH-N (CH)₃)-CH₃. Up to two consecutive hetero atoms, e.g. -CH₂-NH-OCH₃and-CH₂-O-Si(CH₃)₃. The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkyl radical, such as-CH₂-CH₂-S-CH₂CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-。

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean the cyclic forms of "alkyl" and "heteroalkyl", respectively, unless otherwise specified. Examples of cycloalkyl groups include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- (1, 2, 5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The term "halo" or "halogen" by itself or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom. In addition, terms such as "fluoroalkyl" include monofluoroalkyl and polyfluoroalkyl groups. More specifically, the term "fluoroalkyl" also includes perfluoroalkyl, wherein each hydrogen in the alkyl group is replaced with a fluorine.

The term "aryl" used alone or in combination with other terms (e.g., aryloxy, thioaryl (arylthioaxy) aralkyl), unless otherwise specified, refers to an aromatic substituent which may be a single ring or multiple rings (up to three rings) covalently fused together or linked together. The ring may contain 0 to 4 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atom may be optionally quaternized. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 5-pyrrolyl, and the like, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. The substituents for each of the above-described aryl ring systems are selected from the following acceptable substituents.

The term "bicyclic fused aryl-cycloalkyl" as used herein refers to a group wherein the aromatic ring is fused to a cycloalkyl (including cycloheteroalkyl). The group may be attached to the remainder of the molecule through a bond available on the aryl portion of the group, or through a bond available on the cycloalkyl portion of the group. Examples of such bicyclic fused aromatic-cycloalkyl groups are: 2, 3-indanyl, benzotetrahydrofuranyl, benzotetrahydropyranyl and 1, 2, 3, 4-tetrahydronaphthyl.

Each of the above terms (e.g., "alkyl" and "aryl" and "bicyclic fused aryl-cycloalkyl") typically includes both substituted and unsubstituted forms of that group. Preferred substituents for each type of group are as follows. If a group contains two moieties, aryl (including heteroaryl) and alkyl (including, for example, heteroalkyl, cycloalkyl and cycloheteroalkyl), each moiety may be substituted.

Substituents for alkyl groups (including those commonly referred to as alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: -OR ', = O, = NR', = N-OR ', -NR' R ", -SR ', -halogen, -SiR' R" R '", -oc (O) R', -CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR”-C(O)-OR’、-NH-C(NH₂)=NH、-NR’C(NH₂)=NH、-NR’-C(NH₂)=NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR' R ", -CN and-NO₂The number of substituents ranges from 0- (2N +1), where N is the total number of carbon atoms in such group. R ', R ' and R ' are each independentlyRefers to hydrogen or C1-C10 alkyl. Preferably, the substituted alkyl group can have 1 to 6 independently selected groups. More preferably, the substituted alkyl group has 1 to 4 independently selected groups. In any event, a particular substituted alkyl group (e.g., perfluoroalkyl) has 2N +1 total substitutions (where N is the number of carbon atoms in the saturated alkyl group). Examples of substituted alkyl groups include: -C (O) -CH₃、-C(O)CH₂OH、-CH₂-CH(CO₂H)-NH₂And Si (CH)₃)₂-CH₂-C(O)-NH₂。

Similarly, the substituents of the aryl group are different and can be selected from: -halogen, -OR ', -OC (O) R ', -NR ' R ", -SR ', -R ', -CN, -NO₂、-CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR”-C(O)-OR’、-NH-C(NH₂)=NH、-NR’C(NH₂)=NH、-NH-C(NH₂)=NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-N₃、-CH(Ph)₂Perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl having a number of substituents ranging from O to the total number of valences on the aromatic ring system (open valences); wherein R 'and R' are independently selected from hydrogen, (C1-C8) alkyl, aryl- (C1-C4) alkyl, and aryloxy- (C1-C4) alkyl.

Two substituents on adjacent atoms of the aromatic ring may optionally be substituted by a group of formula-TC (O) - (CH)₂)_s-U-substituent, wherein T and U are each-NH-, -O-, -CH₂-or a single bond, subscript s is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aromatic ring may optionally be replaced by a group of formula-A- (CH)₂)_pA substituent of-B-, wherein A and B are each-CH₂-、-O-、-NH-、-S-、S(O)-、-S(O)₂、-S(O)₂NR' -or a single bond, p is an integer of 1 to 3. One or more single bonds on the new ring so formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aromatic ring may optionally be substituted by a group of the formula- (CH)₂)_q-Z-(CH₂)_r-wherein q and r are each an integer of 1 to 3, Z is-O-, NR', -S-, -S (O)₂-or-S (O)₂NR' -. NR' -and-S(O)₂the substituent R 'in NR' -is selected from hydrogen or (C1-C6) alkyl.

The term "heteroatom" as used herein includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The term "pharmaceutically acceptable salts" includes salts of the active compounds prepared by reaction with the corresponding non-toxic acids or bases, according to the particular substituents on the compounds defined herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts are obtained by contacting the neutral forms of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts are obtained by contacting the neutral forms of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphonic acids, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine salts and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, for example, Berge, s.m., et al, "pharmaceutically acceptable salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Particular compounds of the invention contain both basic and acidic functionalities and these compounds can be converted into base addition salts or acid addition salts.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional means. Certain physical properties of the parent form of the compound, such as solubility in polar solvents, may differ from the various salt forms, but otherwise the salts are equivalent to the parent form of the compound of the invention for the purposes of the invention.

In addition to salt forms, the present invention provides compounds that may be in the form of prodrugs. Prodrugs of the compounds disclosed herein are those compounds which readily undergo chemical changes under physiological conditions to yield compounds of formula I.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain compounds of the present invention have a chiral carbon atom (optical center) or a double bond; racemates, diastereomers, geometric isomers and individual isomers (indolidual isomers) are all within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be prepared using radioactive isotopes, such as tritium (A), (B), (C), (³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) And performing radioactive labeling. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Embodiments of the invention

Compound (I)

In one aspect, the invention provides compounds of formula I:wherein X represents-NR³R⁴、-OR³、-SR³Aryl, alkyl or aralkyl. The letter Y represents a covalent bond, -N (R)⁶) -, -O-, -S-, -C (= O) -or alkylene. Y is preferably Y is-N (R)⁶) -or-O-, wherein R⁶The definition of (A) is as above. More preferably, Y is-N (R)⁶) -. For embodiments where Y is alkylene, the alkylene chain typically has from 1 to 8 carbon atoms, with alkylene groups having from 1 to 3 carbon atoms being preferred.

R¹And R²Independently selected from hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl, -S-aryl, -NO₂、-NR⁷R⁸、-C(O)R⁹、-CO₂R¹⁰、-C(O)NR⁷R⁸-N(R⁷)C(O)R⁹、-N(R⁷)CO₂R¹¹、-N(R⁹)C(O)NR⁷R⁸、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen or-N (R)⁷)S(O)_mR¹¹Wherein R is⁷、R⁸、R⁹、R¹⁰And R¹¹Is defined as follows.

In a preferred group of embodiments, R¹Is an electron withdrawing group, R²Is an electron donating group. In this group of embodiments, R¹Preference is given to-NO₂、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen, fluoroalkyl, -C (O) R⁹、-CO₂R¹⁰or-C (O) NR⁷R⁸(ii) a More preferably, R¹is-CF₃、-NO₂、-CN、-S(O)_mNR⁷R⁸or-CO₂R¹⁰preferably-NO₂。R²Preferably, hydrogen, lower alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl or-S-aryl. More preferably, R is²Is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, methoxymethyl, methylthio, ethylthio or propylthio.

In another preferred group of embodiments, R¹Is an electron donating group, R²Are electron withdrawing groups. In this group of embodiments, R¹Preference is given to hydrogen, lower alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl or-S-aryl. More preferably, R is¹Is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, methylthio, ethylthio or propylthio. R²Preference is given to-NO₂、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen, fluoroalkyl, -C (O) R⁹、-CO₂R¹⁰or-C (O) NR⁷R⁸(ii) a More preferably, R²is-CF₃、-NO₂、-CN、-S(O)₈NR⁷R⁸or-CO₂R¹⁰preferably-NO₂。

R³And R⁴Independently is hydrogen, alkyl, aryl or arylalkyl, or, R³And R⁴Together with the nitrogen atom to which they are attached, form a ring containing 1-3 heteroatoms in a 5-, 6-or 7-membered ring. In a preferred group of embodiments, R³And R⁴And the nitrogen atom to which it is attached, form a 5-or 6-membered ring. By R³、R⁴The ring enclosed by the nitrogen atom may be saturated, unsaturated or aromatic and may contain further heteroatoms. Examples of suitable rings include pyrrolidine, pyrrole, pyrazole, imidazole, imidazoline, thiazoline, piperidine, morpholine, and the like. In a particularly preferred embodiment, R³And R⁴Together with the nitrogen atom to which they are attached form a 5-membered ring containing two nitrogen atoms, preferably an imidazole ring, most preferably a 2-alkylimidazole ring or a 5-alkylimidazole ring. Particularly preferred X groups are 2-methylimidazol-1-yl, 2, 4-dimethylimidazol-1-yl, 2-ethylimidazol-1-yl, 2-propylimidazol-1-yl, 2-isopropylimidazol-1-yl and 5-methylimidazol-1-yl.

R⁵The group is alkyl, aryl, arylalkyl or a bicyclic fused aryl-cycloalkyl. Preferred alkyl groups have 1 to 8 carbon atoms, substituted or unsubstituted. Preferred aryl groups include substituted or unsubstituted phenyl, pyridyl, or naphthyl. Preferred arylalkyl groups include substituted and unsubstituted benzyl, phenethyl, pyridylmethyl and pyridylethyl. Particularly preferred R⁵Are phenyl, 4-halophenyl, benzyl, n-butyl, propionyl, acetyl and methyl. Other preferred R⁵The radical being R⁵、R⁶Together with the nitrogen atom to which they are attached form a ring. Other preferred R⁵The groups (including some preferred fused bicyclic aryl-cycloalkyl) are selected from:in the above groups and others disclosed herein, the wavy line is used to indicate the point of attachment to the remainder of the molecule.

In a particularly preferred group of embodiments, R⁵Selected from the following groups:in a particularly preferred further group of embodiments, R⁵Selected from the following groups:

the above groups are meant to include mixtures of stereochemically isomeric forms as well as pure isomers and enantiomers (those having less than 5% of another diastereomer or enantiomer, more preferably less than about 2% of another isomer, and most preferably less than about 1% of another isomer).

R⁶The group is typically hydrogen, alkyl, aryl or arylalkyl. It is preferred that R is⁶Is hydrogen, lower alkyl having 1 to 3 carbon atoms, a phenyl ring or phenylalkyl, such as benzyl or phenethyl. R⁷And R⁸Each independently hydrogen, alkyl, aryl or aralkyl, or taken together with the nitrogen atom to which each is attached, form a 4-, 5-, 6-, 7-or 8-membered ring containing 1-3 heteroatoms in the ring. Preferably, R is⁷And R⁸Each independently (C1-C8) alkyl, or taken together to form a 5-, 6-or 7-membered ring. R⁹And R¹⁰Independently selected from hydrogen, alkyl, aryl and aralkyl. In a preferred embodiment, R⁹And R¹⁰Independently selected from hydrogen, (C1-C8) alkyl, phenyl and phenyl (C1-C4) alkyl. R¹¹Is an alkyl, aryl or aralkyl radical, preferably (C1-C8) alkyl, phenyl and phenyl (C1-C4) alkyl.

In addition to the above pairs of R¹To R¹¹In addition to the description, the above formula also represents a number of compounds in which a second ring is fused to the pyrimidine ring, includingIncluding structures in which one of the pyrimidine ring nitrogen atoms is the ring attachment point. For the purposes of the following discussion and claims, nitrogen each means: n is a radical of¹Is a nitrogen atom in the 1-position of the ring (which carries an-R group)²And having a carbon atom of-y-R⁵Between carbon atoms of (c). N is a radical of³Is a nitrogen atom in the 3-position of the pyrimidine ring (which carries a-Y-R group)⁵And the carbon atom bearing the group-X). Examples of fused rings are those wherein R is¹And R²Is connected to R¹And R³Is connected to R³And N³Is connected to R⁵And N³Is connected to R⁵And N¹Is linked, or R²And N¹Are linked to form a fused 5-, 6-or 7-membered ring. The rings formed by these combinations contain 1-3 heteroatoms (e.g., O, N or S), and may be aromatic or non-aromatic. Preferably the additional ring formed is a 5-or 6-membered ring.

