WO2017109088A1 - Pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease - Google Patents

Abstract

The present invention relates to a compound having the general formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, (I) which are useful in treating, ameloriating or preventing a viral disease, in particular influenza.

Description

Pyrimidone derivatives

and their use in the treatment, amelioration or prevention of a viral disease

Field of the invention

The present invention relates to a compound having the general formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate. enantiomer. or diastereomer or mixture thereof,

(i) which is useful in treating, ameloriating or preventing a viral disease, in particular influenza.

Background of the invention

Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. Based on antigenic differences of viral nucleocapsid and matrix proteins, influenza viruses are further divided into three types named influenza A, B. and C viruses. All influenza viruses have an envelope, and their genomes are composed of eight or seven single-stranded, negative-sensed RNA segments. These viruses cause respiratory diseases in humans and animals with a significant morbidity and mortality. The influenza pandemic of 1918, Spanish flu, is thought to have killed up to 100 million people. The reassortment of avian flu RNA fragments with circulating human viruses caused the other two pandemics in 1957 H2N2 "Asian influenza" and 1968 H3N2 "Hong Kong influenza". Now, people around the world face the challenges of influenza from various angles: seasonal influenza epidemics affect about 5-15% of the world's population with an annual mortality ranging from 250,000 to 500,000. Infections of avian flu strains, mostly H5N1 , have been reported in many Asian countries. Although no frequent human-to- human spreading has been observed, avian flu infection is serious and associated with a high mortality of up to 60% of infected persons. In 2009, an H1 N1 swine flu infection appeared initially in North America and evolved into a new pandemic. Currently, seasonal trivalent influenza vaccines and vaccines specific for H5N1 or swine flu are either available or in the phase of clinical trials. The prophylaxis is an effective method, at least in some populations, for preventing influenza virus infection and its potentially severe complications. However, continuous viral antigenicity shifting and drafting makes future circulating flu strains unpredictable. Furthermore, due to the limitations of mass production of vaccines within a relatively short period of time during a pandemic, other anti-flu approaches such as anti-flu drugs are highly desirable. On the market, there are two types of anti-flu drugs available: neuraminidase inhibitors such as oseltamivir phosphate (Tamilflu) and zanamivir (Relenza); and 2 ion channel blockers such as amantadine and rimantadine. To increase the effectiveness of current anti-flu drugs and prevent or attenuate appearance of drug-resistant viruses it is invaluable to discover compounds with new mechanisms of anti-influenza action that can be used as a therapeutic or prophylactic agent alone or combined with current anti-flu drugs.

!t appears realistic that H5N1 and related highly pathogenic avian influenza viruses could acquire mutations rendering them more easily transmissible between humans. In addition, the new A/H1 N1 could become more virulent and only a singie point mutation would be enough to confer resistance to oseltamivir (Neumann et al._: Nature 2009, 18, 459(7249), 931-939). This has already happenend in the case of some seasonal H1 1 strains which have recently been Identified (Dharan et al., The Journal of the American Medical Association, 2009, 301 (10), 1034-1041 ; Moscona et al. , The New England Journal of Medicine 2009, 360(10), 953-956). The unavoidable delay in generating and deploying a vaccine could in such cases be catastrophically costly in human lives and societal disruption.

In view of the currently elevated risk of infections of pandemic H1 N1 swine flu, highly pathogenic H5N 1 avian flu, and drug-resistant seasonal flu, the development of new anti- influenza drugs has again become high priority. In many cases, the development of anti-viral medicament may be facilitated by the availability of structural data of viral proteins. The availability of structural data of influenza virus surface antigen neuraminidase has, e.g. led to the design of improved neuraminidase inhibitors (Von Itzstein et al.. Nature 1993, 363, 418-423). Examples of active compounds which have been developed based on such structural data include zanamivir (Glaxo) and oseltamivir (Roche). However, although these medicaments may lead to a reduction of the duration of the disease, there remains an urgent need for improved medicaments which may also be used for curing these diseases. Adamantane-containing compounds such as amantadine and rimantadine are another example of active compounds which have been used in order to treat influenza. However, they often lead to side effects and have been found to be ineffective in a growing number of cases (Magden et al., Appl. Microbiol. Biotechnol. 2005, 66, 612-621 ). More unspecific viral drugs have been used for the treatment of influenza and other virus infections (Eriksson et ai., Antimicrob. Agents Chemother. 1977, 11 , 946-951 ), but their use Is limited due to side effects (Furuta et al., Antimicrobial Agents and Chemotherapy 2005, 981-

986). Influenza viruses being Orthomyxoviridae. as described above, are negative-sense ssRNA viruses. Other examples of viruses of this group include Arenaviridae, Bunyaviridae, Ophioviridae, Deltavirus, Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae and Nyamiviridae. These viruses use negative-sense RNA as their genetic material. Single- stranded RNA viruses are classified as positive or negative depending on the sense or polarity of the RNA. Before transcription, the action of an RNA polymerase is necessary to produce positive RNA from the negative viral RNA. The RNA of a negative-sense virus alone is therefore considered non-infectious.

The trimeric viral RNA-dependent RNA polymerase, consisting of polymerase basic protein 1 (PB1 ), polymerase basic protein 2 (PB2) and polymerase acidic protein (PA) subunits, is responsible for the transcription and replication of the viral RNA genome segments Structural data of the two key domains of the polymerase, the mRNA cap-binding domain in the PB2 subunit (Guilligay et al. , Nature Structural & Molecular Biology 2008. 15(5). 500-506) and the endonuclease-active site in the PA subunit (Dias et al., Nature 2009, 458, 914-918) has become available. The ribonucleoprotein represents the minimal transcriptional and replicative machinery of an influenza virus. During transcription, the viral RNA polymerase synthesizes capped and polyadenylated mRNA using 5^' capped RNA primers. During replication, the viral RNA polymerase generates a complementary RNA (cRNA) replication intermediate, a full-length complement of the vRNA that serves as a template for the synthesis of new copies of vRNA. The nucleoprotein is also an essential component of the viral transcriptional machinery The polymerase complex which is responsible for transcribing the single-stranded negative-sense viral RNA into viral mRNAs and for replicating the viral mRNAs. is thus a promising starting points for developing new classes of compounds which may be used in order to treat influenza (Fodor, Acta virologica 2013, 57, 1 13-122). This finding is augmented by the fact that the polymerase complex contains a number of functional active sites which are expected to differ to a considerable degree from functional sites present in proteins of cells functioning as hosts for the virus (Magden et al., Appl. Microbiol. Biotechnol. 2005, 66, 612-621 ). As one example, a substituted 2.6-diketopiperazine has been identified which selectively inhibits the cap- dependent transcriptase of influenza A and B viruses without having an effect on the activities of other polymerases (Tomassini et al.. Antimicrob Agents Chemother. 1996, 40, 1 189-1 193). In addition, it has been reported that phosphorylated 2'-deoxy-2'-fluoroguanosine reversibly inhibits influenza virus replication in chick embryo cells. While primary and secondary transcription of influenza virus RNA were blocked even at low concentrations of the compound, no inhibition of cell protein synthesis was observed even at high compound concentrations (Tisdale et al., Antimicrob. Agents Chemother. 1995, 39. 2454-2458).

WO 2005/087766 discloses certain pyridopyrazine- and pyrimidopyrazine-dione compounds which are stated to be inhibitors of HIV integrase and inhibitors of HIV replication. The compounds are described as being useful in the prevention and treatment of infection caused by HIV and in the prevention, delay in the onset, and treatment of AIDS.

WO 2010/147068 also discloses compounds which allegedly have antiviral activities, especially inhibiting activity for influenza viruses.

WO 2012/039414 relates to compounds which are described as having antiviral effects, particularly having growth inhibitory activity on influenza viruses. WO 2014/108406 discloses certain pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease.

It is an object of the present invention to identify further compounds which are effective against viral diseases and which have improved pharmacological properties.

Summary of the invention Accordingly, in a first embodiment, the present invention provides a compound having the general formula (I).

It is understood that throughout the present specification the term "a compound having the general formula (I)" encompasses pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, codrugs, cocrystals, tautomers. racemates, enantiomers, or diastereomers or mixtures thereof unless mentioned otherwise.

A further embodiment of the present invention relates to a pharmaceutical composition comprising a compound having the general formula (I) and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s). The compounds having the general formula (I) are useful for treating, ameliorating or preventing viral diseases. Detailed description of the invention

Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (lUPAC Recommendations)", Leuenberger. H.G.W, Nagel. B. and Kdlbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as 'comprises" and "comprising", will be understood to impiy the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps In the following passages different aspects of the invention are defined in more detail Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.). whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior Invention. Definitions

The term "alkyl" refers to a saturated straight or branched carbon chain. The term "cycloalkyl" represents a cyclic version of "alkyl". The term "cycloalkyl" is also meant to include bicyclic, tricyclic and polycyclic versions thereof. Unless specified otherwise, the cycloalkyl group can have 3 to 12 carbon atoms.

The term "heterocycloalky!" represents a version of "cycloalkyl" in which one or more CH₂ groups are independently replaced by O, NH, N(Ci_-6-alkyl) or S. Unless specified otherwise, the heterocycloalkyl group can have 3 to 12 carbon atoms and 1 to 3 atoms selected from O, N and S.

"Hal" or "halogen" represents F. CI, Br and I.

"3- to 7-membered carbo- or heterocyclic ring" refers to a three-, four-, five-, six- or seven- membered ring wherein none, one or more of the carbon atoms in the ring have been replaced by 1 or 2 (for the three-membered ring), 1 , 2 or 3 (for the four-membered ring), 1 , 2, 3, or 4 (for the five-membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) and 1 , 2. 3, 4. 5 or 6 (for the seven-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S.

The term "aryl" preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphthyl or anthracenyl, preferably phenyl.

The term "heteroaryl" preferably refers to a five-or six-membered aromatic ring wherein one or more of the carbon atoms in the ring have been replaced by 1 , 2, 3, or 4 (for the five- membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S. Examples of the heteroaryl group include pyrrole, pyrrolidine, oxolane. furan. imidazolidine. imidazole, pyrazole, oxazolidine, oxazole, thiazole, piperidine, pyridine, morpholine, piperazine, and dioxolane. The term "hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring" refers to any group having 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and 2 as long as the group contains at least one ring. The term is also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one ring is present, they can be separate from each other or be annelated. The ring(s) can be either carbocyclic or heterocyclic and can be saturated, unsaturated or aromatic. The carbon atoms and heteroatoms can either all be present in the one or more rings or some of the carbon atoms and/or heteroatoms can be present outside of the ring, e.g., in a linker group (such as -(CH₂)_P- with p = 1 to 6). Examples of these groups include -(optionally substituted C₃_₇ cycloalkyl), -(optionally substituted aryl) wherein the aryl group can be, for example, phenyl, -(optionally substituted biphenyl), adamantyl, -(C₃.₇ cycloalkyl)-aryl as well as the corresponding compounds with a linker. if a compound or moiety is referred to as being "optionally substituted", It can in each instance include 1 or more of the indicated substituents, whereby the substituents can be the same or different.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Suitable pharmaceutically acceptable salts include acid addition salts which may, for example, be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g. , sodium or potassium salts); alkaline earth metal salts (e g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, aikyi sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate. alginate, ascorbate, aspartate, benzenesu!fonate, benzoate, bicarbonate, bisulfate, bitartrate. borate, bromide, butyrate. calcium edetate, camphorate, camphorsulfonate, camsylate. carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate. edisylate. estolate esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate. glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate. hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide. 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate. napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate. 3-phenylpropionate. phosphate/diphosphate. picrate. pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. ScL 66, pp. 1-19 (1977)).