When R is¹And R²When combined together to form a ring, the combination may be of the formula-T-C (O) - (CH)₂)_s-U-wherein T and U are independently selected from-NH-, -O-, -CH₂-or a single bond, and subscript s is an integer from 0 to 2. Or, R¹And R²The group may be represented by the formula-A- (CH)₂)_pA substituent of-B-, wherein A and B are independently selected from-CH₂-、-O-、-NH-、-S-、-S(O)-、-S(O)₂-、-S(O)₂NR' -or a single bond, p is an integer of 1 to 3. One or more single bonds of the new ring so formed may optionally be replaced by a double bond. Or, R¹And R²Can be represented by formula- (CH)₂)_q-Z-(CH₂)_rWherein q and r are independently an integer of 1 to 3, Z is-O-, -NR' -, -S (O)₂-or-S (O)₂NR' -. -NR' -and-S (O)₂The substituent R 'in NR' is selected from hydrogen or (C1-C6) alkyl.

The subscript m in the above groups is an integer of from 1 to 2, preferably 2. The subscript n is an integer of from 1 to 3, preferably 2.

Finally, the compounds of the present invention typically have a molecular weight of about 150 and 750. The compounds of the above formula also include all pharmaceutically acceptable salts thereof.

Combinations of a plurality of substituents on the pyrimidine ring are particularly preferred. For example, one group of preferred embodiments has the formula:

in the compounds of the formula IIa, R¹Preference is given to-NO₂、-CF₃、-C(O)NR⁷R⁸、-CO₂R¹⁰、-S(O)₂NR⁷R⁸、-S(O)₂R⁹、-SO₂NH₂or-CN, R²Preferred are alkyl groups having 1 to 8 carbon atoms. In a preferred embodiment, R³And R⁴The groups are joined together to form a 5-membered ring which is optionally fused to an aryl group. Examples of suitable 5-membered ring groups (and optionally aryl-fused 5-membered ring groups) include pyrrolidine, pyrrole, imidazole, pyrazole, benzimidazole, imidazoline, 1, 2, 4-triazole, 1, 2, 3-triazole, imidazolidin-2-one, and the like. More preferably, R³And R⁴Taken together to form an imidazole ring, which is substituted or optionally fused with an aryl group. Preferred substituted (and fused) imidazole rings include, for example, 2-methylimidazole, 2-ethylimidazole, 2-isopropylimidazole, 2-aminoimidazole, 5-methylimidazole, 5-ethylimidazole, 5-isopropylimidazole, 2, 5-dimethylimidazole, benzimidazole, and 2-methylbenzimidazole. R⁵And R⁶The groups are independently selected from hydrogen, alkyl, aryl and aralkyl groups, or may be bonded to a nitrogen atom to which they are attached to form a ring optionally fused to an aryl group. FIG. 1 provides exemplary structures of compounds within this group of preferred embodiments.

Another group of preferred embodiments is represented by the formula:

in the formula, contains R¹And R²The fused ring of (A) is typically a heterocycle, wherein-R¹-R²-is selected from, e.g., -S (O)₂NR’C(O)-、-S(O)₂NR’C(O)NR”-、-NR’S(O)₂NR "C (O) -, -C (O) NR 'C (O) -, -NR' C (O) NR" C (O) -, -NR 'C (S) NR "C (S) -, wherein R' and R" are independently hydrogen or (C1-C8) alkyl. R³And R⁴The groups preferably combine to form a 5-membered ring which is optionally fused to an aryl group. More preferably R³And R⁴Combine to form an imidazole ring optionally fused with an aryl group. R⁵And R⁶Independently selected from hydrogen, alkyl, aryl and aralkyl groups, or may combine to form a ring optionally fused to an aryl group. FIG. 2 provides the structures of exemplary compounds in this group of preferred embodiments.

Another group of preferred embodiments is represented by the formula:

in the formula, a divalent group-R¹-R³Typically alkylene, -C (O) NR 'C (O) -, -C (O) NR' S (O)₂-or-S (O)₂NR 'C (O) -, wherein R' is hydrogen or lower alkyl. Preferably, R is²And R⁴Each independently is alkyl, more preferably lower alkyl. R⁵And R⁶The groups are independently selected from hydrogen, alkyl, aryl and aralkyl groups, or may be joined together to form a ring optionally fused to an aryl group. Fig. 3 provides exemplary compound structures in a preferred group of this embodiment.

Another group of preferred embodiments is represented by the formula:

in the formula, is represented by-R²The defined fused ring moieties are typically (C3-C5) alkylene groups, alkyleneamine groups (e.g., -NHCH₂CH₂CH₂-、-NHCH₂CH₂-) or-NR' C (O) CH₂-a group, wherein R' is hydrogen or lower alkyl. R¹typically-NO₂、-S(O)₂NR⁷N⁸、-S(O)₂R⁹、-CN、-CF₃、-C(O)R⁹、-CO₂R¹⁰or-C (O) NR⁷R⁸. More preferably, R¹is-NO₂、-CN、-CF₃or-CO₂R¹⁰Most preferred is-NO₂。R³And R⁴Preferably joined to form a 5-membered ring optionally fused to an aryl group. More preferably, R³And R⁴Taken together to form an imidazole ring optionally fused with an aryl group. R⁵And R⁶The groups are independently selected from hydrogen, alkyl, aryl and aralkyl groups, or may combine to form a ring optionally fused to an aryl group. The symbol X-represents a suitable counterion for the quaternary nitrogen. Preferred counterions are those that form pharmaceutically acceptable salts. Fig. 4 provides exemplary compound structures in this preferred group.

Another group of preferred embodiments is represented by the formula:

in the formula, R¹Preference is given to-NO₂、-S(O)₂NR⁷R⁸、-S(O)₂R⁹、-CN、-CF₃、-C(O)R⁹、-CO₂R¹⁰or-C (O) NR⁷R⁸. More preferably, R¹is-NO₂、-CN、-CF₃or-CO₂R¹⁰Most preferred is-NO₂。R²Preferred are alkyl groups having 1 to 8 carbon atoms. R³And R⁴The groups preferably combine to form a 5-membered ring which is optionally fused to an aryl group. More preferably, R³And R⁴Combine to form an imidazole ring optionally fused to an aryl group. R⁵Preference is given to hydrogen, (C1-C8) alkyl, phenyl or phenylalkyl. from-R⁶The fused ring moiety of the definition is typically (C3-C5) alkylene or substituted alkylene (e.g., -C (O) CH)₂CH₂CH₂-、-C(O)CH₂CH₂-, or-NR' C (O) CH₂-a group, wherein R' is hydrogen or lower alkyl. The symbol X-represents a suitable counterion for the quaternary nitrogen. Preferred counterions are those that form pharmaceutically acceptable salts. FIG. 5 provides the structure of exemplary compounds of formula IIe.

Composition comprising a metal oxide and a metal oxide

Another aspect of the invention provides a composition suitable for pharmaceutical or diagnostic use. Compositions comprise a compound of formula I above together with a diagnostic or pharmaceutically acceptable carrier or excipient.

In one embodiment, the present invention provides the subject compounds in combination with pharmaceutically acceptable excipients, such as sterile saline or other media, water, gelatin, oil, and the like, to form a pharmaceutically acceptable composition. The compositions and/or compounds may be administered alone or in combination with any conventional carrier, diluent, or the like, and such administration may be single or multiple dose. Useful carriers include solid, semi-solid, or liquid media, including water and non-toxic organic solvents.

In another embodiment, the invention provides a prodrug form of the subject compound, which can be metabolized or chemically converted by the recipient to the subject compound. Various prodrug derivatives are known to those skilled in the art, for example, they rely on hydrolytic cleavage or oxidative activation of the drug.

The compositions may be in any conventional form, including tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, suppositories, and the like. As a result, the composition in pharmaceutically acceptable dosage unit form or the composition in bulk can be placed into a variety of containers. For example, the unit dose can be placed in a variety of containers including capsules, pills, and the like.

The compositions may advantageously be used in admixture or in combination with other therapeutic or prophylactic antiviral agents, other than the compounds of the subject invention. The compositions may also be advantageously combined and/or co-administered with agents, such as anti-HIV agents or immunosuppressive agents, for treating or alleviating viral infectious diseases susceptible to the compounds of the present invention. In many instances, administration of the compositions of the present invention can enhance the efficacy of such agents. Examples of antiviral agents include ganciclovir, foscarnet and cidofovir. Examples of anti-HIV drugs include indinavir, ritonavir, AZT, lamivudine, and saquinavir. Examples of immunosuppressive agents include cyclosporin and FK-506. The compositions may also be advantageously used in combination with immunosuppressive regimens, such as the destruction of bone marrow (by radiation or chemotherapy), as antiviral prophylactic treatments.

Application method

In another aspect, the invention provides novel methods of use of the aforementioned compounds and compositions. In particular, the invention provides methods for treating or preventing herpes family virus infections, particularly cytomegalovirus infections. The methods typically involve administering to a patient one or more subject compositions in an effective dosage form.

The present invention provides methods of using the subject compounds and compositions for treating or preventing diseases in individuals having an impaired immune system or who are expected to have immunosuppressive diseases, such as patients undergoing immunosuppressive therapy prior to organ transplantation or anticancer chemotherapy. These methods generally involve administering to a host an effective amount of the subject compound or pharmaceutically acceptable composition.

The compositions and compounds of the invention and pharmaceutically acceptable salts thereof may be administered by any effective route, such as orally, parenterally or topically. Generally, the compounds will be administered in a dosage range of about 2 to 2000 mg/day, but the dosage will vary depending on the condition being treated, the patient and the route of administration. A preferred oral dosage range is from about 0.05mg/kg to about 20mg/kg, more preferably from about 0.05mg/kg to about 2mg/kg, and most preferably from about 0.05mg/kg to about 0.2mg/kg per kilogram of body weight per day.

Preparation of the Compounds

The compounds of the invention can be prepared using general synthetic schemes, such as those outlined in FIGS. 6-14. It will be apparent to those skilled in the art that the following synthesis can be varied using different starting materials and other reagents to obtain the desired transformations. Accordingly, the figures and reagents are non-limiting embodiments, as described below.

Briefly, Y is-N (R)⁶) The compounds of the formula I can be prepared from various known pyrimidinedionesIs prepared by the following steps. As shown in fig. 6, using a material such as POCl₃The reagent treatment of (a) converts the pyrimidinedione (i) into the corresponding dichloride (ii). Treatment of ii with the desired amine (including heterocyclic amines) affords the target compound, typically a mixture of isomers (iii). The isomers may be separated by conventional means, such as column chromatography or HPLC. Alternatively, (e.g. hydrolysis of ii to the monochloro compound with sodium acetate, acetic acid, water and ethanol) gives (iv), which is treated with a suitable amine, alkoxide or thiolate ion to give (v). The 4-hydroxy group is converted to a 4-chloro substituent and substituted with the appropriate nucleophilic amine to give the target (vi).

Many pyrimidinediones are commercially available and can be used as starting materials for the above-mentioned transformations, for example 5-cyano-6-methyl-2, 4-pyrimidinedione (vii), 6-methyl-2, 4-pyrimidinedione-5-carboxamide (x), 6-methyl-2, 4-pyrimidinedione-5-sulfonic acid (xv) and 6-methyl-5-nitro-2, 4-pyrimidinedione. Each of these compounds can be converted to the target compound of formula (IIa) as shown in FIG. 7. For example, 5-cyano-6-methyl-2, 4-pyrimidinedione (vii) can be used such as POCl₃Conversion of the reagent into dichlorides (viii) and subsequent reuse of the amine R³-NH-R⁴(e.g., 2-methylimidazole) and R⁵-NH-R⁶(N-methylbenzylamine) treatment into a compound of interest (e.g., ix).