When the compounds of the present invention are provided in crystalline form, the structure can contain solvent molecules. The solvents are typically pharmaceutically acceptable solvents and include, among others, water (hydrates) or organic solvents. Examples of possible solvates include ethanolates and iso-propanolates.

The term "codrug" refers to two or more therapeutic compounds bonded via a covalent chemical bond. A detailed definition can be found, e.g., in N. Das et al., European Journal of Pharmaceutical Sciences, 41 , 2010, 571-588. The term "cocrystal" refers to a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components co-exist as a stoichiometric or non-stoicho etric ratio of a target molecule or ion (i.e., compound of the present invention) and one or more neutral molecular cocrystal formers. A detailed discussion can be found, for example, in Ning Shan et al.. Drug Discovery Today, 13(9/10), 2008, 440-446 and in D. J. Good et al.. Cryst. Growth Des., 9(5), 2009, 2252-2264.

The compounds of the present invention can also be provided in the form of a prodrug. namely a compound which is metabolized in vivo to the active metabolite. Suitable prodrugs are, for instance, esters. Specific examples of suitable groups are given, among others, in US 2007/0072831 in paragraphs [0082] to [01 18] under the headings prodrugs and protecting groups. Preferred examples of the prodrug include compounds in which R¹⁰ is replaced by

P(0)(0)OR¹⁹; C(0)OR^1s; C(0)R¹⁹; or C-R¹⁹; wherein R¹⁹ is selected from

(with n = 1 to 30), C.₆aikyi-C(0)OR, and C₅.-₀aryl-C(O)OR. The group R is H or d_₆ alkyl.

Compounds having the general formula (I)

The present invention provides a compound having the general formula (I).

The present invention provides a compound having the general formuia (I) in which the following definitions apply R¹⁰ is -H. -(optionally substituted C^₆ aikyl group) or -C(0)-(optionaliy substituted Ci..₆ alkyl group). R¹⁰ is preferably -H, -C(0)-C-,_s alkyl group, wherein the alkyl group can be optionally substituted by one or more halogen atoms, or a -C _;_₆ alkyl group which may optionally be substituted by one or more halogen atoms. More preferably, R¹⁰ is -H, -C, alky! group or -C(0)-C₁_₆ alkyl group. Even more preferably R¹⁰ is -H.

R ¹ is -H, -OH, -CH₂-OH, a -Ci_e. alkyl group, or a -Ci_₆ alkyl group which is substituted by one or more halogen atoms; preferably R¹¹ is -H, or -OH, -CH₂-OH.

R¹² is -H, -OH, -CH₂-OH, a -C,_6 alkyl group, or a -C e alkyl group which is substituted by one or more halogen atoms; preferably R¹² is -H.

In one embodiment R ¹ and R¹² can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring. is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring). Preferably, the at least one ring is aromatic such as an aryl or heteroaryl ring. More preferably, R^{1 '1} is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms and which contains at least two rings, wherein the hydrocarbon group can be optionally substituted. Even more preferably, at least one of the at least two rings is aromatic such as an aryl or heteroaryl ring. Preferred examples of R¹³ can be selected from the group consisting of

More preferably R is selected from

X is absent, CH₂, NH, C(0)NH, S or O. Furthermore,

Y is CH₂.

In an alternative embodiment, X and Y can be joined together to form an annulated, carbo- or heterocylic 3- to 8-membered ring which can be saturated or unsaturated. Specific examples of X-Y include -CH₂-, -CH₂-CH₂-. -0-, and -NH-.

Z is O or S.

R is independently selected from. -C-__f; alkyl. -d-,-, alkenyl, -C,__e a!kinyl, -CF₃, -halogen. -CN, -OH. -CH₂C(0)OH, -CH₂C(0)OC- _Λ alkyl. -O-C, ₆ alkyl, -Ca_₇ cycloalkyl. -(CH₂)₁_₄-0-C₁^₆ alkyl, -(CH₂)_1-4-CN, -(CH₂)i-4-OH, -(CHa^-CMC^ alkyl). -C-C-0-C._₆ alkyl. -a yi, -heterocycloalkyi or -heteroaryl.

R^e is independently selected from -H, -C^ alkyl. -C-.₆ alkenyl, -C ,_e alkinyl, -CF₃, - halogen, -CN, -OH, -CH₂C(0)OH, -CH₂C(0)OC- « alkyl, -O-C-e alkyl, -C₃-7 cycloalkyl. -(CH₂),.,-0-C^_B alkyl, -(CH₂),,-CN, -(CH₂)₁_₄-OH, -(CH₂)i-4-0-(C₁_6 alkyl), -C=C-0-C₁_₆ alkyl, -aryi, -heterocycloalkyi or -heteroaryl. t is 0 to 5, preferably 0 to 3. is -H, -(optionally substituted C ₆ alkyl), -(optionally substituted C₃_₇ cycloalkyl). -(optionally substituted aryi), -(optionally substituted heterocycloalkyi). -(optionally substituted heteroaryl), -C<_₄ alkyl— (optionally substituted C₃_₇ cycloalkyl), -C_1-4 aikyl— (optionally substituted aryl), -C^ alkyl— (optionally substituted heterocycloalkyl), or -C _-4 alkyi— (optionally substituted heteroaryl). R¹⁴ is preferably -(optionally substituted Ci_₆ alkyl). R¹⁴ is more preferably selected from -CH₃. CH(CH₃)₂ and CH(CH₃)(CF₃).

R'⁷ is -R or -0,-4 aikyl— R, wherein R is selected from -XH, -COOH, -COO-(optionally substituted C_1-B alkyl), -(optionally substituted d_6 alkyl), -(optionally substituted C₃_7 cycloalkyl). -(optionally substituted aryl), -(optionally substituted heteroaryl), -(optionally substituted heterocycloalkyl), -X-(optionally substituted d-e alkyl), -X-(optiona!!y substituted C₃-₇ cycloalkyl), -X-(optionally substituted aryl),

-X-ioptiona!!y substituted heterocycloalkyl), or -X-(optional!y substituted heteroaryl), wherein X is O or S. In a preferred embodiment, R¹⁷ is -R, particularly -XH or -d-6 alkyl, wherein X is preferably O. R¹⁸ is independently selected from -d_₆ alkyl, and -C_3-.₇ cycloalkyl, preferably -d-e alkyl.

In one embodiment R¹⁷ and R '⁸ can be joined together to form an optionally substituted 3- to 7-membered carbo- or heterocyclic ring, wherein the heteroatom is, for example, chosen from N, O and S. in one embodiment R¹⁴ and R ' can be joined together to form an optionally substituted 3- to 7-membered (e.g., 5 or 6-membered) heterocyclic ring which can include one or more additional heteroatoms selected from N. O and S in addition to the nitrogen atom to which R¹⁴ is attached. This optionally substituted 3- to 7-membered heterocyclic ring may optionally be benzannulated, wherein benzannulated preferably indicates that two neighboring carbon atoms in the 3- to 7-membered heterocyclic ring are at the same time two neighboring carbon atoms in the benzene ring.

The optional substituent(s) of the optionally substituted alkyl group is one or more substituents R^a, wherein each R^a is independently selected from -C(0)-C-_₆ alkyl, -Hal, -CF₃, -CN, -COOR^**, -(CH₂)_P-OR^**, -S(Q)R^**, -S(0)₂R^**, -(CH₂)_qNR^**R***, -C(0)-NR**R*** and -NR**-C(0)-d-₆ alkyl;

The optional substituent(s) of the optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted 3- to 7-membered carbo- or heterocyclic ring and/or optionally substituted 3- to 7-membered heterocyclic ring is one or more substituents R^b, wherein each R is independently selected from -C_V6 alkyl. -C(0)-C^₆ alkyl, -Hal, -CF₃, -CN, -COOR**, -(CH₂)_q-OR^**, -S(0)R**, -S(0)₂R^**, -(CH₂)_qNR**R***, -C(0)-NR**R*^** and -NR^**-C(0)- 0,_₆ alkyl;

The optional substituent(s) of the optionally substituted hydrocarbon group is one or more substituents R^d, wherein each R^d is independently selected from -C^ alkyl, -Ci..._e alkenyl, -C _B alkinyl, -C(0)-C^₆ alkyl, -Hal, -CF₃, -CN, -OH, -CH₂C(0)OH, -CH₂C(0)OC,_₆ alkyl, -0-d_₆ alkyl, -C₃_₇ cyc!oalky!, -COOR^**, -(CH₂)_c-OR*^*, =(CH₂)_q-CN, -S(0)R**, =S(0)₂R^**, -(CH₂)_qNR**R***, -C(0)-NR**R***,

alkyl, -aryl, -heterocycloalkyl and -heteroaryl; wherein

R*** Is selected from -H. and -Ci_.₆ alkyl;

R** is selected from -H, -C,__s alkyl which is optionally substituted with one or more halogen atoms, and -(CH₂CH₂0)_rH;

r 1 to 3; and

q is 0 to 4.

Furthermore, the optional substituent(s) of any group which is indicated as being "optionally substituted" in the present specification may be one or more substituents R^a as defined above, unless other substituents are defined for this group. Preferably, the optional substituent(s) of the optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group and/or optionally substituted hydrocarbon group is -halogen (preferably F), -OCH₃ or -CN. Preferably, the optional substituent of the optionally substituted alkyl group Is selected from the group consisting of halogen, -CN, -NR^**R^** (wherein each R^** is chosen independently of each other), -OH, and -0-C_;.-_e alkyl. Preferably the substituent of the optionally substituted alkyl group is -halogen, more preferably F.

The present inventors have surprisingly found that the compounds according to the present invention which contain both substituents R¹⁷ and R¹⁸ exhibit improved pharmacological properties. The compounds of the present invention can be administered to a patient in the form of a pharmaceutical composition which can optionally comprise one or more pharmaceutically acceptable excipient(s) and/or carrier(s).

The compounds of the present invention can be administered by various weli known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Oral, intranasal and parenteral administration are particularly preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.

Thus, preferably, a compound of the invention is formulated as a syrup, an infusion or injection solution, a spray, a tablet, a capsule, a capsiet, lozenge, a liposome, a suppository, a piaster, a band-aid, a retard capsule, a powder, or a slow release formulation. Preferably, the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from cocoa butter and vitebesole. Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for iniectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the final solution or dispersion form must be sterile and fluid. Typically, such a solution or dispersion will include a solvent or dispersion medium. containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. A compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.

Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersai. Further, isotonic agents, such as sugars or salts, in particular sodium chloride, may be incorporated in infusion or injection solutions.

Production of sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary. Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions. Preferred carriers are cocoa butter and vitebesole. Excipients which can be used with the various pharmaceutical forms of a compound of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystailine cellulose, carboxymethyl cellulose, hydroxyethy! cellulose, polyvinyl pyrrolidone and the like;

b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates, c) disintegrants such as starches, croscarmellose, sodium methyl cellulose, agar, bentonite. a!glnic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.

In one embodiment the formulation is for oral administration and the formulation comprises one or more or all of the following ingredients: pregelatinized starch, talc, povidone K 30, croscarmellose sodium, sodium stearyi fumarate, gelatin, titanium dioxide, sorbitol, monosodium citrate, xanthan gum, titanium dioxide, flavoring, sodium benzoate and saccharin sodium.

If a compound of the invention is administered intranasally in a preferred embodiment, it may be administered in the form of a dry powder inhaler or an aerosol spray from a pressurized container, pump, spray or nebulizer with the use of a suitable prope!!ant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoro- alkane such as 1 , 1 , 1 .2-tetrafluoroethane (HFA 134A™) or 1 , 1 , 1 ,2 3,3.3-heptafluoropropane (HFA 227EA™), carbon dioxide, or another suitable gas. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the compound of the invention, e.g., using a mixture of ethanol and the prope!lani as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate. Other suitable excipients can be found in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, which is herein incorporated by reference.

It is to be understood that depending on the severity of the disorder and the particular type which is treatable with one of the compounds of the invention, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc.. different doses of the respective compound are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. It is contemplated that the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g of the active ingredient (i.e. compound of the invention) per kg body weight. However, in a preferred use of the present invention a compound of the invention is administered to a subject in need thereof in an amount ranging from 1 .0 to 500 mg/kg body weight, preferably ranging from 1 to 200 mg/kg body weight. The duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient In one preferred embodiment of a prophylactic or therapeutic use from 10 mg to 200 mg of the compound are orally administered to an adult per day. depending on the severity of the disease and/or the degree of exposure to disease carriers.

As is known in the art, the pharmaceutically effective amount of a given composition will also depend on the administration route. In general, the required amount will be higher if the administration is through the gastrointestinal tract, e.g., by suppository, rectal, or by an intragastric probe, and lower if the route of administration is parenteral, e.g., intravenous. Typically, a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 10 mg to 500 mg/kg body weight. If rectal or intragastric administration is used and in ranges of 1 to 100 mg/kg body weight if parenteral administration is used. For intranasal administration, 1 to 100 mg/kg body weight are envisaged.

If a person is known to be at risk of developing a disease treatable with a compound of the invention, prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible. In these cases the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, from 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective viral disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daiiy.

The compounds of the present invention are particularly useful for treating, ameliorating, or preventing viral diseases. The type of viral disease is not particularly limited. Examples of possible viral diseases include, but are not limited to, viral diseases which are caused by Poxviridae, Herpesviridae, Adenoviridae, Papiliomaviridae, Po!yomaviridae, Parvoviridae, Hepadnaviridae, Reovindae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae. Coronaviridae, Picomaviridae, Hepeviridae, Caliciviridae, Astroviridae, Togavlridae, Flaviviridae, Deltavirus, Bornaviridae, and prions. Preferably viral diseases which are caused by Herpesviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae. Coronaviridae. Picomaviridae, Togaviridae. Flaviviridae. more preferably viral diseases which are caused by orthomyxoviridae.

Examples of the various viruses are given in the following table.

Family Virus (preferred examples)

Poxviridae Smallpox virus

Molluscum contagiosum virus

Herpesviridae Herpes simplex virus

Varicella zoster virus

Cytomegalovirus

Epstein Barr virus

Kaposi^'s sarcoma-associated herpesvirus

Adenoviridae Human adenovirus A-F

Papiliomaviridae Papillomavirus

Polyomaviridae BK-virus

JC-Virsu

Parvoviridae B19 virus

Adeno associated virus 2/3/5

Hepadnaviridae Hepatitis B virus Reoviridae Reovirus 1/2/3

Rotavirus A/B/C

Colorado tick fever virus

Filoviridae Ebola virus

Marburg virus

Paramyxoviridae Parainfluenza virus 1 -4

Mumps virus

Measles virus

Respiratory syncytial virus

Hendravirus

Rhabdoviridae Vesicular stomatitis virus

Rabies virus

Mokola virus

European bat virus

Duvenhage virus

Orthomyxoviridae Influenza virus types A-C

Bunyaviridae California encephalitis virus

La Crosse virus

Hantaan virus

Puumala virus

Sin Nombre virus

Seoul virus

Crimean- Congo hemorrhagic fever virus

Sakhalin virus

Rift valley virus

Sandfly fever virus

Uukuniemi virus

Arenaviridae Lassa virus

Lymphocytic choriomeningitis virus

Guanarito virus

Junm virus.

Machupo virus

Sabia virus

Coronavlridae Human coronavirus

Picornaviridae Human enterovirus types A-D (Poliovirus, Echovirus,

Coxsackie virus A/B)

Rhinovirus types A/B/C

Hepatitis A virus

Parechovirus

Food and mouth disease virus

Hepeviridae Hepatitis E virus Caliciviridae Norwalk virus

Sapporo virus

Astroviridae Human astrovirus 1

Togaviridae Ross River virus

Chikungunya virus

O'nyong-nyong virus

Rubella virus

Flaviviridae Tick-borne encephalitis virus

Dengue virus

Yellow Fever virus

Japanese encephalitis virus

Murray Valley virus

St. Louis encephalitis virus

West Nile virus

Hepatitis C virus

Hepatitis G virus

Hepatitis GB virus

Deltavirus Hepatitis deltavirus

Bornaviridae Bornavirus

Prions

Preferably, the compounds of the present invention are employed to treat influenza. The present invention covers all virus genera belonging to the family of orthomyxoviridae. specifically influenza virus type A, B, and C, Isavirus. and thogotovlrus. Within the present invention, the term "influenza" includes influenza caused by any influenza virus such as influenza virus type A, B, and C including their various stains and isolates, and also covers influenza A virus strains commonly referred to as bird flu and swine flu. The subject to be treated is not particularly restricted and can be any vertebrate, such as birds and mammals (including humans).

Without wishing to be bound by theory it is assumed that the compounds of the present invention are capable of inhibiting endonuclease activity, particularly that of influenza virus.

A possible measure of the in vitro endonuclease inhibitory activity of the compounds having the formula (I) is the FRET (fluorescence-resonance energy transfer)-based endonuclease activity assay disclosed herein. In this context, the % reduction is the % reduction of the initial reaction velocity (vO) measured as fluorescence increase of a dua!-!abel!ed RNA substrate cleaved by the influenza virus endonuclease subunit (PA-Nter) upon compound treatment compared to untreated samples.

The compounds having the general formula (I) can be used in combination with one or more other medicaments. The type of the other medicaments is not particularly limited and will depend on the disorder to be treated. Preferably, the other medicament will be a further medicament which is useful in treating, ameliorating or preventing a viral disease, more preferably a further medicament which is useful in treating, ameliorating or preventing influenza that has been caused by influenza virus infection and conditions associated with this viral infection such as viral pneumonia or secondary bacterial pneumonia and medicaments to treat symptoms such as chills, fever, sore throat, muscle pains, severe headache, coughing, weakness and fatigue. Furthermore, the compounds having the general formula (I) can be used in combination with anti-inflammatories. Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention which is defined by the appended claims in any way.

EXAMPLES

Biological Assays and Data

Luciferase Reporter Assay (LRA)

Assay purpose and principle

This in vitro, cell-based assay, is used to identify small molecule inhibitors of influenza A virus and relies upon a replication competent influenza reporter virus. This virus was generated in a A/WSN background (Szretter KJ, Balish AL, Katz J . Curr Protoc Microbiol, Influenza: propagation, quantification, and storage. 2006 Dec:Chapter 15:Unit 15G.1 . doi: 10.1002/0471729256. mc15g01 s3) and contains the extremely bright luciferase variant, NanoLuc (Promega), which has been appended to the C-terminus of the polymerase subunit, PA. The reporter virus replicates with near native properties both in cell culture and in vivo. Thus, NanoLuc luciferase activity can be used as a readout of viral infection.

In order to identify small molecule inhibitors of influenza A virus, A549 (human non-small cell iung cancer) cells are Infected with the reporter virus and following infection, the cells are treated with serially diluted compounds. The inhibitory effect of the small molecules tested is a direct measure of viral levels and can be rapidly obtained by measuring a reduction in luciferase activity

Determination of viral replication inhibition by Luciferase Reporter Assay (LRA)

A549 cells were plated in 384-well plates at a density of 10,000 cells per well in Dulbecco's modified Eagle^'s medium with Glutamax (DMEM, Invitrogen) supplemented 10% fetal bovine serum (FBS, Invitrogen) and I X penicillin/streptomycin (invitrogen), herein referred to as complete DMEM, and incubated at 37°C, 5% C0₂ overnight. The following day, cells were washed once with IX PBS and then infected with virus, MO! 0.1 in Ι Ομί of Infection media for 60 min. 15μΙ of complete media and diluted compounds (1 % DMSO final) added to the wells, and the plates were incubated for 24 h at 37"C, 5% C0₂. 15μΙ of Nanc-Glo reagent (Promega) was added to each well and luminescence was read using a Paradigm Microplate reader (Molecular Devices). Cell viability was determined similarly, in the absence of virus, by measurement of ATP levels with Cel!Titer-Glo reagent (Promega). EC₅₀ and CC₅₀ values were calculated by fitting dose-response curves with XLFit 4-parameter model 205 software (IDBS). Virus and cell culture methods

A WSN/33 influenza virus containing the NanoLuc reporter construct was obtained from the laboratory of Andrew Mehle (University of Wisconsin). A549 human lung carcinoma cells were purchased (ATCC). All studies were performed with A549 cells cultured in complete DMEM. Influenza virus stocks were propagated in MDBK cells (ATCC) using standard methods (Szretter KJ, Balish AL, Katz JM. Curr Protoc Microbiol, influenza: propagation, quantification, and storage. 2006 Dec;Chapter 15:Unit 15G.1. doi: 10.1002/0471729256.mc15g01 s3), and stocks frozen at -80°C. Viral infections were carried out using DMEM Glutamax supplemented with 0.3% BSA (Sigma), 25mM Hepes (Sigma), and IX penicillin/streptomycin (!nvitrogen).

Experimental:

General: Silica gel chromatography was either performed using cartridges packed with silica gel (ISOLUTE© Columns, TELOSTM Flash Columns) on ISCO Combi Flash Companion or on glass columns on silica gel 60 (32-60 mesh, 60 A). MS: Mass spectra (MS) were measured with electrospray ionization (ESI) on a Perkin-Elmer SCIEX API 300.

Compounds having the general formula (I) may be prepared by any method known in the art. in the following, general methods of their preparation are exemplified which are, however, not limiting on the scope of the present invention.