The carboxamide group of 6-methyl-2, 4-pyrimidinedione-5-carboxamide (x) can be hydrolysed to carboxylic acid (xi) with an aqueous base and then with POCl₃Converted to the acid chloride (xii) (trichloride formation). Stepwise addition of amine or other suitable nucleophile provides the desired compound (e.g. xiv). Similarly, by using chlorinating agents, e.g. POCl₃6-methyl-2, 4-pyrimidinedione-5-sulfonic acid (xv) was treated to form a trichloride (xvi). Furthermore, stepwise addition of amine or other suitable nucleophile may produce the desired target class (x).

FIG. 8 shows another process for preparing compounds of formula IIa. Treatment of beta-ketoester (ix) or alpha-methylate (xxi) with a base (e.g., sodium alkoxide) and an electrophilic agent (e.g., an alkylating agent, acylating agent, sulfonating agent, etc.) provides an appropriately derivatized beta-ketoester (xxi)An ester (xx), which can be converted to a pyrimidinedione (xxiii) by treatment with substituted guanidine (xxii), typically in acid (acetic acid), under heat. The 5-and 6-positions (R respectively) are determined by the groups present on the derivatized beta-ketoester¹And R²) A substituent as defined above. Chlorination of the pyrimidinedione gives (xiv), followed by treatment with a nucleophilic azacyclo (such as imidazole, 2-alkylimidazole, pyrrolidine, piperidine, etc.) and other amines to give the target compound of formula IIa. The substituted guanidines used in this preparation can be obtained commercially or by treating secondary amines with cyanamide. Additional literature methods for preparing substituted guanidines are known in the art.

Many transformations can be made to the unsubstituted position on the pyrimidine ring to attach various groups, or changes can be made to existing groups (see figure 9). For example, 4-chloro substituents (e.g., present in xxv) may be substituted with ammonia to give 4-aminopyrimidine (e.g., xxvi). Treatment of primary amine with succinic anhydride gave (xvii) and treatment with acetic anhydride gave succinimide compound x (fig. 9A). Exocyclic amino groups can also be acylated with standard acylating agents as shown in FIG. 9B. The metallation reaction can be performed at the unsubstituted 6-position of the pyrimidine (FIG. 9C). For example, the 5-nitropyrimidine derivative (xxxi) can be catalytically reduced (Hxix @)₂) Or chemically reduced (e.g. Fe/HCl) to the 5-aminopyrimidine derivative (xxxii), which is then protected to tert-butyl carbamate (xxxiii). Treatment of the protected 5-aminopyrimidine derivative with an metallizing agent such as sec-butyllithium gives an metallized intermediate (xxxvi), which can be acylated (xxxv), sulfonated (xxxvi) or alkylated (xxxvii) as shown. Similarly (see FIG. 9D), pyrimidine derivatives (x viii) may be metallised, giving rise to intermediates (x ix), followed by acylation (x 1), sulphonation (x 1 i) or alkylation (x 1 ii). Similar metallochemistry on pyrimidine derivatives (x 1 iii) enables the introduction of a functional group at the 5-position, resulting in intermediates (x 1 iv) which can be acylated (x 1 v), sulphonated (x 1 vi) and alkylated (x 1 vii).

FIGS. 10A-10D provide synthetic schemes for some compounds, which follow the scheme shown in FIGS. 6-8The general method is shown. For example, FIG. 10A shows that substituted guanidine (1) can be prepared from secondary amine (x 1 viii) and chloroimidate (x 1 ix), and ethyl cyanoacetate (1 i) converted to ketoester (1 ii). Condensation of 1 and 1 ii affords a pyrimidinedione (1 iii) which may be chlorinated to give 1 iv, which is then treated with an amine nucleophile such as 2-methylimidazole to give the desired compound 1 v. FIG. 10B shows a similar pathway in which ethyl acetoacetate (1 vi) was acylated to give the tricarbonyl compound (1 vii). Condensation of 1 vii with a substituted guanidine (1 viii) gives a pyrimidinedione (1 ix), which is converted into the target (1 x) by standard methods. FIG. 10C shows the general process in which the sulfonamide group is present in the starting material (1 xi) and the substituted guanidine (1 xiii) contains a nitrogen heterocycle. Thus, condensation of 1 xiii and 1 xiii gives pyrimidinedione (1 xiv) using POCl₃(or other chlorinating agent) and then reacted with an amine nucleophile such as 1, 2, 4-triazole to convert the target (1 xv). In addition, compounds having-O-Ar, -S-Ar, -O-alkyl and-S-alkyl groups at the 2-position of the pyrimidine ring can be prepared by a general method (FIG. 10D). For example, treatment of ketoesters (xx) with a substituted guanidine (1 xvi) gives pyrimidinediones (1 xvii) which can be chlorinated with R³-NH-R⁴Condensation to give 1 ix. The protecting group was removed to give 2-aminopyrimidine compound (1 xx). Diazotisation followed by chlorination can be carried out by standard procedures to give 1 xx. Di-substitution of the chloride with an oxygen-containing nucleophile or a sulphur-containing nucleophile gives the desired compound 1 x xi or 1 x iii, respectively.

FIG. 11 shows the preparation of compounds of formula IIb. In one group of embodiments, a substituted pyrimidine having a sulfonamide at the 5-position and an ester group at the 6-position is saponified to give 1 xx v, and then cyclized to a fused heterocyclic ring 1 xx vi using a dehydrating agent (e.g., sulfuric acid or acetic anhydride) (see FIG. 11A). In other embodiments, the diester is saponified to a diacid (1 x viii) and converted to a mixture of amides (1 x ix by successive treatments with acetic anhydride and methylamine) and then cyclized by treatment with a dehydrating agent (such as acetic anhydride) to give a bicyclic system (1 x, see FIG. 11B). From 2-oxocyclopentanecarboxylic acid ethyl ester by the above-described method for converting beta-ketoesters to substituted pyrimidinesThe ester initially produced another fused bicyclic ring system (1 xx i) (see FIG. 11C). Another set of embodiments can be made by manipulating the nitrile and ester substituents (see fig. 11D). Briefly, ethyl cyanoacetate is first condensed with ethyl oxalyl chloride and the resulting product is treated with a substituted guanidine (exemplified herein as N, N-diethylguanidine) to give a substituted pyrimidinedione (1 x ii). By POCl₃(or other chlorinating agent) followed by treatment with a suitable amine (e.g., imidazole, 2-alkylimidazole, isopropylethylamine, pyrrolidine) to afford substituted pyrimidines (1 xxxiii). The ester is hydrolysed and rearranged by Curtius (for example with diphenyl phosphoryl azide) to give the aminonitrile (1 x xiv). The nitrile group is converted to the amide by acid hydrolysis followed by treatment with phosgene (or phosgene equivalents such as diphosgene or dimethyl carbonate) to give a fused bicyclic ring system, 1 xx xv, which can be further converted to 1 xx xv by treatment with a strong base (e.g. NaH) and an alkylating agent (e.g. MeI). Certain intermediates in these synthetic pathways can be converted to other useful derivatives (fig. 11E). For example, 1 xx vii may be treated with Lawesson's reagent to give thioamide 1 x ix and phosgene (or phosgene equivalent) to give fused bicyclic system 1 x ix. Alternatively, treatment with sulfuryl chloride in the presence of a tertiary amine base was 1 xx vii, giving the fused bicyclic ring system xc. FIGS. 11F and 11G show additional methods for preparing compounds within the scope of formula IIb. In FIG. 11F, substituted pyrimidines (xci) with sulfonamide at the 5-position and carboxylic acid at the 6-position can be prepared in a manner similar to that described above. The carboxylic acid groups in xci undergo Curtius rearrangement to amino groups to give xcii, which is then cyclized to xciii using phosgene or a phosgene equivalent. FIG. 11G shows the preparation of the pyrimidine diester (xciv) and its conversion to the fused bicyclic ring system xcvii. Briefly, the silyl group present in xciv is hydrolyzed to the acid, which undergoes the Curtius rearrangement to give xcv. The remaining ester groups may be converted to amides by standard methods to give xcvi. Cyclizing xcvi to xcvii with phosgene or a phosgene equivalent.

The compound of formula IIc may be prepared by the process of FIG. 12. In one set of embodiments (FIG. 12A), a 4-chloropyrimidine derivative (xc viii, prepared as described above) is treated with an amine (e.g., allylamine) to provide xc ix. Treatment with methylamine in an alcoholic solvent causes the ester group to be then converted to the N-methylamide (c). Cyclizing c to ci by treatment with phosgene or an equivalent thereof. Similarly, compounds having multiple electronegative groups at the 6-position can be prepared as shown in FIG. 12B. For example, chloropyrimidine cii may be prepared as described above and then converted to bicyclic compound cii by the method described for xc ix. Another fused system of formula IIc can be prepared as shown in FIG. 12C. Here, the chloropyrimidine derivative (xiv) is treated with a primary amine (e.g., allylamine) to provide the amino moiety at the 4-position of the pyrimidine ring. Cyclization of the amino moiety to the sulfonamide (at the 5-position) can be achieved with phosgene or its equivalent to afford the target compound (cv).

In one embodiment, as shown in FIG. 13, compounds of formula Id may be prepared. Briefly, ethyl nitroacetate may be condensed with a mixed anhydride (cvi) to give a nitroketoester (cvi) which is converted to pyrimidine (viii) by treatment with an appropriately substituted guanidine. Removing the protecting group and then using POCl₃Treatment chlorinates and cyclizes the pyrimidine ring to form a pyrimidinium salt (c ix). Treatment of c ix with an amine nucleophile yields the target compound (cxx). Other compounds of this group can be prepared starting from ethyl 3, 3, 3-trifluoropropionate or ethyl cyanoacetate by varying the substituted guanidines and amino hydrophilicizers used.

The compound of formula IIe can be prepared using the procedure outlined in FIG. 14. According to the scheme shown in FIG. 14, an appropriately substituted guanidine (cxi, prepared from protected hydroxypropylamine) is condensed with ethyl 2-nitroacetoacetate (or a similar ethyl 2-trifluoromethylacetoacetate) to give pyrimidinedione (cxii). The protecting group was removed, and chlorination and cyclization were carried out in a similar manner to that shown in FIG. 13 to give a salt (c xiii). Subsequent treatment of cxiii with a nucleophilic amine gives the target (cxiv).

The compounds used as starting materials for the present invention are either commercially available or can be readily synthesized using standard methods well known in the art.

Some of the compounds of the present invention exist as stereoisomers, and the present invention includes all such active stereoisomeric forms of these compounds. For the optically active isomers, such compounds can be obtained from the corresponding optically active precursors in the manner described above, or by resolution of racemic mixtures. Resolution can be carried out by a variety of techniques well known in the art, such as chromatography with a chiral solid support or chiral solvent, repeated recrystallization of the derivatized asymmetric salt, or derivatization.

The compounds of the invention may be labeled in various ways. For example, the compounds may contain radioisotopes, such as³H (tritium),¹²⁵I (iodine-125) and¹⁴c (carbon-14). Similarly, the compounds may advantageously be linked, covalently or non-covalently, directly or via a linker molecule, to a variety of other compounds which provide prodrugs or which function as carriers, labels, adjuvants, co-activators, stabilizers and the like. Such labeled and linked compounds are also within the scope of the invention.

Analysis of Compounds

The subject compounds and compositions exhibit pharmacological activity in vitro and in vivo assays, e.g., they specifically modulate cellular physiology, reduce associated pathogenicity, or provide or enhance prophylaxis.

Certain preferred compounds and compositions specifically inhibit cytomegalovirus infection. To evaluate activity on human CMV, the CMV-inhibitory antibodies were assayed by hybridization with Kohler et al at j.virol.68: 6589 and 6597 (1994). Briefly, recombinant Human Cytomegalovirus (HCMV) containing a marker gene (luciferase) was prepared under the control of the phosphoprotein pp28 promoter of the latter 28kDa viral structure. Human Foreskin Fibroblast (HFF) cells were infected with the recombinant HCMV virus (MOI 5), plated in 96-well plates and cultured under standard cell culture conditions. After 1 hour, the compound to be evaluated for its anti-HCMV activity was added to the infected cells. Luciferase expression levels were measured 24 hours after treatment with test compounds. Biological Activity of test Compounds from their IC₅₀The value: expression of late stage genes of recombinant HCMV (in HFF culture) relative to control (vehicle-treated) infected cellsRepresentative of luciferase expression) by 50% of the test compound concentration. As an additional control, the cytotoxicity of test compounds on untreated HFF cells was also evaluated in cultured cell growth experiments.