Scheme 1

Compounds of formula i (Scheme 1 ) can be prepared by reaction of a substituted phenylmagnesium halogenide (ha!ogen being CI. Br or I) with an alky! 2-cyano-2- cyclopentyliden acetate or an alkyl 2-cyano-2-cyclohexyliden acetate in the presence of copper (I) cyanide and in a solvent such as ethers, e.g. diethyl ether or preferably tetrahydrofuran at temperatures between -5Q°C to 22°C to give compounds of general formula 2.

Decarboxylation of compounds 2 can be effected in solvent mixtures of dimethyl sulfoxide and water at elevated temperature, e.g. at 100 to 200°C, preferably at 160°C affording the nitriles of general formula 3.

Conversion of the nitriles 3 to the methylimidates 4 can be accomplished in methanol saturated with hydrogen chloride gas at temperatures between -20 to Q°C, preferably at 0°C.

Amidines of formula 6 are prepared by the reaction of methylimidates 4 with piperazinones 6 in the presence of a base such as e.g. diisopropylethylamine and an acid. e.g. acetic acid in a solvent such as ethers, preferably tetrahydrofuran at room temperature. Compounds of formula I are prepared from amidines 6 by reaction with an alkyl oxalate, preferably diethyl oxalate and a base, preferably lithium hexamethyldisilazide in a solvent, e.g. tetrahydrofuran at -30 to 0°C.

Piperazinones 5 can be prepared by various routes. The route depicted in Scheme 2 starts with the protected amino acids 7 and introduces the R¹ residue at the beginning of the synthesis

Scheme 2

12 5

Thus, Z-protected amino acids 8 are obtained from 7 by reaction with an alky! halogenide (halogen being CI, Br or I) and a base such as a hydride, preferably sodium hydride in a solvent such as tetrahydrofuran at room temperature.

The acids 8 can be reduced to the alcohols 9 using, e.g., lithium aluminium hydride or preferably borane tetrahydrofuran complex in an ether as the solvent, preferably tetrahydrofuran at 0 to 22°C.

Oxidation of the alcohols 9 to the aldehydes 10 can be effected with aqueous sodium hypochlorite and 2,2,6.6-tetramethylpiperidine 1 -oxyl (TEMPO) as the catalyst in the presence of sodium bicarbonate and potassium bromide in a solvent mixture of dichloromethane and water at 0 to 22°C.

Conversion of the aldehydes 10 to the Z-protected piperazinones 12 proceeded via the Z- protected amine 11 followed by shift of the Z-group to the other nitrogen and cyclization to 12. The reaction can be accomplished with methyl 2-aminoacetate hydrochloride and a borohydride complex, preferably sodium triacetoxyborohydride, and a base, e.g. N,N- diisopropylethylamine, in a solvent such as dichloromethane at temperatures between 0 to 22°C.

Deprotection of compounds 12 to the piperazinones 5 (R¹ = Me, R²-R³ = cyclobutyl, tetrahydrofuran and tetrahydropyran) can be effected by hydrogenation with e.g. palladium on carbon in an alcohol, preferably methanol at normal pressure and at room temperature. Alternatively, aldehydes 10 can be treated with methyl 2-aminoacetate hydrochloride and sodium triacetoxyborohydride as described above to give the isolated amino ester 11.

Hydrogenation of the amino ester 11 as described above followed by treatment with a base, preferably potassium carbonate affords the piperazinone 5 (R = Me, R²-R³ = cyclopropyl).

The route depicted in Scheme 3 starts with the protected amino esters 13 and introduces the R residue at the end of the synthesis. Scheme 3

13 14 15 16 17 6

Thus, esters 13 can be reduced to the aldehydes 14 using e.g. lithiuma!uminum hydride in an ether as the solvent, preferably tetrahydrofuran at 0"C. Subsequent steps to the piperazinone 5 (R¹ = Me, R²-R³ = oxetane) can be performed by analogous reactions as described in Scheme 2. The route depicted in Scheme 4 starts with the reductive amination of aldehydes 18 and ethyl 2-(benzylamino)acetate to give the amino esters 19. Subsequent steps to the piperazinones 5 (R¹ = Me. R² and R³ = methyl) can be accomplished by analogous reactions as described previously.

Scheme 4

18 19 20 21 5

The route depicted in Scheme 5 starts with the reaction of neat amines 22 and 2-hydroxy-2- methylpropanenitrile in the presence of molecular sieves. The in situ generated intermediate nitrite can be reduced to intermediate amine with lithium aluminum hydride in a solvent such as an ether, preferable tetrahydrofuran, at 0°C, which is followed by the reaction with benzyl chloroformate to give the diamine 23 Subsequent steps to the piperazinones 5 (R¹ = CH₂CF₃, and CH(Me)CF₃₎ R² and R³ = methyl) can be accomplished by analogous reactions as described previously.

Scheme 5

Example 1

Preparation of 9-hydroxy-2-isopropyl-3,3-dimethyl-6-[[1 -(m-tolyl)cyclopentyl]methyl]- 4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Ethyl 2-cyano-2-[1 -(m-tolyl)cyclopentvnacetate

To a light brown suspension of copper (I) cyanide (2 25 g) in tetrahydrofuran (30 ml) was added dropwise at -30°C m-toiyimagnesium chloride 1 M in tetrahydrofuran (1 M, 50 ml) and stirring was continued at OX for 30 min. After cooling to -30"C, a solution of ethyl 2-cyano-2- cyclopentylideneacetate (3.0 g) in tetrahydrofuran (10 ml) was added dropwise. the reaction mixture was allowed to warm to 22°C and stirring was continued for 2h. The mixture was partitioned between aqueous saturated NH₄CI and ethyl acetate, the organic layer was dried, evaporation and the residue purified by flash chromatography (silica gel, n-heptane/ethy! acetate, gradient) to give the title compound (3.65 g) as a light yellow oil. MS (ESI, m/z): 270.3 [(M-H)^"]. J J b) 2-[1 -(m-Tolvl)cvclopentvl1acetonitrile

To a light yellow solution of ethyl 2-cyano-2-(1-(m-tolyl)cyclopentyl)acetate (3.65 g) in dimethyl sulfoxide (36 ml) was subsequently added water (565 mg) and sodium chloride (267 mg) and the mixture was heated to 160°C for 6 h. The mixture was partitioned between water and ethyl acetate, the organic layer was washed with water, dried and evaporated to give the crude title compound (2.2 g) as a light brown oil, which was used without further purification.

MS (ESI, m/z): 200.2 [(M+H)^*]. c) Methyl 2-Γ1 -(m-toiyl)cyciopentyi]ethanimidate hydrochloride

To a light brown solution of 2-(1-(m-tolyl)cyciopentyi)acetonitriie (500 mg) in methanol (5 mi) was bubbled through at -15°C hydrogen chloride gas until the solution was saturated. The ixtu e was kept in the fndqe for 24 h. !n case of incomoiete conversion the reaction mixture has to be saturated again at -15°C with hydrogen chloride gas and kept in the fridge. The mixture was evaporated, the residue triturated with ethyl ether and dried to give the title compound as light brown solid. MS (ESI, m/z): 232.2 [(M+H)⁺J. When the residue did not solidify it could be used directly in the next step. d) To a solution of methyl 2-(1 -(m-to!yl)cyclopentyi)acetimidate hydrochloride (50 mg) and 1- isopropyl-6.6-dimethyl-piperazin-2-one (32 mg) in tetrahydrofuran (1 .5 ml) were added at 22°C diisopropylethyl amine (98 μΙ) and after 5 min acetic acid (1 1 μΙ) and stirring was continued at 22°C for 16 h. The mixture can be further processed as described below or the intermediate 1 - isopropyl-6,6-dimethyl-4-[2-[1 -(m-tolyl)cyclopentyl]ethanimidoyl]piperazin-2-one hydrochloride can be isolated by dilution with ethyl ether followed by filtration and drying of the residue. The mixture containing the intermediate was diluted with tetrahydrofuran (1 ml) and cooled down to -30X. Lithium hexamethyldisilazide (1 M, 1.3 mi) was added followed by diethyl oxalate (101 ul) and stirring was continued at -30°C. In case of incomplete conversion a further portion of lithium hexamethyldisilazide and diethyl oxalate has to be added. The mixture was warmed to 0°C, diluted with aqueous hydrochloric acid (1 N, 4 ml), warmed to 22°C, extracted with dichioromethane, dried, evaporated and the residue purified by preparative HPLC (RP-18, eCN/H₂0 containing 0.23% of HCOOH) to give example 1 (6 mg).

MS (ESI, m/z): 424.3 [(M+H)⁺].

Example 2

Preparation of 6-[[1 -{3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-isopropyl-3,3- dimethyl-4H-pyrazino[1 ,2-c]pyrimidine-1,8-dione

The title compound was prepared according to example 1 a - c but using 3,5- dimethylphenyl)magnesium bromide in step a and isolated as a light brown solid.

MS (ESI, m/z): 246.2 [(M+H)^*]. b) Methyl 2-[1-(3,5-dimethylphenyl)cyclopentyl]ethanimidate hydrochloride was reacted with 1 - isopropyl-6,6-dimethyl-piperazin-2-one according to example 1 d to give example 2 (26%) as a white solid.

MS (ESI, m/z): 438.4 [(M+H)⁺], Example 3

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyclohexyl]methyl]-9-hydroxy-2-isopropyl-3,3- dimethyl-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Methyl 2-i1 -(3.5-dimethylphenvl^'jcyclohexvnethanimidate hydrochloride

The title compound was prepared according to example 1 a - c but using 3,5- dimethyiphenyl)magnesium bromide and ethyl 2-cyano-2-cyciohexylidene-acetate in step a. b) Methyl 2-[1 -(3,5-dimethylphenyl)cyclohexyl]ethanimidate hydrochloride was reacted with 1 - isopropyl-6,6-dimethyl-piperazin-2-one according to example 1 d to give example 3 (24%) as a colorless solid.

MS (ESI, m/z): 452.4 [(M+H)⁺j.

Example 4

Preparation of 6-[[1 -(3-ethylphenyl)cyclopentyl]methyI]-9-hydroxy-2-isopropyl-3,3- dimethyI-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Methyl 2-Γ1 -(3-ethylphenvDcyclopentyllethanimldate hydrochloride

The title compound was prepared according to example l a

ethylphenyl)magnesium bromide in step a and isolated as a white solid.

MS (ESI, m/z): 246.1 [(M+H)⁺]. b) Methyl 2-[1 -(3-ethylphenyl)cyclopentyl]ethanimidate hydrochloride was reacted with 1 - isopropyl-6.6-dimethyl-piperazin-2-one according to example 1 d to give example 4 (25%) as a light brown solid.

MS (ESI. m/z): 438.3 [(M+H)⁺].