Table 1 provides biological data for selected compounds from the following examples.

TABLE 1

Compound (I)	IC50(μM)
		a	0.8
c	0.1
		d	0.02
f	6.0
		g	0.8
h	0.3
		j	0.01
k	1.0
		m	2.0
n	0.4
		o	2.0
p	0.3
		q	3.0
s	3.0
		t	10.0
u	0.1

The following examples are given by way of illustration and not by way of limitation.

Examples

¹H-NMR spectra were recorded on a Varian Gemini 400MHz NMR spectrometer. The distinct peaks are listed in order: proton number, peak number (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet), coupling constant (in Hz). Electron Ionization (EI) Mass Spectrometry in a Hewlett Packard5989A Mass spectrometerAnd (4) recording. Mass spectrometry results were recorded as mass to charge ratio, followed by the relative abundance of each ion (in parentheses). All reagents, starting materials and intermediates used in the examples are commercially available or can be prepared by methods well known in the art.

Example 1

This example discloses the synthesis of 2- (N-methylanilino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (a) and the isomer 4- (N-methylanilino) -2- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (b).

To a stirred cold solution (-78 ℃) of 2, 4-dichloro-6-methyl-5-nitropyrimidine (2.25g, 10.8 mmol, 1.0 eq) in THF (15 ml) was added dropwise a solution of 2-methylimidazole (977 mg, 11.9 mmol, 1.1 eq) in THF (15 ml). After 1 hour, the dry ice bath was replaced with an ice water bath and stirred for an additional 2 hours and 15 minutes. N-methylaniline (4.6ml, 43.2 mmol, 4.0 equiv) was added at this point. The reaction solution was stirred at-78 ℃ for 1 hour 15 minutes and at room temperature overnight. At this point the solvent was removed and the residue was diluted with dichloromethane, washed three times with 0.1M HCl and three times with saturated aqueous NaCl. The organic phase was evaporated and the residue was purified by silica gel chromatography (1: 1 hexane/diethyl ether, 1% AcOH as eluent) to give 209 mg of the title compound a (6%) and its isomer (400 mg), and b (104.8 mg). (a)¹H NMR (400MHz)(CD₃OD): δ 2.26(3H, br s); 2.58(3H, br s); 3.61(3H, s); 6.88(1H, s); 7.02(2H, d); 7.31-7.34(3H, m); 7.43-7.48(2H, m). Calculations: c₁₆H₁₆N₆O₂: c, 59.25; h, 4.97; n, 25.91. measurement: c, 59.16; h, 4.95; n, 25.86.(b)¹H NMR (400MHz)(CDCl₃)：δ2.40(3H，s)；2.80(3H，s)；3.55(3H，s)；6.95(1H，s)；7.13(2H，m)；7.30-7.39(3H，m)；7.86(2H，s).

Example 2

This example shows the synthesis of 2- (N-methylanilino) -4- (2-methylimidazol-1-yl) -6-ethyl-5-nitropyrimidine (c).

To a stirred ice-cold solution (-78 ℃) of a (54.4 mg, 0.168 mmol, 1.0 equiv) in THF (1.0 mL) was added LiN (SiMe) dropwise₃)₂(0.20 mmol, 0.20 ml, 1.0M in THF). After stirring for 10 min, MeI (0.105ml, 1.68 mmol, 10 equivalents) was added dropwise. The reaction was held at-78 ℃ for 40 minutes and stirred at 0 ℃ for an additional 4 hours. A small amount of acetic acid (0.25ml) was poured into the flask and the brown residue was evaporated to dryness. The residue was then dissolved in dichloromethane, washed three times with saturated aqueous NaCl solution and the organic phase was evaporated to dryness to give a crude yellow oil.

Purification by column chromatography on silica gel with 1: 1 hexane/ether, 1% AcOH, 3% MeOH as eluent afforded 21.4mg of the desired product (37%).

(c) ¹H NHR (400MHz)(CD₃OD)：δ1.29(3H，br s)；2.28(3H，br s)；2.86(2H，br s)；3.63(3H，s)；6.89(1H，s)；7.02(1H，s)；7.30-7.39(3H，m)；7.42-7.49(2H，m) 。

MS ESI m/z (relative intensity): m + H, 339.2 (100); m = Na, 361.1 (15).

Example 3

This example shows the synthesis of 2- (N-benzyl-N-methylamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (d), 2, 4-bis- (N-benzyl-N-methylamino) -6-methyl-5-nitropyrimidine (e), and 4- (N-benzyl-N-methylamino) -2- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (f).

To a stirred cold (-78 ℃) solution of 2, 4-dichloro-6-methyl-5-nitropyrimidine (187.7mg, 0.9 mmol, 1.0 eq) in THF (2.25ml) and EtOH (2.25ml) was added dropwise a solution of 2-methylimidazole (148 mg, 1.8 mmol, 2.0 eq) in EtOH (2.25 ml). After 45 minutes, the dry ice bath was replaced with an ice water bath and the mixture was stirred for an additional 2.2 hours. N-methylbenzylamine (0.465ml, 3.6 mmol, 4.0 equiv) was added at this point. After stirring for 2.7 hours, the solvent was removed by evaporation and the residue was diluted with dichloromethane, washed three times with 0.1MHCl and three times with saturated aqueous NaCl solution. The solvent was removed from the organic phase and the residue was purified by silica gel chromatography (1: 1 hexane/diethyl ether, 1% AcOH as eluent) to give d (32mg), e (116.3mg) and f (104.8 mg).

(d) ¹H NMR (400MHz)(CDCl₃)：δ2.30(1.5H，s)；2.53(1.5H，s)；2.57

(1.5H，s)；2.59(1.5H，s)；3.15(1.5H，s)；3.27(1.5H，s)；4.88(1H，s)；4.97(1H，s)；6.87

(0.5H，s)；6.90(0.5H，s)；6.96(0.5H，s)；6.99(0.5H，s)；7.16(1H，d)；7.24-7.37(4H，m).

MS ESI m/z (relative intensity): m + H, 339.2 (100); m + Na, 361.1(8)

(e) ¹H NMR (400MHz)(CDCl₃): δ 2.49(3H, s); 2.79(3H, s); 2.90-3.20(3H, brm); 4.70-4.88(4H, br m); 7.12-7.35(10H, brm). MS ESI m/z (relative intensity): m + H, 378.2 (100); m + Na, 400.1(15)

(f) ¹H NMR (400MHz)(CDCl₃)：δ2.52(3H，s)；2.67(3H，s)；2.90(3H，s)；

4.92(2H，s)；6.89(1H，s)；7.20(2H，d)；7.28-7.35(3H，m)；7.74(1H，s).MS ESI m/z

(relative intensity): m + H, 339.2(100).

Example 4

This example shows the synthesis of 2- (N-methyl-4-chloroanilino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (g).

To a stirred cold (-78 ℃) solution of 2, 4-dichloro-6-methyl-5-nitropyrimidine (207.5mg, 1.0 mmol, 1.0 eq) in THF (2.25ml) and EtOH (2.25ml) was added dropwise a solution of 2-methylimidazole (164 mg, 2.0 mmol, 2.0 eq) in EtOH (2.25 ml). After 45 minutes, the dry ice bath was replaced with an ice water bath and the mixture was stirred for an additional 2.25 hours. Then 4-chloro-N-methylaniline (0.485ml, 4.0 mmol, 4.0 equiv) was added and the reaction solution was stirred for 2.7 hours. The solvent was removed by evaporation and the residue was diluted with dichloromethane, washed three times with 0.1MHCl, three times with saturated aqueous NaCl solution, and MgSO₄And (5) drying. The solvent was removed from the organic phase and the residue was purified by silica gel chromatography (1: 1 hexane/ether, 1% AcOH as eluent) to give g (55.9mg, 15.6%).

(g) ¹H NMR (400MHz)(CD₃OD)：δ2.30(3H，br s)；2.57(3H，br s)；3.59

(3H，s)；6.91(1H，s)；7.02(1H，s)；7.36(2H，d)；7.44(2H，d).

MS ESI m/z (relative intensity): m + H, 359.1 (100).

Example 5

This example shows the synthesis of 2- (N-methylanilino) -4- (2-methylimidazol-1-yl) -6-isopropyl-5-nitropyrimidine (h).

To a stirred ice-cold (-78 ℃ C.) solution of a (38.6mg, 0.12 mmol, 1.0 equiv) in THF (0.5ml) was added NaH (9.5mg, 60% in oil, 0.24 mmol, 2.0 equiv). After stirring for 15 min, MeI (0.074ml, 1.19 mmol, 10 equiv.) was added. The reaction was held at-78 ℃ for 2 hours and then stirred at 0 ℃ for a further 2.5 hours. A small amount of acetic acid (0.25ml) was poured into the flask and the brown residue was evaporated to dryness. The residue was dissolved in dichloromethane, washed three times with water and three times with saturated aqueous NaCl solution. The solvent was removed from the organic phase and the product was chromatographed on silica gel (1: 1 hexane/ether, 1% AcOH as eluent) to give the title compound (13.3mg, 33%).

(h) ¹H NMR (400MHz)(CDCl₃)：δ1.20-1.35(6H，m)；2.29(3H，br s)；3.24

(1H，m)；3.62(3H，s)；4.92(2H，s)；6.89(1H，br s)；7.03(1H，br s)；7.30-7.40(3H，m)；

7.71-7.48(2H, m). MS ESI m/z (relative intensity): m + H, 353.1(100).

Example 6

This example shows the synthesis of 2- (N-benzyl-N-methylamino) -4- (2-methylimidazol-1-yl) -6-ethyl-5-nitropyrimidine (j).

To a stirred ice-cold solution of d (57.7mg, 0.170 mmol) in THF (0.5mL) (-78 deg.C) was added LiN (SiMe) dropwise₃)₂(0.17ml, 0.17 mmol, 1.0 eq, 1.0M/THF). After stirring for 10 min, MeI (0.106ml, 1.70 mmol, 10 equivalents) was added dropwise. The reaction was allowed to stir at-78 ℃ for 2 hours and then at 0 ℃ for an additional 3 hours. A small portion of acetic acid (0.25ml) was poured into the flask and the brown mixture was evaporated to dryness. The residue is taken up in dichloromethane, washed three times with water, three times with saturated aqueous NaCl solution and the organic phase is evaporated to dryness. After purification by silica gel chromatography (1: 1 hexane/diethyl ether, 1% AcOH, 3% MeOH as eluent), the title compound was obtained. The yield is as follows: 30.3mg (50.4%).

(j)¹H NMR (400MHz)(CD₃OD)：δ1.26-1.41(3H，m)；2.21(1.5H，s)；2.45

(1.5H，s)；2.86-2.94(2H，m)；3.22(1.5H，s)；3.35(1.5H，s)；4.93(1H，s)；5.05(1H，s)；6.91

(0.5H，s)；6.94(0.5H，s)；7.07(0.5H，s)；7.12(0.5H，s)；7.23-7.38(5H，m).MS ESI m/z

(relative intensity): m + H, 353.1(100).

Example 7

This example shows the synthesis of 2- (N, N-diethylamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (k).

To a stirred cold solution (-78 ℃) of 2, 4-dichloro-6-methyl-5-nitropyrimidine (208mg, 1.0 mmol, 1.0 equiv in 2 ml EtOH and 2 ml THF) was added dropwise a solution of 2-methylimidazole (164 mg, 2.0 mmol, 2.0 equiv) in 2 ml EtOH. The resulting solution was stirred at-78 ℃ for 1 hour and then at 0 ℃ for 2 hours. Diethylamine was added dropwise and the reaction was allowed to stir overnight. The resulting mixture was diluted with dichloromethane, washed with 0.1MHCl, saturated NaCl, and dried (MgSO)₄) And (4) filtering. The solvent was removed by evaporation and the residue was purified by silica gel chromatography to give 35 mg of the title compound K as an oil.

(k)¹H NMR (400MHz，CDCl₃)：δ1.15-1.23(3H，m)；2.48(3H，s)；2.53

(3H，s)；3.59-3.60(2H，q)；3.68-3.70(2H，q)；6.86(1H，s)；6.95(1H，s).MS ESI m/z

(relative intensity): m + H, 291.2(100).