Example 5

Preparation of 6-[[1-{3,5-dimethylphenyl)cyclopentyI]methyl]-9-hydroxy-2,3,3-trimethyl- 4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Ethyl 2-fbenzvl-[2-[tert-butoxvcarbonvi(methvl)amino1-2-methvi-propy iaminolacetate

A solution of tert-butyl methyl(2-methyl-1 -oxopropan-2-yi)carbamate (30.0 g, prepared according to Conte. I. et al., US 2009/0048239) acetic acid (9.3 g) and ethyl 2- (benzylamino)acetate (34.7 g) in dichloromethane (300 mi) was stirred at 10°C for 2 h. NaBH(OAc)₃ (95.4 g) was added to the mixture and stirring was continued at 10°C for 14 h. The mixture was diluted with methanol (100 ml), filtered and the filtrate evaporated. The residue was partitioned between water (300 ml) and ethyl acetate (300 ml, 2x), the organic layers were dried, evaporated and the residue purified by flash chromatography (silica gel, n- heptane/ethyl acetate, 100: 1 ) to afford the title compound (29.0 g) as a colorless oil. b) Ethyl 2-ibenzyl-f2-methyl-2-(methylamino)propyllamino1acetate hydrochloride

To a solution of ethyl 2-[benzyl-[2-[tert-butoxycarbonyl(methyl)amino]-2-methyl- propyl]amino]acetate (29.0 g) in methanol (100 ml) was added HCI/methanol (4N, 100 ml) and stirring was continued at 10°C for 12 h. The solution was evaporated and the residue purified by flash chromatography (silica gel) to afford the title compound (5.0 g) as a colorless oil. c) 4-Benzy!-1 ,6,6 rime†hyi-piperazln-2-one

A mixture of ethyl 2-[benzyl-[2-methyl-2-(methylamino)propyl]amino]acetate hydrochloride (5.0 g) in methanol (50 ml) and K₂C0₃ (6.6 g) was heated to 75°C for 5 h. The solution was evaporated, the residue triturated with dichloromethane/methanol (20/1 , 100 ml), filtered and the filtrate was evaporated to give the title compound (3.5 g) as a colorless oil. d) 1 ,6,6-Trimethvipiperazin-2-one

To a suspension of 4-benzyl-1 .6.6-trimethylpiperazin-2-one (3.5 g) and Pd(OH)₂ (2.0 g) in methanol (100 ml) was added concentrated aqueous NH₃ (1.0 ml) and stirring was continued under hydrogen pressure (3.0 MPa) at 60°C for 3 d. The mixture was filtered, the filtrate evaporated and the residue purified by preparative HPLC (RP-18) to give the title compound (200 mg) as a yellow solid. MS (ESI. m/z): 142.1 [(M)^*].

Example 6

Preparation of 6-[[1 -(4-fIuoro-3,5-dimethyl-phenyl)cyclopentyi]methyl]-9-hydroxy-2- isopropyl-3,3-dimethy!-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Methyl 2-f1-(4-fluoro-3,5-dimethyl-phenyl)cyc!opentyllethanimidate hydrochloride

The title compound was prepared according to example 1 a - c but using (4-fluoro-3,5- dimethylphenyl)magnesium bromide in step a and isolated as a white powder. MS (ESI, m/z): 264.2 [(M+Hfj. b) Methyl 2-[1 -(4-fluoro-3.5-dimethyl-phenyl)cyclopentyl]ethanimidate hydrochloride was reacted with 1 -isopropyl-6,6-dimethyl-piperazin-2-one according to example 1 d to give example 6 (24%) as an off-white powder.

MS (ESI, m/z): 456.3 [(M+H)⁺l

Example 7

Preparation of S-hydroxy-2-isopropyl-3,3-dimethyl-6-[[1 -[3-methyl-5-(trifluoromethyl)- phenyl]cyclopentyl]methyl]-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Methyl 2-ri-[3-methvl-5-(trifluoromethyl)phenvllcvclopentvl]ethanimidate hydrochloride

The title compound was prepared according to example 1 a - c but using (3-methyl-5- (trifluoromethyl)phenyl)magnesium bromide in step a and isolated as a white solid. MS (ESI, m/z): 300.2 [(M+H)⁺]. b) Methyl 2-[1 -[3-methyl-5-(trifluoromethyl)phenyl]cyclopentyl]ethanimidate hydrochloride was reacted with 1-isopropyl-6,6-dimethyl-piperazin-2-one according to example 1 d to give example 7 (40%) a white solid.

MS (ESI, m/z): 492.3 [(M+H)⁺].

Example 8

Preparation of 6'-((1-{3,5-dimethylphenyl)cyclopentyi)methyl)-9'-hydroxy-2'-methylspiro- [cyclobutane-1 ,3'-pyrazino[1 ,2-c]pyrimidine]-1 ^,,8^,(2'H,4'H)-dione

a) 1 -f BenzyloxycarbonvKmethvPaminolcyclobutanecarboxylic acid

To a solution of 1 -(((benzyloxy)carbony!)amino)cyclobutanecarboxylic acid (440 mg, prepared according to Gatos, M. et al., Journal of Peptide Science (1997), 3(2), 1 10-122) in tetrahydrofuran (6.5 ml) was added at OX iodomethane (2.0 g) followed by portion wise addition of sodium hydride (60% in oil, 388 mg) and stirring was continued at 22°C for 20 min. The mixture was partitioned between ethyl acetate and water, the pH of the aqueous layer was adjusted to 4 with solid citric acid and extracted with ethyl acetate (2 x 10 ml). The organic layers were dried and evaporated to give the title compound (407 mg) as a yellow oil. MS (ESI, m/z): 264.1 [(M+H)⁺]. b) Benzyl N-H -(hydroxymethvPcyclobutyll-N-methyl-carbamate

To a solution of 1-[benzyloxycarbonyl(methyl)amino]cyclobutanecarboxylic acid (380 mg) in tetrahydrofuran (1.5 ml) was added at 0°C borane tetrahydrofuran complex (1 in tetrahydrofuran, 2.9 ml) and stirring was continued at 22°C for 1 h. The mixture was partitioned between saturated aqueous NaHC0₃ and ethyl acetate (3 x 20 ml), the organic layers were dried, evaporated and the residue purified by fiash chromatography (silica gel, ethyl acetate in heptane. 0% to 60%) to give the title compound (244 mg) as a colorless oil.

MS (ESI, m/z): 250.2 [(M+H)⁺j. c) Benzyl -(1 -formylcyclobutyi )-N-methyl-carbamate

To a solution of benzyl N-[1-(hydroxymethyi)cyclobutyl]-N-methyl-carbamate (175 mg) In dichloromethane (3 ml) was added subsequently at 22 °C sodium bicarbonate (24 mg), a solution of potassium bromide (25 mg) in water (1.4 ml) and TEMPO (2,2,6,6- tetramethylpiperidine 1 -oxyl. 1.7 mg). The mixture was cooled to 0 °C, aqueous sodium hypochlorite (13%, 603 mg) was added dropwise over a period of 60 min and stirring was continued at OX for 30 min. The mixture was extracted with dichloromethane. the organic layer was washed with half-saturated aqueous NH₄CI, dried and evaporated to give the title compound (159 mg) as a light yellow oil which was used in the next step without further purification.

MS (ESI, m/z): 248.1 [(M+H)⁺]. d) Benzyl 5-methyl-6-oxo-5.8-diazaspirof3.51nonane-8-carboxylate

To a solution of benzyl N-(1 -formylcyclobutyl)-N-methyl-carbamate (156 mg) in dichloromethane (4.5 ml) was subsequently added at 0°C methyl 2-aminoacetate hydrochloride (127 mg) and N.N-diisopropylethylamine (98 mg) and stirring was continued at 0°C for 30 min. Sodium triacetoxyborohydride (160 mg) was added in three portions, the mixture was allowed to warm to 22^' C and stirring was continued for 15 h. The mixture was washed with saturated aqueous NaHCCX. the organic layer was dried, evaporated and the residue purified by flash chromatography (Si-NH₂, ethyl acetate in n-heptane, 10% to 60%) to give the title compound (92 mg, with migrated Z-group) as a colorless oil.

MS (ESI , m/z): 289.1 [(M+H)^*j e) 5-Methyl-5.8-diazaspirof3.51nonan-6-one

To a solution of benzyl 5-methyl-6- oxo-5.8-diazaspiro[3.5jnonane-8-carboxylate (92 mg) in methanol (4 mi) was added at 22°C palladium on carbon (10 mg) and the mixture was hydrogenated at norma! pressure (balloon) for 1 h. The suspension was filtered and the filtrate evaporated to give the title compound (45 mg) as a colorless oil.

MS (ESI. m/z): 155.1 [(M+Hf], f) Methyl 2-[1 -(3.5-dimethylphenyl)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with 5-methyl-5,8-diazaspiro[3.5]nonan-6-one according to example 1 d to give example 8 (27%) as a light yellow solid. MS (ESI, m/z): 422.3 [(M+H)⁺].

Example 9

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-spiro- [4H-pyrazinot1 ,2-c]pyrimidine-3,1'-cyclopropane]-1 ,8-dione

a) Benzyl N-d -formylcyclopropyD-N-methyl-carbamate

The title compound was prepared in analogy to example 8c starting from benzyl N-[1 - (hydroxymethyl)cyc!opropyl]-N-methyl-carbamate prepared according to Gao, D. et al., WO 2013/091502 to give the title compound (99%) as a colorless oil which was used in the next step without further purification. MS (ESI, m/z): 234.1 [(M+H)l b) Methyl 2-[[1 -[benzvloxvcarbonyl(methvl)amino1cvclopropvl1methylarninolacetate

To a solution of benzyl N-(1-formylcyclopropyl)-N-methyl-carbamate (1.08 g) in dichloromethane (32 ml) was subsequently added at 0°C methyl 2-aminoacetate hydrochloride (930 mg) and N,N-diisopropy!ethylamine (718 mg) and stirring was continued at 0°C for 30 min. Sodium triacetoxyborohydride (1 .18 g) was added in three portions, the mixture was allowed to warm to 22°C and stirring was continued for 3 h. The mixture was washed with saturated aqueous aHC0₃, the organic iayer was dried, evaporated and the residue purified by flash chromatography (Si- H₂, ethyl acetate in n-heptane, 10% to 50%) to give the title compound (1.05 g) as a colorless oil.

MS (ESI, m/z): 307.2 [(M+Hf]. c) 4-Methyl-4 7-diazaspiro[2.51octan-5-one

To a solution of methyl 2-[[1 -[benzyloxycarbonyl(methyl)amino]cyclopropyl]methylamino]- acetate (950 mg) in methanol (20 ml) was added at 22°C palladium on carbon (10% Pd, 99 mg) and the mixture was hydrogenated at normal pressure (balloon) for 1 h. The suspension was filtered and the filtrate evaporated. The residue was dissolved in methanol (5 ml) and treated with K₂C0₃ (214 mg) and stirring was continued at 22°C for 15 min. The suspension was filtered, the filtrate evaporated and the residue purified by flash chromatography (Si-NH_2l ethyl acetate in n-heptane, 70 to 100%, then dichloromethane) to give the title compound (303 mg) as a white solid.

MS (ESI, m/z): 141 .1 [(M+H)⁺]. d) Methyl 2-[1 -(3,5-dimethylphenyl)cyclopentyi]ethanimidate hydrochloride from example 2a was reacted with 4-methyl-4,7-diazaspiro[2.5]octan-5-one according to example 1 d to give example 9 (37%) as an off-white solid.

MS (ESI, m/z): 408.3 [(M+H)^*].

Example 10

Preparation of 6-[[1 -<4-fluoro-3,5-dimethyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2,3,3- trimethyl-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Methyl 2-[1 -(4-fluoro-3,5-dimethyl-phenyl)cyclopentyl]ethanimidate hydrochloride from example 6a was reacted with 1 ~isopropyl--6,6-d;rnethyl-piperazin-2-one from example 5d according to example I d to give example 0 (10%) as a white solid.

MS (ESI, m/z): 428.3 [(M+H)^*j. Example 11

Preparation of 6'-((1 -(3-bromo-5-rrseihylphenyl)cyc!opentyl)methy!)-9'-hydroxy-2'- meihylspiro[cyclopropane-1 ,3'-pyrazino[1 ,2-c]pynmidine]-1\8'(2'H,4'H)-dione

a) 2-(3-Bromo-5-methvl-phenyl)acetonitrile

To a suspension of 1 -bromo-3-ibromomethyl)-5-methylbenzene (2.5 g) in ethanoi (10 mi) were added at 60"C potassium cyanide (925 mg) and water (5 ml) and stirring was continued at 60°C for 20 h. The mixture was evaporated, the residue partitioned between ethyl acetate and water, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate/n-heptane) to give the title compound (1.47 g) as a light brown oil.

MS (ESI, m/z): 208.2/210.0 [(M+H)⁺]. b) 1 -(3-Bro_.mo-5rmethyl-phenyl)cvclopentanecarbonitrile

To a solution of 2-(3-bromo-5-methylphenyl)acetonitrile (1.30 g) in dimethyl sulfoxide (15 ml) and ethyl ether (15 ml) was added 1 ,4-dibromobutane (1.35 g). The obtained solution was added at 22°C to a suspension of sodium hydride (743 mg) in dimethyl sulfoxide (5 ml) and stirring was continued for 2 h. The mixture was diluted with water, the pH was adjusted to 1 using aqueous hydrochloric acid (1 M) and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate/n-heptane) to give the title compound (0.90 g) as a colorless oil. c) 1 -(3-Bromo-5-methyl-phenyl)cvclopentanecarba!dehyde

To a solution of 1 -(3-bromo-5-methylphenyl)cyclopentanecarbonitrile (1.0 g) in dichioromethane (25 mi) was added dropwise at -78 'C a solution of diisobutylaluminium hydride in dichioromethane (1 M. 5.7 ml) and stirring was continued at -78' C for 2 h. The mixture was quenched by dropwise addition of aqueous hydrochloric acid (25%. 1 1 ml) and stirring was continued at 78°C for 16 h. After complete addition, the mixture was stirred overnight and allowed to warm up to RT. The mixture was washed with water, the organic layer dried and evaporated to give the crude title compound which was used without further purification in the next step. d) 2-i 1 -(3-Bromo-5-methvl-phenvl)cvclopentyilacetonitrile

To a suspension of potassium tert-butoxide (1.51 g) in tetrahydrofuran (25 ml) was added at - 78°C a solution of toluenesulfonylmethyl isocyanide (1.32 g) in tetrahydrofuran (8 ml) and stirring was continued at -78°C for 20 min. A solution of 1 -(3-bromo-5- methylphenyl)cyclopentanecarbaldehyde (900 mg) in tetrahydrofuran (6 ml) was added and stirring was continued at -78°C for 1.5 h. Methanol (8.3 ml) was added, the mixture was allowed to warm to 22°C and stirring was continued at 60°C for 2 h. The mixture was partitioned between ethyl acetate and water, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate/n-heptane) to give the title compound (572 mg) as a light yellow oil. e) Methyl 2-f1 -(3-bromo-5-methyl-phenyl)cvclopentvnethanimidate hydrochloride

The title compound was obtained from 2-[1-(3-bromo-5-methyl-phenyl)cyclopentyl]acetonitrile, which was processed according to the procedure for example 1 c and obtained as a white solid. f) Methyl 2-[1 -(3-bromo-5-methyl-phenyl)cyclopentyl]ethanimidate hydrochloride was reacted with 4-methyl-4,7-diazaspiro[2.5]octan-5-one from example 9c according to example I d to give example 1 1 (40%) as a white solid.

MS (ESI, m/z): 472.2 and 474.2 [(M+H)^*]. Example 12

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl- spiro[4H-pyrazino[1 ,2-c]pyrimidine-3,3'-tetrahydrofuran]-1,8-dione

a) Benzyl N-[3-(hvdroxymethyi)tetrahvdrofuran-3-yl1-N-methyl-carbamate

To a solution of (3-(methylamino)tetrahydrofuran-3-yl)methanol hydrochloride (140 mg) in 1 ,4- dioxane (2 ml) were subsequently added at 22°C a solution of sodium carbonate (266 mg) in water (2 ml) and a solution of benzyl carbonochloridate (214 mg) in 1 ,4-dioxane (1 ml) and stirring was continued at 22 °C for 45 min. The mixture was partitioned between dichloromethane and water, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gei, methanol in dichloromethane, 0 to 6%) to give the title compound (52 mg) as a yellow oil.

MS (ESI, m/z): 266.2 [(M+H)⁺]. b) 6-Methyl-2-oxa-6.9-diazaspiro[4.51decan-7-one

Benzyl N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]-N-methyl-carbamate was converted according to the procedures for examples 8c to e to give the title compound as a colorless oil.

MS (ESI, m/z): 171 .1 [(M+H) c) Methyl 2-[1 -(3.5-dimethylphenyl)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with 6-methyi-2-oxa-6.9-diazaspiro[4.5]decan-7-one according to example I d to give example 12 (41 %) as an off-white solid.

MS (ESI, m/z): 438.3 [(M+H)"].

Example 13

Preparation of 2-(3-(1 -((9'-hydroxy-2'-methyl-1 \8'-dioxo-1 ',2^!,4',8^!-tetra ydrospiro-

[cyclopropane-I .S'-pyrazinotl ^-clpyrimidinJ-e'-y methy cyclopenty -S- methylphenyI)acetonitrile

To a solution of 6'-((1 -(3-bromo-5-methylphenyl)cyclopentyl)methyl)-9'-hydroxy-2'- methylspiro[cyciopropane-1 .3^,-pyrazino[1.2-c]pyrimidine]-1 '.8'(2'H,4'H)-dione (34 mg from example 11 ) in dimethyisuifoxide (0.9 ml) were subsequently added under argon 4- isoxazoleboronic acid pinacolester (17 mg) and a solution of potassium fluoride in water (1 M, 216 ul). Argon was bubbled through the mixture for 10 min, which was followed by the addition of 1 .1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (6 mg) and stirring was continued in a sealed vial at 130 for 18 h. The mixture was treated with acetic acid (32 mg), filtered, the residue washed with dichloromethane (5 ml), the filtrate evaporated and the residue purified by prepartive HPLC (RP-18, acetonitrile/H₂0 containing 0.23% of HCOOH) to give the title compound (16 mg) as an orange solid.

MS (ESI, m/z): 433.2 [(M+H)⁺].

Example 14

Preparation 6-ΓΓ1 -(3,5-dimethylphenyl)cyc!opentyl]methyl]-9-hydroxy-3,3-dimethyl-2- (2,2,2-trif luoroethyl)-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Benzyl N-[2-methvl-2-(2,2.2-trifluoroethylamino)propvncarbamate

To a mixture of 2,2.2-trifluoroethanamine (5 0 g) and 2-hydroxy-2-methylpropanenitrile (4.51 g) was added molecular sieves (4A) and stirring of the orange suspension was continued at 22°C for 4 days. The mixture was diluted with tetrahydrofuran (10 ml) and treated at 0°C with a suspension of LiAIH₄ (1.92 g) in tetrahydrofuran (50 ml) and after 2 h a second portion of LiAIH₄ (958 mg) was added carefully and stirring was continued for 10 min. The mixture was quenched at 0°C with water (10 ml), followed by the addition of benzyl chloroformate (8.61 g) and stirring was continued at 22°C for 15 min. A further portion of benzyl chloroformate (861 mg) was added at 0^CC and stirring was continued for 10 min. The mixture was filtered over Dicalite, the filtrate evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate in heptane 0 to 50%) to give the title compound (7.55 g) as a yellow oil. MS (ESI, m/z): 305.2 [(M+Hf]. b) 2-Methvl-N2-(2.2.2-trifluoroethyl)propane-1.2-diamine

A suspension of benzyl N-[2-methyl-2-(2,2.2-trifluoroethylamino)propyl]carbamate (1 0 g) and palladium on carbon (10% Pd, 18 mg) in methanol (20 ml) was hydrogenated at normal pressure for 16 h. The mixture was filtered and the filtrate evaporated to give the crude title compound (400 mg) as a colorless oil, which was used without further purification.

MS (ESI, m/z): 171.1 [(M+H)+j. c) Ethyl 2-[r2-methvl-2-(2.2.2-trifluoroethylamino)propvl1aminolacetate

To a solution of 2-methyl-N2-(2,2,2-trifluoroethyl)propane-1 ,2-diamine (255 mg) in tetrahvdrofuran (5.0 ml) were added subsequently at 0°C ethyl 2-bromoacetate (275 mg) and triethylamine (485 mg) and stirring was continued at 22"C for 1 .5 h. The mixture was evaporated and the residue partitioned between dichioromethane and saturated aqueous NaHCOa, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate/n-heptane) to give the title compound (289 mg) as a colorless oil.

MS (ESI, m/z): 257.2 [(M+H)^']. d) 6.6-Dimethyl-1 -(2,2,2-trifluoroethy!)piperazin-2-one

A solution of ethyl 2-[[2-methyl-2-(2.2.2-trifluoroethylamino)propyl]amino]acetate (288 mg) in aqueous hydrochloric acid (2N, 6 ml) was heated to 100 C and stirring was continued for 2.5 h. The pH of the mixture was adjusted to 10 with solid K₂C0₃, evaporated and the residue purified by flash chromatography (silica gel, methanol in dichloromethane, 0 to 10%) to give the title compound ( 32 mg) as a white soiid.

MS (ESI, m/z): 21 1 .1 [(M+H)^']. e) ) Methyl 2-[1 -(3,5-dimethy!phenyl)cyclopentyi]ethanimidate hydrochloride from example 2a was reacted with 6,6-dimethyl-1 -(2,2.2-trifluoroethyl)piperazin-2-one according to example Id to give example 14 (27%) as a yellow oil.

MS (ESI, m/z): 478.3 [(M+H)⁺].

Example 15

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl- spiro[4H-pyrazino[1 ,2-c]pyrimidine-3,3'-oxetane]-1 ,8-dione

To a suspension of benzyl (2,5-dioxopyrrolidin-l -yl) carbonate (2.34 g) in tetrahydrofuran (2.4 ml) was added at 0°C a suspension of methyl 3-aminooxetane-3-carboxylate (1 .0 g, prepared according to Eickmeier, C. et al. , US 20 3/0225593) in water (3.6 ml) followed by a suspension of sodium bicarbonate (1 .41 g) in water (7.2 ml) and stirring was continued at 22°C for 24 h. The mixture was extracted with ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate 3: 1 ) to give the title compound (1 .1 1 g, 62%) as a colorless oil.