In a similar manner, the specified amine was used in place of diethylamine to give each of the following yellow oils.

2- (N-Benzylbutylamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine compound m (N-butylbenzylamine) … 40 mg.¹H NHR(400MHz)(CDCl₃): δ 0.86-0.95 (3H, m); 1.23-1.38(2H, m); 1.51-1.68(2H, m); 2.52(3H, m); 3.52(2H, t); 4.83(1H, s); 6.80(1H, s); 6.92(1H, s); 7.13(2H, d); 7.26-7.31(3H, m). MS ESI m/z (relatively strong)Degree): m + H, 381.2 (100).

2- (N-methylbutylamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine compound N (N-methylbutylamine) … 68 mg.¹H NHR(400MHz)(CDCl₃): δ 0.95(3H, t); 1.32(2H, m); 2.51(3H, br s); 2.55(3H, s); 3.15-3.24(3H, d); 3.58-3.72(2H, t); 6.85(1 H.s); 6.95(1H, s). MS ESI m/z (relative intensity): m + H, 305.4 (100).

2- (N, N-dibenzylamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine compound o (dibenzylamine) … 20 mg.¹H NHR (400MHz) (CDCl₃): δ 2.53(3H, br s); 2.55(3H, brs); 4.81(2H, s); 4.96(2H, s); 6.85(1H, s); 6.95(1H, s). MS ESI m/z (relative intensity): m + H, 415.6 (100).

… 45 mg of compound p (4-methylpiperidine).¹H NHR(400MHz)(CDCl₃): δ 1.12-1.16(3H, m); 2.46(3H, s); 2.51(3H, s); 3.40-3.47(8H, m); 6.84(1H, s); 6.99(1H, s). MS ESI m/z (relative intensity): m + H, 317.1 (100).

Compound q (N- (cyclopropylmethyl) butylamine) … 41 mg.¹H NHR(400MHz)(CDCl₃): δ 0.23-0.64(4H, m); 0.89-0.93(3H, m), 1.18(1H, t); 1.59-1.73(2H, m); 2.49-2.51(3H, d); 2.54-2.55(3H, d); 3.46-3.58(2H, m). MS ESI m/z (relative intensity): m + H, 331.2(100).

Example 8

This example discloses the synthesis of 2- (N-methylanilino) -4-pyrrolidinyl-6-methyl-5-nitropyrimidine (r).

To a stirred cold solution (-78C) of 2, 4-dichloro-6-methyl-5-nitropyrimidine (208mg, 1.0 mmol, 1.0 equiv. in 2 mL EtOH and 2 mL THF) was added pyridineA solution of pyrrolidine (78 mg, 1.1 eq) in 1.0 ml of EtOH. The resulting solution was stirred at-78 ℃ for 1 hour and then at 0 ℃ for 2 hours. N-methylaniline (0.432 mL, 4.0 equiv.) was added dropwise and the reaction was allowed to stir overnight. The resulting mixture was diluted with dichloromethane, washed with 0.1MHCl, saturated NaCl, and dried (MgSO)₄) And (4) filtering. The solvent was removed by evaporation and the residue was purified by silica gel chromatography to give the title compound (r).

Example 9

This example shows the synthesis of 2- (N-methyl-N-benzylamino) -4- (2-methylimidazol-1-yl) -5-nitropyrimidine(s).

To a solution of 2, 4-dichloro-5-nitropyrimidine (200 mg, 1.0 mmol) in dioxane (5 ml) was added 2-methylimidazole (85 mg, 1.0 mmol) and N-methyl-N-benzylamine (133 μ l, 1 mmol) at 80 ℃. The solution was stirred at 80 ℃ overnight, cooled and directly chromatographed (1/1 hexane/ether) to give the title compound(s).

(s)¹H NMR (400MHz) (CD₃OD)：δ3.09(s，1.5H)，3.17(s，1.5H)，3.18

(s，1.5H)，4.5-4.8(m，2H)，7.2-7.5(m，8H).

Example 10

This example shows the synthesis of 2- (N-methylanilino) -4- (4-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (t).

To a solution of 2, 4-dichloro-6-methyl-5-nitropyrimidine (150 mg, 0.72 mmol) in dioxane (5 ml) was added 4-methylimidazole (60 mg, 0.72 mmol) and N-methyl-N-methylaniline (77 mg, 0.72 mmol) at 80 ℃. The solution was stirred at 80 ℃ overnight, cooled and directly chromatographed (1/1 hexane/ether) to give the title compound (t).

(t)¹H NMR (400MHz) (CD₃OD)：δ2.37(s，3H)，2.74(s，3H)，3.30(s，

3H)，7.25-7.55(m，5H)，7.75(s，1H)，9.31(s，1H).

Example 11

This example shows the synthesis of 2- (4-benzylpiperazin-1-yl) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (u).

To a solution of 2, 4-dichloro-6-methyl-5-nitropyrimidine (175 mg, 0.84 mmol) in dioxane (5 ml) was added 4-methylimidazole (60 mg, 0.72 mmol) and 1-benzylpiperazine (148 μ l, 0.84 mmol) at 80 ℃. The solution was stirred at 80 ℃ overnight, cooled and directly chromatographed (1/1 hexane/ether) to give the title compound (u).

(u)¹H NMR (400MHz) (CD₃OD)：δ2.42(s，3H)，2.60(s，3H)，3.38(br

s, 4H), 3.80(br s, 4H), 4.38(s, 2H), 7.30-7.55(m, 7H). MSESI 347 m/e (relative intensity):

M+H， 348.0(100).

example 12

This example shows the synthesis of 2- (4-trifluoromethylbenzylamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (v).

To a stirred mixture of 2-chloro-4-hydroxy-6-methyl-5-nitropyrimidine (300 mg, 1.58 mmol, 1.0 eq) in absolute ethanol (20 ml) was added 4- (trifluoromethyl) -benzylamine (540 mg, 3.1 mmol, 2.0 eq) and sodium acetate (130 mg, 1.58 mmol, 1.0 eq). The mixture was heated slowly and the resulting solution refluxed for 22 hours. Then cooling the mixture and vacuumThe ethanol was removed. The oily residue was dissolved in ethyl acetate, washed three times with 1M HCl, three times with saturated NaCl solution and then with MgSO₄And (5) drying. The solvent was removed to give a crude yellow solid intermediate, dried in vacuo and then dissolved in 4ml of POCl₃. Heating (95-100 deg.C) for 0.5 hr. Removal of POCl by rotary evaporation₃The crude brown product was purified by chromatography (1: 1 hexane/dichloromethane) to give the chloropyrimidine intermediate (313 mg), which was used directly in the next step without further purification.

To a stirred solution of the above chlorinated pyrimidine (150 mg, 0.4 mmol, 1.0 equiv.) in acetonitrile (2.5 ml) was added 2-methylimidazole (142 mg, 1.7 mmol, 4.0 equiv.). The resulting mixture was heated at reflux for 5 hours, cooled and the solvent removed by rotary evaporation. The residue was dissolved in ethyl acetate, washed with 0.1MHCl, water, brine, and MgSO₄Drying and removal of the solvent gave a crude yellow solid. The solid was purified by chromatography eluting with 2.5% MeOH in dichloromethane to give a yellow oil. The title compound was obtained by precipitation with dichloromethane and hexane. The yield is as follows: 152.3mg, the yield from the starting 2-chloro-4-hydroxy-6-methyl-5-nitropyrimidine was 51%.

(v)¹H NMR (400MHz) CDCl₃δ2.28(1.5H，s)；2.42(1.5H，s)；2.55(1.5H，

s)；2.58(1.5H，s)；4.71(1H，d)；4.80(1H，d)；6.67(0.5H，br s)；6.80(0.5H，br s)；6.88(1H，

d)；6.96(1H，s)；7.41(1H，d)；7.49(1H，d)；7.62(2H，d).MS ESI m/z

(relative intensity):

M+H 392.9(100).

example 13

This example discloses the preparation of 2- ((1-phenyl-1-propyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine (w) by the addition of an imidazole group to the pyrimidine core by an alternative method.

To a stirred solution of 2- ((1-phenylpropyl) amino) -4-hydroxy-6-methyl-5-nitropyrimidine (78 mg, 0.27 mmol, 1.0 equivalent, prepared in a similar manner to example 12 above) in pyridine (1 ml) was added trifluoroacetic anhydride (115 μ l, 0.81 mmol, 3.0 equivalents). The mixture was stirred for 15 minutes, then imidazole (184 mg, 2.7 mmol, 10 equivalents) was added and the mixture was allowed to stir overnight. Pyridine was removed by rotary evaporation and the brown residue was dissolved in ethyl acetate, washed with 0.M HCl and then brine. The crude solid obtained after removal of the solvent was purified by silica gel chromatography (2.5% MeOH/CH)₂Cl₂) 36.1 mg (42%) of the title compound are obtained.

(w)¹H NMR (400MHz) CDCl₃δ0.99(3H，m)；1.73-2.02(2H，m)；2.48(3H，

s)；4.81(0.66H，dd)；5.07(0.33H，dd)；6.16(0.66H，d)；7.02(0.33H，d)；7.08-7.12(2H，m)；

7.25-7.38(5H, m); 7.89(0.66H, s); 8.18(0.33H, s). MS ESI m/z (relative intensity): m + H

339.2(100).

Example 14

This example shows the synthesis of pyrimidine derivatives having an alkoxy group in the 2-position, such as 2- (1-propoxy) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine (x).

To a flask charged with n-propanol (5 ml) was added NaH (128mg, 60% in oil, 3.19 mmol, 2.0 eq) and the mixture was stirred under nitrogen for 10 min. The resulting solution was transferred by cannula to a flask containing a solution of 2-chloro-4-hydroxy-6-methyl-5-nitropyrimidine (302 mg, 1.6 mmol, 1.0 eq.) in n-propanol (5 ml). The resulting mixture was heated in an oil bath at 100 ℃ for 1 hourInto a separatory funnel containing dilute HCl and extracted with dichloromethane. The organic phase was separated, washed with water, brine, MgSO₄After drying and removal of the solvent, a crude solid was obtained (yield 297 mg). Crude solid in pure POCl₃(3ml) heated at 85-90 ℃ for 6 minutes, cooled on ice and POCl removed in vacuo₃. The chloropyrimidine intermediate was purified by chromatography to give 117 mg of intermediate, which was converted to the title compound by the method described in example 12. The product obtained was a yellow oil (191 mg, calculated from 2-chloro-4-hydroxy-6-methyl-5-nitropyrimidine, 43% yield).

(x)¹H NMR (400MHz) CDCl₃δ1.04(3H，t)；1.86(2H，dq)；2.52(3H，s)；

2.61(3H, s); 4.38(2H, t); 6.90(1H, d); 6.98(1H, d). MS ESI m/z (relative intensity): m + H

278.1(100).

Example 15

The compounds listed in Table 2 were prepared using the procedures outlined in examples 12-13. The compounds were tested by the CMV assay described above and showed the following levels of activity: + IC₅₀＞500nM；++，100nM＜IC₅₀≤500nM；+++，IC₅₀≤100nM。

TABLE 2

Table 2 (continuation)

Table 2 (continuation)

Table 2 (continuation)

Table 2 (continuation)

Example 16

The compounds listed in Table 3 were prepared in a similar manner to examples 12-14. The compounds were subjected to the CMV assay described above and they showed + IC₅₀Activity level > 500 nM.

TABLE 3

Example 17

This example shows the synthesis of 2- (2-indanamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine.

2- (2-Indanylamino) -4-chloro-6-methyl-5-nitropyrimidine prepared according to the procedure of example 12 but using 2-indanamine as the nucleophile (56mg, 0.18 mmol) was dissolved in 2.0mL EtOH and 2-methylimidazole (38 mg, 0.46 mmol, 2.5 equiv.) was added. The resulting yellow solution was placed in a water bath at 80 ℃ and stirred for 24 hours. The solution was then concentrated under reduced pressure. Purification by flash chromatography (SiO)₂，2％MeOH/CH₂Cl₂) 34 mg of the title compound (52%) are obtained as an amorphous yellow solid: melting point 203-.