MS (ESI , mix): 266.1 [(M+H)⁺]. b) Benzyl N-(3-formvloxetan-3-vl)carbamate

To a soiution of methyl 3-(benzyloxycarbony!amino)oxetane-3-carboxylate (1 .93 mg) In tetranydrofuran (19 ml) was added dropwise at O' C a solution of lithium aluminum hydride (1 M in tetranydrofuran (6.5 ml) and stirring was continued at 0°C for 30 rniri. The mixture was partitioned between ethyl acetate and saturated aqueous potassium sodium tartrate, the organic layer was washed with brine, dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate in n-heptane. 20 to 100%) to give a first fraction containing benzyl N-[3-(hydroxymethy!)oxetan-3-yl]carbarrtate (759 mg). The second fraction contained the title compound (890 mg) as a colorless oil. MS (ESI , m/z): 234.1 [(M-H)^"]. c) Methyl 2-[[3-(benzvloxvcarbonvlamino)oxetan-3-vnmethylamino1acetate

To a solution of benzyl N-(3-formyloxetan-3-yl)carbamate (880 mg) in dichloromethane (27 ml) was added subsequently at 0°C methyl 2-aminoacetate hydrochloride (752 mg) and N. N- diisopropylethylamine (580 mg) and stirring was continued at 0°C for 30 min. Sodium triacetoxyborohydride (951 mg) was added In three portions and stirring was continued at 22°C for 15 h. The mixture was washed with saturated aqueous NaHC0₃, dried and evaporated. The residue was partitioned between aqueous hydrochloric acid (1 N) and ethyl acetate. The pH of the aqueous layer was adjusted to 10 using solid Na₂C0₃ and extracted with dichloromethane. The organic layer was dried and evaporated to give the title compound (318 mg) as a light yellow oil.

MS (ESI, m/z): 309.2 [(M+H)⁺].

2-Qxa-5,8-diazaspirof3.5]nonan-6-one

To a solution of methyl 2-[[3-(benzyloxycarbonylamino)oxetan-3-yl]methylamino]acetate (300 mg) in methanol (6 ml) was added at 22 °C palladium on carbon (10% Pd, 31 mg) and the mixture was hydrogenated at 22^CC and under normal pressure for 1 h. The suspension was filtered, the filtrate (consisting of a mixture of cyclized product and ring open intermediate) treated with potassium carbonate (67 mg) and stirring was continued at 22 'C for 15 min. The suspension was filtered and the filtrate evaporated to give the crude title compound (214 mg) as off-white waxy solid, which was used without further purification.

MS (ESI. m/z): 143.0 [(M+H)⁺], e) tert-Butyl 6-oxo-2-oxa-5.8-diazaspiro[3.5lnonane-8-carboxylate

To a solution of 2-oxa-5,8-diazaspiro[3.5]nonan-6-one (213 mg) in dimethylformamide (4 ml) was added subsequently at 22°C a solution of Boc-anhydride (382 mg) in dimethylformamide (4 ml) and N,N-diisopropyiethylamine (289 mg) and stirring was continued at 22 C for 15 h. The mixture was evaporated (at high vacuum, 45°C), the residue partitioned between water (10 ml) and ethyl acetate (10 ml), the organic layer was washed with aqueous hydrochloric acid (0.1 M), dried, evaporated and the residue purified by flash chromatography (silica gel, n- heptane/ethyl acetate 2:3) to give the title compound (126 mg) as a light yellow solid. MS (ESI, m/z): 185 9 [(M+H- isobutenef]. f) tert-Butyl 5-methvl-6-oxo-2-oxa-5.8-diazaspiro[3.51nonane-8-carboxylate

To a solution of tert-butyl 6-oxo-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate (125 mg) In dimethylformamide (1 ml) was added at 22°C sodium hydride (60% in oil, 29 mg) in 2 portions and stirring was continued at 22°C for 10 minutes. Methyl iodide (1 17 mg) was added and stirring was continued at 22°C for 1 h. The mixture was partitioned between water (10 ml) and ethyl acetate (10 ml), the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, nheptane/ethyl acetate 2:3) to give the title compound (1 16 mg) as a colorless oil.

MS (ESI, m/z): 201 .1 [(M+H- isobutenef]. g) 5-Methyl-2-oxa-5.8-diazaspirof3.51nonan-6-one

To a solution of tert-butyl 5-methyl-6-oxo-2-oxa-5,8-diazaspiro[3 5jnonane-8-carboxylate (1 13 mg) in dichioromethane (1 ml) was added at 22°C trifluoroacetic acid (101 mg) and stirring was continued at 22°C for 30 min. A further portion of trifluoroacetic acid (302 mg) was added and stirring at 22' C was continued for 15 h. The mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous NaHCOj. The organic layer was dried and evaporated to give a few mg of the impure title compound. The aqueous layer was evaporated, the residue triturated with methanol, filtered and the filtrate evaporated to give the title compound (51 mg) as a white, slightly sticky solid.

MS (ESi, m/z): 157.0 [( +H)^*]. h) Methyl 2-[1 -(3,5-dimethyiphenyi)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with 5-methyl-2-oxa-5.8-diazaspiro[3.5]nonan-6-one according to example 1 d to give example 15 (48%) as an off -white solid. MS (ESI, m/z): 424.3 [(M+H)l

Example 16

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyclopentyl]methyl]-3,9-dihydroxy-2,3- dimethyl-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 4-Benzyl-6-hvdroxy-1 ,6-dimethyl-piperazin-2-one

To a solution of 4-benzyl-1 -methyi-piperazine-2.6-dione (104 mg, prepared according to Carotti, A. Et al, Farmaco, Edizione Scientifica (1977), 32(3), pages 186-94) In tetrahydrofuran (1.8 ml) was added at -78°C methyl lithium (3M in diethoxymethane, 174 μΙ) and stirring was continued at -78°C for 3 h. The mixture was partitioned between diethyl ether and aqueous saturated NH₄CI solution, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate in n-heptane, 30 to 100%) to give the title compound (63 mg) as a colorless solid. MS (ESI, m/z); 235.2 [(M+H)^']. b) 4-Benzyl-6-ftert-butyl(dimethyl)silylloxy-1 ,6-dimethyl-piperazin-2-one

To a solution of 4-benzyl-6-hydroxy-1 ,6-dimethyl-piperazin-2-one (440 mg) and 2,6-lutidine (314 mg) in dichloromethane (1 1 ml) was added at 0°C tert-butyldimethylsilyl irifiuoromethanesulfonate (745 mg) and stirring was continued at 22°C for 2 d. The mixture was washed with aqueous saturated NaCI, the organic layer was dried, evaporated and purified by flash chromatography (silica gel, ethyl acetate in n-heptane 0 to 50%) to give the title compound (444 mg) as a colorless solid. MS (ESI, m/z): 349.3 [(M+H)⁺j. c) 6-[tert-Butyl(dimethvnsilvlloxv-1 .6-dimethyl-piperazin-2-one

A suspension of 4- en2yi-6-hydroxy-1 ,6-dimethyl-piperazin-2-orie (440 mg) and palladium hydroxide on carbon (44 mg) in methanol (5 ml) was hydrogenated at normal pressure and 22°C for 4 h. The suspension was filtered and the filtrate evaporated to give the crude title compound (326 mg) as a colorless oil, which was used without further purification. d) 3-rtert-Butyl(dimethyl)silylloxy-6-rf1-(3.5-dimethylphenyl)cvclopentyllmethv[1-9-hvd dimethy[-4H-pyrazinof 1 ,2-clpyrimidine-1 ,8-dione

Methyl 2-[1-(3,5-dimethylphenyi)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with 4-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-1 ,6-dimethyl-piperazin-2-one according to example I d to give the title compound (14%) as a light brown solid. MS (ESI, m/z): 526.4 [(M+H)*]. e) To a mixture of 3-[tert-butyl(dimethyi)siiyl]oxy-6-[[1 -(3,5-dimethylphenyl)cyclopentyl]methylj- 9-hydroxy-2_!3-dimethyl-4H-pyrazino[1 2-c]pyrimidine-1 ,8-dione (29 mg) in tetrahydrofuran (2 ml) was added at 0°C tetrabutylammonium fluoride (1 M, 83 μΙ) and stirring was continued at 22°C for 6 h. The mixture was neutralized with acetic acid (5 mg) evaporated and the residue purified by preparative HPLC (RP-18, acetonitrile/Η,Ο containing 0.23% of HCOOH) to give example 16 (13 mg) as a clorless solid.

MS (ESI, m/z): 412.3 [(M+H)^"'].

Example 17

Preparation of rac-(3S,11aR)-9-[[1 -{3,5-dimethylphenyl)cyclopentyl]rnethyl]-6-hydroxy- 3,11a-dimethyl-3,11-dihydro-2H-oxa2olot6,7]pyrazino[1 ,5-b]pyrimidine-5,7-dione

Methyl 2-[1 -(3,5-dimethylphenyl)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with rac-(3S.8aR)-3.8a-dimethyltetrahydro-2H-oxazolo[3_:2-a]pyrazm-5(3H)-one (prepared according to Bencsik, J. R. et a!., Organic Letters (2003). 5(15), pages 2727 to 2730) according to example 1 d to give the title compound (26%) as an off-white solid.

MS (ESI, m/z): 438.3 [(M+Hf ].

Example 18

Preparation of rac-(3S,11aR)-9-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-6-hydroxy-3- (hydroxymethyl)-11a-methyl-3,11 -dihydro-2H-oxazolo[6,7]pyrazino[1 ,5-b]pyrimidine-5,7- dione

Methyl 2-[1 -(3,5-dimethyiphenyl)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with rac-(3S.8aR)-3-(hydroxymethyl)-8a-methyl-3,6.7,8-tetrahydro-2H-oxazolo[3,2- a]pyrazin-5-one (prepared according to Bencsik, J. R. et a!., Organic Letters (2003), 5(15), pages 2727 to 2730) according to example "I d to give the title compound (16%) as an off-white solid.

MS (ESI, m/z): 454.3 [(M+H)⁺]_

Example 19

Preparation of rac-(3R,11aR)-9-[[1 -{3,5-dimethylphenyl)cyclopentyl]methyl]-6-hydroxy- 3,11a-dimethyl-3,11-dihydro-2H-oxazolo[6,7]pyrazino[1 ,5-b]pyrimidine-5,7-dione

a) Rac-(3R.8aR)-3.8a-dimethvl-3.6.7.8-tetrahvdro-2H-oxazolor3.2-alPvrazin-5-one

rac Rac-(3S,8aR)-3.8a-dimethyltetrahydro-2H-oxazolo[3,2-a]pyrazin-5(3H)-one (used for example 17) was prepared according to Bencsik, J. R. et ai., Organic Letters (2003), 5(15), pages 2727 to 2730. The crude material (1 .4 g) was purified by flash chromatography (silica gel, ethyl acetate in n-heptane, 25 to 50%) to give the faster e!uting rac-(3S,8aR)-3_:8a- dimethyltetrahydro-2H-oxazolo[3,2-a]pyrazin-5(3H)-one (764 mg) as a colorless oil and the title compound (86 mg) as the slower eluting epimer as a colorless oil.