¹H NMR (CDCl₃400MHz, mixture of rotamers) delta 7.28-7.13(m, 5H), 6.99

(s，0.5H)，6.96(s，0.5H)，6.17(d，J=7.9Hz，0.5H)，6.06(d，J=7.3Hz，0.5H)，4.93

(m，0.5H)，4.73(m，0.5H)，3.45-3.34(m，2H)，2.94(dd，J=4.8，16.2Hz，1H)，2.89

(dd，J=4.3，16.0Hz，1H)，2.71(s，1.5H)，2.65(s，1.5H，2.63，s，1.5H)，2.53(s，1.5

H) (ii) a MS ESI m/z (relative)Strength): 351.2(M + H, 100). calculated: c₁₈H₁₈N₆O₂：C，

61.70, respectively; h, 5.18; n, 23.99. measurement: c, 61.08; h, 5.22; n, 23.57.

Example 18

This example shows the synthesis of 2- (2-indanamino) -4-imidazol-1-yl-6-methyl-5-nitropyrimidine.

2- (2-indanylamino) -4-chloro-6-methyl-5-nitropyrimidine (66.8mg, 0.22 mmol) was dissolved in 2.0ml EtOH, followed by the addition of imidazole (37 mg, 0.54 mmol, 2.5 equivalents). The yellow solution was heated to 80 ℃ for 18 hours. The solution was then concentrated under reduced pressure and purified by flash chromatography (SiO)₂，2％MeOH/CH₂C1₂) 52.1mg (71%) of amorphous yellow solid product (0.155 mmol) are obtained: melting point 177-.

¹H NMR (CDCl₃400MHz, mixture of rotamers) delta 8.23 (s, 0.5H), 8.16(s, 0.5H),

7.28-7.11(m, 6H), 6.09 (width s, 0.5H), 5.91(d, J =7.2Hz, 0.5H), 4.93(m, 0.5H),

4.79(m，0.5H)，3.40(dd，J=7.0，15.9Hz，2H)，2.91(dd，J=4.1，15.8Hz，2H)，

2.56(s, 1.5H), 2.46(s, 1.5H); MS ESI (relative abundance) 337.1(M + H, 100). C₁₇H₁₆N₆O₂

The calculated value of (a): c, 60.71; h, 4.79; and N, 24.99. Measurement value: c, 60.29; h, 4.89; n, 24.69.

Example 19

This example discloses the synthesis of 2- (4, 6-difluoro-1-indanylamino) -4- (imidazol-1-yl) -6 methyl-5-nitropyrimidine.

2- (4, 6-difluoro-1-indanylamino) -4-chloro-6-methyl-5-nitropyrimidine prepared according to the method of example 12 using 4, 6-difluoro-1-indanamine as nucleophile (56mg, 0.16 mmol) was dissolved in 2.0ml EtOH, followed by the addition of imidazole (28 mg, 0.411 mmol, 2.5 equivalents). The solution was heated to 80 ℃ for 23 hours. The solution was then concentrated under reduced pressure and purified by flash chromatography (SiO)₂，2％MeOH/CH₂Cl₂) 35.5mg (58% yield) of amorphous yellow solid product are obtained: melting point 175-.

¹H NMR(CDCl₃400MHz, rotamer mixture) delta 8.09(s, 0.5H), 8.06(s, 0.5H0, 7.26-7.10(M, 2H), 6.82(dd, J-7.6, 11.6Hz, 1H0, 6.72(dd, J =8.8, 8.8Hz, 1H0, 5.95 (width s, 0.5H), 5.82(d, J =8.4Hz, 0.5H), 5.72(M, 0.5H), 5.56(M, 0.5H), 3.05(M, 1H), 2.87(M, 1H), 2.73(M, 1H), 2.55(s, 1.5H), 2.49(s, 1.5H), 1.98(M, 1H), MS ESI (relative abundance) 373.1(M + H, 100) C.5H, 1H), MS ESI (M + C.5H)₁₇H₁₄F₂N₆O₂The calculated value of (a): c, 54.84; h, 3.79; n, 22.57. Measurement value: c, 54.95; h, 3.76; n, 22.32.

Example 20

This example shows the synthesis of 2- (4, 6-difluoro-1-indanamino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine.

2- (4, 6-difluoro-1-indanylamino) -4-chloro-6-methyl-5-nitropyrimidine (56mg, 0.16 mmol) was dissolved in 2.0ml EtOH, followed by the addition of 2-methylimidazole (34 mg, 0.41 mmol, 2.5 equiv.). The solution was heated to 80 ℃ and heated with stirring for 26 hours. The solution was then concentrated under reduced pressure and purified by flash chromatography (SiO)₂，2％MeOH/CH₂Cl₂) 42.6mg (67% yield) of amorphous yellow solid product are obtained: melting Point 164-165℃。

¹H NMR(CDCl₃400MHz, rotamer mixture) δ 6.98(s, 1H), 6.90(s, 1H), 6.81(m, 1H), 6.71(m, 1H), 5.87-5.81(m, 1H), 5.73(m, 0.5H), 5.54(m, 0.5H), 3.05(m, 1H), 2.82(m, 1H), 2.70(m, 1H), 2.60(s, 1.5H), 2.53(s, 1.5H), 2.51(s, 1.5H), 2.46(s, 1.5H), 1.98(m, 1H); MS ESI (relative abundance) 387.1(M + H, 100). C₁₈H₁₆F₂N₆O₂The calculated value of (a): c, 55.96; h, 4.17; and N, 21.75. Measurement value: c, 56.15; h, 4.59; n, 20.71.

Example 21

This example shows the synthesis of 2- (4, 6-difluoro-1-indanylamino) -4- (2-ethylimidazol-1-yl) -6-methyl-5-nitropyrimidine.

2- (4, 6-difluoro-1-indanylamino) -4-chloro-6-methyl-5-nitropyrimidine (56mg, 0.16 mmol) was dissolved in 2.0ml EtOH, followed by the addition of 2-ethylimidazole (39 mg, 0.41 mmol, 2.5 equiv). Heating the solution to 80 deg.C for 23.5 hr, concentrating the solution under reduced pressure, and purifying by flash chromatography (SiO)₂，2％MeOH/CH₂Cl₂) 39.6mg (60% yield) of amorphous yellow solid product are obtained, melting point 88-89 ℃.

¹H NMR(CDCl₃400MHz, rotamer mixture) δ 7.02(s, 1H0, 6.88(s, 1H), 6.81(m, 1H), 6.72(m, 1H), 5.85(d, J =9.0Hz, 0.5H), 5.81-5.70(m, 1H), 1.29(t, J =7.5Hz, 3H); MS ESI (relative abundance): 401.1(M + H, 100). C₁₉H₁₈F₂N₆O₂The calculated value of (a): c, 57.00; h, 4.53; and N, 20.99. Measurement value: c, 56.93; h, 4.50; n, 20.71.

Example 22

This example discloses 2- (2-indanylamino) -4-, (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine, synthesis of monohydrochloride.

2- (2-indanylamino) -4-chloro-6-methyl-5-nitropyrimidine prepared according to the method of example 17 (310 mg, 1.02 mmol) was dissolved in 7ml EtOH, followed by the addition of 2-methylimidazole (600 mg, 7.3 mmol, 7.2 equiv.). The resulting yellow solution was then heated to 80 ℃ while magnetic stirring was performed. After 24 hours, the solution is concentrated under reduced pressure in vacuo and purified by flash chromatography (SiO)₂，2％MeOH/CH₂Cl₂) 303.6mg of the free base (0.876 mmol) as an amorphous yellow solid were obtained. The yellow solid was then dissolved in 3ml of anhydrous THF and 2 ml (8.0 mmol, 9.2 eq) of a 4.0MHCl in 1, 4-dioxane was added. A precipitate formed immediately. The resulting slurry was allowed to stir for 10 minutes. The slurry was then concentrated under reduced pressure, dissolved in 3ml of THF and concentrated again. The resulting yellow solid was recrystallized from hot EtOAc to give 179 mg (45% yield) of the pale yellow needle crystalline hydrochloride: melting point 184-.

¹H NMR(CDCl₃400MHz, rotamer mixture) δ 7.76(d, J =2.2Hz, 0.5Hz), 7.71(d, J =2.2Hz, 0.5H), 7.64(d, J =2.2Hz, 0.5H), 7.61(d, J =2.2Hz, 0.5H), 7.22(m, 2H), 7.15(m, 2H0, 4.92(m, 0.5H), 4.72(m, 0.5H), 3.41-3.31(m, 1H), 2.97(m, 1H0, 2.73(s, 1.5H), 2.72(s, 1.5H), 2.68(s, 1.5H), 2.65(s, 1.5H). C₁₈H₁₈N₆O₂Calculated value of HCl: c, 55.89; h, 4.95; n, 21.73; cl, 9.16. Measurement value: c, 55.89; h, 5.00; n, 21.56; cl, 9.14.

Example 23

This example shows the synthesis of 2- (cis-2-ethylcyclohexylamino) -4-imidazol-1-yl-6-methyl-5-nitropyrimidine.

2- (cis-2-ethyl)Cyclohexylamino) -4-chloro-6-methyl-5-nitropyrimidine (58.6mg, 0.196 mmol) was dissolved in 2.0ml of EtOH, followed by the addition of imidazole (53 mg, 0.78 mmol, 4.0 equiv.). The resulting yellow solution was heated to 80 ℃ and magnetically stirred. After 20 hours the solution was concentrated under reduced pressure and purified by flash chromatography (SiO)₂，2％MeOH/CH₂Cl₂) To yield 39.5mg (61% yield) of the title compound as an amorphous yellow solid: melting point 123-.

¹H NMR(CDCl₃400MHz, rotamer mixture) δ 8.22(s, 0.5H), 8.17(s, 0.5H), 7.39-7.27(m, 2H0, 5.92(d, J =7.8Hz, 1H), 4.57(m, 0.5H), 4.42(m, 0.5H), 2.65(s, 1.5H), 2.61(m, 1.5H), 2.02(m, 1H), 1.87-1.34(m, 10H), 1.02(t, J =7.0Hz, 3H); MS ESI (relative abundance) 331.2(M + H, 100). C₁₆H₂₂N₆O₂The calculated value of (a): c, 58.17; h, 6.71; n, 25.44. Measurement value: c, 58.01; h, 6.79; and N, 25.30.

Example 24

The compounds listed in Table 4 were prepared using the procedures set forth in examples 17-23. Compounds were subjected to the CMV assay described above and showed the following levels of activity: IC, IC₅₀＞500 nM；++，100nM＜IC₅₀≤500nM；+++，IC₅₀≤100nM。

TABLE 4

Table 4 (continuation)

Table 4 (continuation)

Table 4 (continuation)

Table 4 (continuation)

Example 24

The compounds of this example were prepared using the methods described above. The starting materials are available as above or commercially.

24.12- (N- (trans-2-methylcyclohexyl) amino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine

¹H NMR (400MHz，CDCl₃): δ 0.92(1.5H, d, J =7.2 Hz); 0.94(1.5H, d, J =7.2 Hz); 1.00-1.30(5H, m); 1.31-1.41(1H, m); 1.74-1.82(2H, m); 1.94-1.96(1H, m); 2.39(1.5H, s); 2.47(1.5H, s); 2.48(1.5H, s); 2.53(1.5H, s); 3.52(0.5H, dq, J =.4.0, 9.8 Hz); 3.69(0.5H, dq, J =4.0, 9.8 Hz); 5.86(0.5H, d, J =9.2Hz), 5.98(0.5H, d, J =9.2 Hz); 6.86(1H, s); 6.93(0.5H, s); 6.95(0.5H, s). MS ESI: m/z (relative intensity): m + H, 331.2(100).