MS (ESI. m/z): 305.1 [(Μ+Η)Ί. b) Methyl 2-[1 -(3,5-dimethylphenyl)cyclopentyl]ethanimidate hydrochloride from example 2a was reacted with rac-(3R.8aR)-3.8a-dimethyl-3,6.7.8-tetrahydro-2H-oxazolo[3,2-a]pyrazin~5- one according to example 1 d to give the title compound (39%) as an off-white solid. MS (ESI, m/z): 438.3 [(M+H)'].

Example 20

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyclopentyl]-hydroxy-methyl]-9-hydroxy-2- isopropyl-3,3-dimethyl-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 1-(3,5-Dimethvlphenyl)cyclopentanecarbaldehyde

To a light yellow solution of 1 -(3,5-dimethylphenyl)cyclopentanecarbonitrile (1 .0 g, prepared according to example 1 a - b but using 3,5-dimethyiphenyi)magnesium bromide in step a) in dichloromethane (25 ml) was added at -78 DIBAL-H (diisobutyialuminium hydride. 1 M in dichloromethane, 7.5 ml) and stirring was continued at -78°C for 3 h. The mixture was quenched at -78' C with aqueous hydrochloric acid (25%, 14 5 ml) and stirring was continued at 22°C for 16 h. The organic layer was dried and evaporated to give the crude title compound, which was used without further purification.

MS (ESI, m/z): 203 1 [(M+H) b) 2-[1-(3.5-Dimethvlphenvl)cvclopentvl1-2-hvdroxy-acetonitrile

To a yellow solution of 1 -(3,5-dimethylphenyl)cyclopentanecarbaldehyde (1 .0 g) in toluene (30 mi) was added at 0°C diethyiaiuminium cyanide (1 M in toluene, 7.4 mi) and stirring was continued at 0°C for 3 h. The reaction mixture was quenched by addition of an aqueous saturated solution of Rochelie salt (potassium sodium tartrate heptahydrate. 40 ml) and stirring was continued at 22°C for 16 h. The aqueous layer was extracted twice with dichloromethane, the combined organic layers were dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate) to give the title compound as a light yellow solid. c) Methyl 2-i1 -(3,5-dimethylphenyl)cyclopentyll-2-hvdroxy-ethanimldate hydrochloride

The title compound was prepared from 2-[1 -(3,5-dimethylphenyl)cyclopentyl]-2-hydroxy- acetonitrile according to example 1 c to give the product as a white solid.

MS (ESI, m/z): 262.2 [(M+H)⁺]. d) Methyl 2-[1 -(3,5-dimethyiphenyi)cyclopentyl]-2-hydroxy-ethanimidate hydrochloride was reacted with 1-isopropyl-6,6-dimethyl-piperazin-2-one according to example I d to give the title compound (7%) as an off -white solid.

MS (ES! . m/z): 454.4 [(M+H)⁺]. Example 21

Preparation of rac-6-[[1 -(3,5-dimethylphenyl)cyclopentyl]-hydroxy-methyl]-9-hydroxy- 2,3,3-trimethyl- H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Methyl 2-[1 -(3_!5-dimethylphenyl)cyclopentyl]-2-hydroxy-ethanimidate hydrochloride was reacted with 1 ,6,6-trimethylpiperazin-2-one (from example 5d) according to example 1 d to give the title compound (6%) as an off-white solid.

MS (ESI, m/z): 426.3 [(M+H)'].

Example 22

Preparation of 6-[[1 -(3,5-dimethylphenyl)cyciopentyl]methyl]-9-hydroxy-2-methyl- spiro[4H-pyrazino[1 ,2-c]pyrimidine-3,4'-tetrahydropyran]-1 ,8-dione

The title compound was prepared in analogy to example 8a - f but using 4- (benzyloxycarbonylamino)tetrahydropyran-4-carboxylic acid (in step a) to give the title compound (21 %) as an off-white solid.

MS (ESI, m/z): 452.4 [(M+H)']. Example 23

Preparation of rac-6-[[1 -(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-3,3- dimethyl-2-(2,2,2-trifluoro-1 -methyl-ethyl)-4H-pyrazino[1 ,2-c]pyrimidine-1 ,8-dione

The title compound was prepared in analogy to example 14 but using 1 , 1 ,1 -trifiuoropropan-2- amine in step a to give the title compound (27%) as a light brown solid.

MS (ESI, m/z): 492.2 [(M+H)l

Claims

A compound having the general formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystai, tautomer. racemate, enantiomer, or diastereomer or mixture thereof,

(I) wherein

R¹⁰ is selected from -H, -(optionally substituted C,_₆ alkyl group) and -C(0)-(optionally substituted d_₆ alky! group),

R¹¹ is -H, -OH, -CH₂-OH, a -d-s alkyl group, or a -d_.₆ alkyl group which is substituted by one or more halogen atoms;

R¹² is -H. -OH, -CH₂-OH, a -Ci_6 alkyl group, or a -d,-e alky! group which is substituted by one or more halogen atoms; wherein R¹¹ and R ² can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring;

R¹³ is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatcms selected from O. N and S and which R is -H, -(optionally substituted alkyl), -(optionally substituted C_:_₇ cycloalkyl), -(optionally substituted aryl), -(optionally substituted heterocycloalkyl), -(optionally substituted heteroaryl), -C^ alkyl— (optionaiiy substituted C₃_7 cycloalkyl), -d_4 alkyl— (optionally substituted aryl), -C^ aikyl— (optionally substituted heterocycloalkyl), or -C,_₄ alkyl— (optionally substituted heteroaryl);

R ⁷ is -R or -Ci ₄ alkyl-R, wherein R is selected from -XH, -COOH, -COO-(optionally substituted C- ._e alkyl). -(optionally substituted C _1-£ alkyl), -(optionally substituted C₃_₇ cycloalkyl), -(optionally substituted aryl), -(optionally substituted heteroaryl), -(optionally substituted heterocycloalkyl), -X-(optional!y substituted C _e alkyl), -X-(optionally substituted Cs_- cycloalkyl), -X-(optionally substituted aryl), -X-(optionally substituted heterocycloalkyl), or -X-(optionally substituted heteroaryl), wherein X is O or S;

R¹⁸ is independently selected from -C-_e alkyl and -C₃_- cycloalkyl; wherein R¹ ' and R '° can be joined together to form an optionally substituted 3- to 7-membered carbo- or heterocyclic ring, or alternatively, wherein R¹⁴ and R¹⁷ can be joined together to form an optionally substituted 3- to 7-membered heterocyclic ring which can optionally be benzannulated, wherein the optional substituent(s) of the optionally substituted alkyl group is one or more substituents R^a wherein each

R^a is independently selected from -C(0)-Ci ₆ alkyl, -Hal, -CF₃, -CN, -COOR^**.

-(CH;)_:-OR^**, -S(0)R^**, -S(0)₂R^**, -(CH₂)_qNR**R*^**, -C(0)~NR^**R^*** and _N **_C(0)-C₁_e alkyl; wherein the optional substituent(s) of the optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted 3- to 7-membered carbo- or heterocyclic ring and/or optionally substituted 3- to 7-membered heterocyclic ring is one or more substituents R , wherein each R^b is independently selected from -C^ alkyl, -C(0)-C, ₆ alkyl, -Hal. -CF₃, -CN, -COOR^**, -(CH₂)_q-OR**, -S(0)R^**, -S(0)₂R^**, ~(CH₂)_qNR^**R*^**, -C(0)-NR*^*R^*** and -NR^4*-C(0)-C_1-6 alkyl; wherein the optional substituent(s) of the optionally substituted hydrocarbon group is one or more substituents R^d, wherein each

R^d is independently selected from -C« alkyl, -C-_e alkenyl, -C-,-₆ alkinyl, -C(0)-d_6 alkyl, -Hal, -CF₃, -CN, -OH, -CH₂C(0)OH. -CH_?C(0)OC, _e alkyl, -O-Ci. 6 alkyl, -C₃-₇ cycloalky!, -COOR**, -(CH₂)_q-OR^**, -(CH₂)_q-CN, -S(0)R**, -S(0)₂R^**, -(CH₂)_qNR^**R***, -C(0)-NR^**R^***. -NR^**-C(0)-C₁__¾ alkyl, -C=C-0- C,_5 alkyl, -aryl, -heterocycloalkyl and -heteroaryl; wherein

R*** is selected from -H, and -C_;_₆ alkyl;

R** is selected from -H, -Ci s alkyl which is optionally substituted with one or more halogen atoms, and -(CH₂CH₂0)_rH;

r i to 3; and

q is 0 to 4.

The compound according to claim 1 , wherein R¹³ comprises at least one cycloalkyl group and at least one aryl group.

The compound according to claim 1 or 2, wherein R ¹ and R¹² are -H.

The compound according to any of claims 1 to 3, wherein R ⁰ is -H, -C(0)-C-._J5 alkyl group, wherein the alkyl group can be optionally substituted by one or more halogen atoms, or a -C,_₆ alkyl group which may optlonai!y be substituted by one or more halogen atoms.

The compound according to any of claims 1 to 4, wherein R^" and R ⁸ are joined together to form an optionally substituted 3- to 7-membered heterocyclic ring.

The compound according to any of claims 1 to 5. wherein R¹⁴ and R¹⁷ are joined together to form an optionally substituted 3- to 7-membered heterocyclic ring. The compound according to any of claims 1 to 6, wherein R¹³ is selected from

wherein one or more R are present and R is independently selected from -C,_₆ aikyi, -CF_3l -halogen, -CN. -OH, and -0-d_₆ alkyl.

A pharmaceutical composition comprising:

a compound having the general formula (I) as defined in any of claims 1 to 7. optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug. cocrystal, tautomer, racemate, enantiomer. or diastereomer or mixture thereof, and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).

A compound having the general formula (!) as defined in any of claims 1 to 7, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal tautomer. racemate, enantiomer. or diastereomer or mixture thereof, wherein the compound is for use in the treatment, amelioration or prevention of a viral disease caused by Herpesviridae, Filoviridae, Paramyxoviridae. Rhabdoviridae. Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae. Picornaviridae, Togaviridae, or Flaviviridae.

A method of treating, ameliorating or preventing a viral disease caused by Herpesviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae Picornaviridae, Togaviridae, or Flaviviridae; the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (I) as defined in any of claims 1 to 7, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.

A compound having the general formula (I) as defined in any of claims 1 to 7, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate. enantiomer, or diastereomer or mixture thereof, wherein the compound is for use in the treatment, amelioration or prevention of influenza.

A method of treating, ameliorating or preventing influenza; the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (I) as defined in any of claims 1 to 7, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.