24.22- (N- (cis-2-methylcyclohexyl) amino) -4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃): δ 0.93(3H, d, J =7.2 Hz); 1.22-1.41(3H, m); 1.48-1.68(4H, m); 1.71-1.78(1H, m); 1.95(1H, m); 2.44(1.5H, s); 2.51(3H, s); 2.57(1.5H, s); 4.13(0.5H, m); 4.28(0.5H, m); 5.68(0.5H, d, J =9.0Hz), 5.59(0.5H, d, J =9.0 Hz); 6.87(1H, s); 6.94(0.5H, s); 6.96(0.5H, s). MS ESI: m/z (relative intensity): m + H, 331.2(100) 24.32- (N- (trans-2-methylcyclohexyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃)：δ0.96(3H，d，J=6.5Hz)；1.11-1.29(3H，m)；1.33-1.39(2H，m)；1.70(1H，m)；1.75-1.83(2H，m)2.05(1H，dd，J=2.8，13.4Hz)；2.45(1.5H，s)；2.50(1.5H，s)；3.54(0.5H, dq, J =4.0, 9.8 Hz); 3.70(0.5H, dq, J =4.0, 9.8 Hz); 5.43(0.5H, s), 5.46(0.5H, s); 7.12(0.5H, s); 7.15(0.5H, s); 7.17(0.5H, s); 7.18(0.5H, s); 8.04(0.5H, s); 8.08(0.5H, s). MS ESI: m/z (relative intensity): m + H, 317.2(100). 24.42- (N- (cis-2-methylcyclohexyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine

¹H NMR (400MHz，CDCl₃)：δ0.93(3H，d，J=7.2Hz)；1.22-1.41(3H，m)；

1.48-1.68(4H，m)；1.76-1.82(1H，m)；1.94-1.99(1H，m)；2.48(1.5H，s)；2.52(1.5H，s)；

4.15(0.5H，m)；4.29(0.5H，m)；5.65(0.5H，d，J=7.6Hz)，5.73(0.5H，d，J=7.6Hz)；7.16(1H，

s); 7.21(1H, s); 8.04(0.5H, s); 8.10(0.5H, s.) MS SEI m/z (relative intensity): m + H is the sum of the total weight of the alloy,

317.2(100)

24.52- (N- (trans-2-methyl-4-cyclohexenyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine

¹H NMR (400MHz，CDCl₃)：δ 0.93(1.5H，d，J=6.8Hz)；1.00(1.5H，d，

J=6.8Hz)；1.22(1H，m)；1.83-1.88(1H，m)；1.93-2.00(1H，m)；2.12(1H，m)2.27(1H，m)；

2.44(1.5H，s)；2.49(1.5H，s)；3.93(0.5H，dq，J=1.2，7.2Hz)；4.08(0.5H，dq J=1.2，7.2Hz)；

5.51(0.5H，d，J=7.0Hz)，5.60(1.5H，m)；5.68(0.5H，m)；7.13(1H，s)；7.16(1H，s)；

8.00(0.5H, s); 8.07(0.5H, s). MS ESI: m/z (relative intensity): m + H, 315.2(100).

24.62- (N- (cis-2-methyl-4-cyclohexenyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine

¹H NMR (400MHz，CDCl₃)：δ0.96(3H，d，J=6.8Hz)；1.26(1H，m)；1.84-

1.92(1H，m)；2.10-2.18(1H，m)；2.27(1H，m)2.42(1H，m)；2.47(1.5H，s)：2.51(1.5H，s)；

4.32(0.5H，m)；4.47(0.5H，m)；5.63(1H，s)，5.72(1H，s)；5.79(0.5H，d，J=9.0Hz)；

5.88(0.5H，d，J=9.0Hz)；7.13(0.5H，s)；7.15(0.5H，s)；7.17(0.5H，s)；7.21(0.5H，s)；

8.03(0.5H, s); 8.08(0.5H, s). M ESI: m/z (relative intensity): m + H, 315.2(100).

24.72- (N- (trans-3-methylcyclohexyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃)：δ0.93(1.5H，d，J=6.5Hz)；0.96(0.5H，d，J=6.5Hz)；1.01-1.12(1H，m)；1.33-1.41(1H，m)；1.45-1.54(1H，m)；1.60-1.83(5H，m)；2.40(1.5H，s)；2.49(1.5H，s)；2.50(1.5H，s)；2.56(1.5H，s)；4.19(0.5H，m)；4.32(0.5H，m)；5.98(0.5H，d，J=6.0Hz)，6.03(0.5H，d，J=6.0Hz)；6.88(1H，s)；6.96(1H，s).MS ESI：m/z

(relative intensity): m + H, 331.2(100).

24.82- (N-cis-3-methylcyclohexyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃)：δ0.90(3H，d，J=6.5Hz)；1.08(1H，m)；1.29-1.38(1H，m); 1.42-1.52(1H, m); 1.60-1.70(1H, m); 1.76(1H, m); 1.92-2.03(4H, m); 2.36(1.5H, s); 2.46(1.5H, s); 2.49(1.5H, s); 2.54(1.5H, s); 3.73(0.5H, m); 3.91(0.5H, m); 6.06(0.5H, bs), 6.22(0.5H, bs); 6.85(1H, s); 6.93(1H, s). MS ESI: m/z (relative intensity): m + H, 331.2(100). 24.92-Cyclohexylamino-4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃): δ 1.39(2H, m); 1.53(2H, m); 1.74(2H, m); 1.90(2H, m); 2.15(2H, m); 2.58(1.5H, s); 2.65(1.5H, s); 2.67(1.5H, s); 2.72(1.5H, s); 3.95(0.5H, m); 4.10(0.5H, m); 5.68(0.5H, d, J =4.0Hz), 5.79(0.5H, d, J =4.0 Hz); 7.03(1H, s); 7.12(1H, s). MS ESI: m/z (relative intensity): m + H, 317.2(100). 24.102-Cyclohexylmethylamino-4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃): δ 0.93-1.03(2H, m); 1.12-1.28(3H, m); 1.50-1.61(1H, m); 1.53-1.80(5H, m); 2.44(1.5H, s); 2.50(1.5H, s); 3.31(2H, dt, J =6.5, 24 Hz); 5.88(0.5H, bs); 6.40(0.5H, bs); 7.10(0.5H, s); 7.13(1.5H, s), 7.19(0.5H, s); 8.07(1H, s). MS ESI m/z (relative intensity): m + H, 317.2(100) 24.112-Cyclohexylmethylamino-4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃): δ 0.96(2H, m); 1.14-1.30(4H, m); 1.55(1H, m); 1.67(1H, m); 1.67-1.80(5H, m); 2.39(1.5H, s); 2.47(1.5H, s); 2.49(1.5H, s); 2.54(1.5H, s); 3.25(0.5H, t, J =6.3 Hz); 3.35(0.5H, t, J =6.3 Hz); 6.02(1H, bs), 6.86(1H, s); 6.95(1H, s). MSESIm/z (relative intensity): m + H, 331.2(100). 24.122-cyclopentylamino-4- (2-methylimidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400MHz，CDCl₃)：δ1.21(1H, m); 1.49(1H, m); 1.60-1.78(4H, m); 2.38(1.5H, s); 2.47(1.5H, s); 2.55(1.5H, s); 4.21(0.5H, m); 437(0.5H, m); 5.86(0.5H, d, J =4.2 Hz); 5.98(0.5H, d, J =4.2 Hz); 6.86(1H, s); 6.95(1H, s). MS ESI: m/z (relative intensity): m + H, 303.2(100). 24.132- (N- (4-methylcyclohexyl) amino) -4- (imidazol-1-yl) -6-methyl-5-nitropyrimidine¹H NMR (400 MHz，CDCl₃): δ 1.03(1.5H, d, J =6.2 Hz); 1.06(1.5H, d, J =6.2 Hz); 1.08(1H, m); 1.15-1.28(1H, m); 1.30-1.42(2H, m); 1.43-1.55(1H, m); 1.70-1.84(4H, m); 1.85-1.96(2H, m); 2.18(1H, m); 2.54(1.5H, s); 2.64(3H, s); 2.69(1.5H, s); 3.84(0.5H, m); 4.02(0.5H, m); 5.97(0.5H, bs), 6.11(0.5H, bs); 7.01(1H, s); 7.10(1H, s). MS ESI: m/z (relative intensity): m + H, 331.1(100).

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the present invention has been described in detail, it is to be understood that the same is by way of illustration and example for purposes of clarity of understanding, and it will be apparent to those skilled in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims.

Claims (78)

1. A compound having the formula:wherein

X is selected from-NR³R⁴、-OR³、-SR³Aryl, alkyl and aralkyl groups;

y is selected from the group consisting of a covalent bond, -N (R)⁶) -, -O-, -S-, -C (= O) -and alkylene;

R¹and R²Independently selected from hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl, -S-Aryl, -NO₂、-NR⁷R⁸、-C(O)R⁹、-CO₂R¹⁰、-C(O)NR⁷R⁸-N(R⁷)C(O)R⁹、-N(R⁷)CO₂R¹¹、-N(R⁹)C(O)NR⁷R⁸、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen and-N (R)⁷)S(O)_mR¹¹；

R³And R⁴Independently selected from hydrogen, alkyl, aryl or arylalkyl, or, R³And R⁴And the nitrogen atom to which they are attached form an aromatic or non-aromatic ring containing 1 to 3 heteroatoms in the 5-, 6-or 7-membered ring;

R⁵selected from alkyl, aryl, aralkyl and bicyclic fused aryl-cycloalkyl;

R⁶selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl; or with R⁵And R⁵And R⁶The attached nitrogen atoms combine to form a 5-, 6-, 7-, or 8-membered ring;

R⁷and R⁸Each independently selected from hydrogen, alkyl, aryl or arylalkyl, or R⁷And R⁸And the nitrogen atom to which they are attached are joined together to form a 4-, 5-, 6-, 7-, or 8-membered ring containing 1-3 heteroatoms in the ring;

R⁹and R¹⁰Independently selected from hydrogen, alkyl, aryl and arylalkyl;

R¹¹selected from alkyl, aryl and arylalkyl;

m is an integer of 1 to 2;

n is an integer of 1 to 3;

optionally, R is¹And R²Connection, R¹And R³Connection, R³And N³Connection, R⁵And N³Connection, R⁵And N¹Is linked to R²And N¹The linkage forms a 5-, 6-, 7-or 8-membered ring,

said compound having a molecular weight of about 150-750, with the proviso that when Y is a bond, R⁵Not an imidazole ring.

2. The compound of claim 1, wherein R¹Is selected from-NO₂、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, fluoroalkyl, -C (O) R⁹、-CO₂R¹⁰and-C (O) NR⁷R⁸；R²Selected from the group consisting of hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl and-S-aryl.

3. The compound of claim 2, wherein X is-NR³R⁴Y is selected from-N (R)⁶) -, -O-and-S; r²Selected from the group consisting of hydrogen, alkyl, -S-alkyl, -O-alkyl and halogen.

4. A compound according to claim 3, wherein R¹Is selected from-CF₃、-S(O)_mNR⁷R⁸、-CO₂R¹⁰-CN and-NO₂，R²Selected from the group consisting of hydrogen, (lower) alkyl, -O- (lower) alkyl and-S- (lower) alkyl.

5. The compound of claim 4, wherein Y is-N (R)⁶) -or-O-, R¹is-NO₂，R²Is hydrogen or (C)₁-C₄) An alkyl group.

6. The compound of claim 5, wherein R³And R⁴And the nitrogen atoms to which they are attached are joined together to form a 5-membered ring.

7. The compound of claim 6, wherein said 5-membered ring contains two nitrogen atoms.

8. The compound according to claim 7, wherein said 5-membered ring is a substituted or unsubstituted imidazole ring.

9. The compound of claim 8, wherein Y is-N (R)⁶) -, wherein R⁶Is hydrogen or lower alkyl, R⁵Selected from alkyl, aryl, arylalkyl and bicyclic fused aryl-cycloalkyl.

10. The compound of claim 9, wherein R⁵Selected from cycloalkyl, heterocycloalkyl, aryl, arylalkyl and bicyclic fused aryl-cycloalkyl, R⁶Selected from hydrogen, methyl, ethyl and propyl, -NR³R⁴Selected from imidazol-1-yl, 2-methylimidazol-1-yl, 2, 4-dimethylimidazol-1-yl, 2-ethylimidazol-1-yl, 2- (1-propyl) imidazol-1-yl, 2-ethyl-4-methylimidazol-1-yl and 2- (2-propyl) imidazol-1-yl.

11. The compound of claim 10, wherein R6 is selected from the group consisting of hydrogen, methyl, and ethyl, -NR³R⁴Selected from imidazol-1-yl, 2-methylimidazol-1-yl, 2, 4-dimethylimidazol-1-yl, and 2-ethylimidazol-1-yl, R⁵Is an optionally substituted group selected from:

12. the compound of claim 11, wherein R⁵Selected from:

13. the compound of claim 12, wherein said compound is selected from the group consisting of:

14. the compound of claim 12, wherein said compound is selected from the group consisting of:

15. the compound of claim 12, wherein said compound is selected from the group consisting of:

16. the compound according to claim 12, selected from the group consisting of:

17. the compound of claim 1, having the formula:

wherein R is¹²Selected from hydrogen, methyl and ethyl; r⁵Selected from:

18. the compound of claim 17, wherein R¹²Is methyl.

19. The compound of claim 18, wherein R⁵Selected from:

20. the compound of claim 18, wherein R⁵Selected from:

21. the compound of claim 18, wherein R⁵Selected from:

22. the compound of claim 18, wherein R⁵Selected from:

23. the compound of claim 18, wherein R⁵Selected from:

24. a pharmaceutical composition comprising a pharmaceutically or diagnostically acceptable excipient and a compound of the formula:wherein

X is selected from-NR³R⁴、-OR³、-SR³Aryl, alkyl and aralkyl groups;

y is selected from the group consisting of a covalent bond, -N (R)⁶) -, -O-, -S-, -C (= O) -and alkylene;

R¹and R²Independently selected from hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl, -S-aryl, -NO₂、-NR⁷R⁸、-C(O)R⁹、-CO₂R¹⁰、-C(O)NR⁷R⁸-N(R⁷)C(O)R⁹、-N(R⁷)CO₂R¹¹、-N(R⁹)C(O)NR⁷R⁸、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen and-N (R)⁷)S(O)_mR¹¹；

R³And R⁴Independently selected from hydrogen, alkyl, aryl or arylalkyl, or, R³And R⁴And the nitrogen atom to which it is attached, form a 5-, 6-or 7-membered aromatic or non-aromatic ring containing 1-3 endocyclic heteroatoms;

R⁵selected from alkyl, aryl, aralkyl and bicyclic fused aryl-cycloalkyl;

R⁶selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl; or with R⁵And R⁵And R⁶The attached nitrogen atoms combine to form a 5-, 6-, 7-, or 8-membered ring;

R⁷and R⁸Each independently selected from hydrogen, alkyl, aryl or arylalkyl, or R⁷And R⁸And the nitrogen atom to which they are attached are joined together to form a 4-, 5-, 6-, 7-, or 8-membered ring containing 1-3 heteroatoms in the ring;

R⁹and R¹⁰Independently selected from hydrogen, alkyl, aryl and arylalkyl;

R¹¹selected from alkyl, aryl and arylalkyl;

m is an integer of 1 to 2;

n is an integer of 1 to 3;

optionally, R is¹And R²Connection, R¹And R³Connection, R³And N³Connection, R⁵And N³Connection, R⁵And N¹Is linked to R²And N¹The linkage forms a 5-, 6-, 7-or 8-membered ring,

said compound having a molecular weight of about 150-750, with the proviso that when Y is a bond, R⁵Not an imidazole ring.

25. The composition of claim 24, wherein R¹Is selected from-NO₂、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, fluoroalkyl, -C (O) R⁹、-CO₂R¹⁰and-C (O) NR⁷R⁸；R²Selected from the group consisting of hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl and-S-aryl.

26. The composition of claim 25, wherein X is-NR³R⁴Y is selected from-N (R)⁶) -, -O-and-S-; and-NO₂，R²Selected from the group consisting of hydrogen, alkyl, -O-alkyl-S-alkyl, and halogen.

27. The compound of claim 26, whereinR¹Is selected from-CF₃、-S(O)_mNR⁷R⁸、-CO₂R¹⁰-CN and-NO₂，R²Selected from the group consisting of hydrogen, (lower) alkyl, -O- (lower) alkyl and-S- (lower) alkyl.

28. The composition of claim 27, wherein Y is-N (R)⁶) -or-O-, R¹is-NO₂，R²Is hydrogen or (C)₁-C₄) An alkyl group.

29. The composition of claim 28, wherein R³And R⁴And the nitrogen atoms to which they are attached are joined together to form a 5-membered ring.

30. The composition of claim 29, wherein said 5-membered ring contains two nitrogen atoms.

31. The composition of claim 30, wherein said 5-membered ring is a substituted or unsubstituted imidazole ring.

32. The composition of claim 31, wherein Y is-N (R)⁶) -, wherein R⁶Is hydrogen or lower alkyl, R⁵Selected from alkyl, aryl, arylalkyl and bicyclic fused aryl-cycloalkyl.

33. The composition of claim 32, wherein R⁵Selected from cycloalkyl, heterocycloalkyl, aryl, arylalkyl and bicyclic fused aryl-cycloalkyl, R⁶Selected from hydrogen, methyl, ethyl and propyl, -NR³R⁴Selected from imidazol-1-yl, 2, 4-dimethylimidazol-1-yl, 2-methylimidazol-1-yl, 2-ethylimidazol-1-yl, 2- (1-propyl) imidazol-1-yl, 2-ethyl-4-methylimidazol-1-yl and 2- (2-propyl) imidazol-1-yl.

34. The composition of claim 33, wherein R⁶Selected from hydrogen, methyl and ethyl, -NR³R⁴Selected from imidazol-1-yl, 2-methylimidazol-1-yl, 2, 4-dimethylimidazol-1-yl, and 2-ethylimidazol-1-yl, R⁵Is an optionally substituted group selected from:

35. the composition of claim 34, wherein R⁵Selected from:

36. the composition of claim 35, wherein R⁵Selected from:

37. the composition of claim 35, wherein R⁵Selected from:

38. the composition of claim 35, wherein R⁵Selected from:

39. the composition of claim 35, wherein R⁵Selected from:

40. the composition of claim 1, said compound having the formula:

wherein R12 is selected from hydrogen, methyl and ethyl; r⁵Is selected from：

41. The composition of claim 40, wherein R¹²Is methyl.

42. The composition of claim 41, wherein R⁵Selected from:

43. the composition of claim 41, wherein R⁵Selected from:

44. the composition of claim 41, wherein R⁵Selected from:

45. the composition of claim 41, wherein R⁵Selected from:

46. the composition of claim 41, wherein R⁵Selected from:

47. a method of preventing or inhibiting a viral infection in a mammal comprising administering to said mammal a viral infection inhibiting amount of a compound of the formula:wherein

X is selected from-NR³R⁴、-OR³、-SR³Aryl, alkyl andaralkyl group;

y is selected from the group consisting of a covalent bond, -N (R)⁶) -, -O-, -S-, -C (= O) -and alkylene;

R¹and R²Independently selected from hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl, -S-aryl, -NO₂、-NR⁷R⁸、-C(O)R⁹、-CO₂R¹⁰、-C(O)NR⁷R⁸-N(R⁷)C(O)R⁹、-N(R⁷)CO₂R¹¹、-N(R⁹)C(O)NR⁷R⁸、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, halogen and-N (R)⁷)S(O)_mR¹¹；

R³And R⁴Independently selected from hydrogen, alkyl, aryl or arylalkyl, or, R³And R⁴And the nitrogen atom to which it is attached, form a 5-, 6-or 7-membered aromatic or non-aromatic ring containing 1-3 endocyclic heteroatoms;

R⁵selected from alkyl, aryl, aralkyl and bicyclic fused aryl-cycloalkyl;

R⁶selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl; or with R⁵And R⁵And R⁶The attached nitrogen atoms combine to form a 5-, 6-, 7-, or 8-membered ring;

R⁷and R⁸Each independently selected from hydrogen, alkyl, aryl or arylalkyl, or R⁷And R⁸And the nitrogen atom to which they are attached are joined together to form a 4-, 5-, 6-, 7-, or 8-membered ring containing 1-3 heteroatoms in the ring;

R⁹and R¹⁰Independently selected from hydrogen, alkyl, aryl and arylalkyl;

R¹¹selected from alkyl, aryl and arylalkyl;

m is an integer of 1 to 2;

n is an integer of 1 to 3;

optionally, R is¹And R²Connection, R¹And R³Connection, R³And N³Connection, R⁵And N³Connection, R⁵And N¹Is linked to R²And N¹The linkage forms a 5-, 6-, 7-or 8-membered ring,

the molecular weight of the compound is about 150-750.

48. The method of claim 47 wherein the compound is administered in combination with a supplemental antiviral compound selected from the group consisting of ganciclovir, foscarnet and cidofovir.

49. The method of claim 47, wherein the compound is administered in combination with an anti-HIV compound.

50. The method of claim 47, wherein the mammal is at risk for immunization.

51. The method of claim 47, wherein said administering is oral.

52. The method of claim 47, wherein said administering is topical.

53. The method of claim 47, wherein said administering is prophylactic, for protecting a patient undergoing organ transplantation from viral infection.

54. The method of claim 47, wherein the viral infection produces a disease selected from the group consisting of CMV-retinitis, CMV-mononucleosis, CMV-pneumonia, and CMV-hepatitis.

55. The method of claim 47, wherein said administering is parenteral.

56. The method of claim 1, wherein R¹Is selected from-NO₂、-S(O)_mNR⁷R⁸、-S(O)_nR⁹-CN, fluoroalkyl, -C (O) R⁹、-CO₂R¹⁰and-C (O) NR⁷R⁸；R²Selected from the group consisting of hydrogen, alkyl, -O-alkyl, -S-alkyl, aryl, arylalkyl, -O-aryl and-S-aryl.

57. The method of claim 56, wherein X is-NR³R⁴Y is selected from-N (R)⁶) -, -O-and-S; r²Selected from the group consisting of hydrogen, alkyl, -O-alkyl, -S-alkyl and halogen.

58. The method of claim 57, wherein R¹Is selected from-CF₃、-S(O)_mNR⁷R⁸、-CO₂R¹⁰-CN and-NO₂，R²Selected from the group consisting of hydrogen, (lower) alkyl, -O- (lower) alkyl and-S- (lower) alkyl.

59. The method of claim 58, wherein Y is-N (R)⁶) -or-O-, R¹is-NO₂，R²Is hydrogen or (C)₁-C₄) An alkyl group.

60. The method of claim 59, wherein R³And R⁴And the nitrogen atoms to which they are attached are joined together to form a 5-membered ring.

61. The method of claim 60, wherein the 5-membered ring contains two nitrogen atoms.

62. The method of claim 61, wherein said 5-membered ring is a substituted or unsubstituted imidazole ring.

63. The method of claim 62, wherein Y is-N (R)⁶)-，Wherein R is⁶Is hydrogen or lower alkyl, R⁵Selected from alkyl, aryl, arylalkyl and bicyclic fused aryl-cycloalkyl.

64. The method of claim 63, wherein R⁵Selected from cycloalkyl, heterocycloalkyl, aryl, arylalkyl and bicyclic fused aryl-cycloalkyl, R⁶Selected from hydrogen, methyl, ethyl and propyl, -NR³R⁴Selected from imidazol-1-yl, 2-methylimidazol-1-yl, 2, 4-dimethylimidazol-1-yl, 2-ethylimidazol-1-yl, 2- (1-propyl) imidazol-1-yl, 2-ethyl-4-methylimidazol-1-yl and 2- (2-propyl) imidazol-1-yl.

65. The method of claim 64, wherein R⁶Selected from hydrogen, methyl and ethyl, -NR³R⁴Selected from imidazol-1-yl, 2-methylimidazol-1-yl, 2, 4-dimethylimidazol-1-yl, and 2-ethylimidazol-1-yl, R⁵Is an optionally substituted group selected from:

66. the method of claim 65, wherein R⁵Selected from:

67. the method of claim 66, wherein R⁵Selected from:

68. the method of claim 66, wherein R⁵Selected from:

69. the method of claim 66, wherein R⁵Is selected from：

70. The method of claim 66, wherein R⁵Selected from:

71. the method of claim 1, wherein the compound has the formula:

wherein R is¹²Selected from hydrogen, methyl and ethyl; r⁵Selected from:

72. the method of claim 71, wherein R¹²Is methyl.

73. The method of claim 72, wherein R⁵Selected from:

74. the method of claim 72, wherein R⁵Selected from:

75. the method of claim 72, wherein R⁵Selected from:

76. the method of claim 72, wherein R⁵Selected from:

77. the method of claim 72, wherein R⁵Selected from:

78. the method of claim 47, wherein the viral infection is a cytomegalovirus infection.