WO2017158147A1 - 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, 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,

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 H1N1 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 M2 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. It 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 single point mutation would be enough to confer resistance to oseltamivir (Neumann et al., Nature 2009, 18, 459(7249), 931-939). This has already happened in the case of some seasonal H1 N1 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 H5N1 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 al., 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, 113-122). 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 89-1 93). 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.

It has been surprisingly found that the compounds according to the present invention which have this type of substituent at the pyrimidone ring exhibit improved properties compared to the compounds disclosed in WO 2010/147068 and WO 2014/108406. In particular, the interaction with protein could be optimized resulting in better binding properties.

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 Kolbl, 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 imply 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.

"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. 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, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, 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. Sci., 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-stoichometric 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 as well as the groups disclosed in Prog. Med. 5: 2157-2161 (1985) and provided by The British Library - "The world's Knowledge". Preferred examples of the prodrug include compounds in which R¹⁰ is replaced by P(0)(0)OR¹⁹; C(0)OR¹⁹; C(0)R¹⁹; C(R)₂-R¹⁹ or R¹⁹; wherein R¹⁹ is selected from C^o aryl, C_1-6 alkylene-C₅-io aryl, d_6 alkyl, d_₆ alkylenei-O-C^ alkyl)n (with n = 1 to 30), C-i_e alkylene-C(0)OR, C5_₁₀ arylene-C(O)OR, alkylene-0-C(0)OR and alkylene-0-C(0)R. The group R is H or d_6 alkyl.

In the prodrugs of the present invention, the "R¹⁰" group in -OR¹⁰ may be a group converted into an -OH group in vivo. Preferably the groups selected from various substituted carbonyl groups, substituted lower alkyl oxy groups (e.g., substituted oxymethyl), optionally substituted cyclic group lower alkyl (e.g., optionally substituted cyclic methyl group), and optionally substituted imino lower alkyl (e.g., optionally substituted imino methyl) are exemplified, and examples preferably include a group selected from the following formulae a) to y).

a) -C(=O)-R^10a,

b) -C(=O)-R^10b,

c) -C(=O)-L^,-R^10b,

d) -C(=O)-L'-O-R^10b, e) -C(=O)-L^,-O-L^,-O-R¹⁰ ,

f) -C(=O)-L'-O-C(=O)-R^10b,

g) -C(=O)-O-R^10c,

h) -C(=O)-N(R^10c)₂,

i) -C(=O)-O-U-O-R^10c,

j) -CH₂-R ^0d,

k) -CH₂-O-L^,-O-R^10d,

I) -CH₂-O-C(=O)-R^10d,

m) -CH₂-O-C(=O)-O-R^10d,

n) -CH(-CH₃)-O-C(=O)-O-R^10d,

o) -CH₂-O-C(=O)-N(-K)-R ^0d,

p) -CH₂-O-C(=O)-O-L'-O-R^10d,

q) -CH₂-O-C(=O)-O-L'-N(R^10d)_2l

r) -CH₂-0-C(=0)-N(-K)-L'-0-R

s) -CH₂-O-C(=O)-N(-K)-L'-N(R^10d)_2l

t) -ΟΗ₂-0-0(=0)-0-Ι_'-0-Ι_·-0-^^ω,

u) -0Η₂-Ο-0(=Ο)-Ο-υ-Ν(-Κ)-0(=Ο)-^^Μ,

v) -CH₂-0-P(=0)(-OH)₂,

w) -CH₂-0-P(=0)(-OBn)₂,

x) -CH₂-R^10e

y) -C(=N⁺R^10f ₂)(-NR ^0f ₂) wherein

L' is straight or branched lower alkylene,

K is hydrogen, or straight or branched lower alkylene, or straight or branched lower alkenylene,

R^10a is lower alkyl optionally substituted with one or more R^10g, or lower alkenyl optionally substituted with one or more R^10g,

R^10b is a carbocyclic group optionally substituted with one or more R^10g, a heterocyclic group optionally substituted with one or more R¹°⁹, lower alkyl amino optionally substituted with one or more R^10g, or lower alkylthio optionally substituted with one or more R^10g,

R^10c is lower alkyl optionally substituted with one or more R^10g, a carbocyclic group optionally substituted with one or more R^10g, or a heterocyclic group optionally substituted with one or more R^10g, R^10d is lower alkyl optionally substituted with one or more R¹°⁹, a carbocyclic group optionally substituted with one or more R^10g, a heterocyclic group optionally substituted with one or more R^10g, lower alkyl amino optionally substituted with one or more R¹°⁹, carbocycle lower alkyl optionally substituted with one or more R^10g, heterocycle lower alkyl optionally substituted with one or more R¹⁰⁹, or lower alkylsilyl,

R^10e is carbocyclic group optionally substituted with one or more R¹°⁹, or heterocyclic group optionally substituted with one or more R^10g, and

R^10f is lower alkyl optionally substituted with one or more R^10g,

R^10g is selected from oxo, lower alkyl, hydroxy lower alkyl, amino, lower alkylamino, carbocycle lower alkyl, lower alkylcarbonyl, halogen, hydroxy, carboxy, lower alkylcarbonylamino, lower alkylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro.

In the above definitions of R^10a to R^10g, the term "lower" refers to d.7, except for lower alkenyl and alkenylene, where it refers to C2-7.

As the group to form a prodrug, the "R¹⁰" group in -OR¹⁰ group in the formula (I) is preferably a group selected from the following b), I), m), and n).

b) -C(=O)-R^10b,

I) -CH₂-O-C(=O)-R^10d,

m) -CH₂-O-C(=O)-O-R^10d,

n) -CH(-CH₃)-O-C(=O)-O-R^10d

wherein each symbol is as defined above.

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 formula (I)

following definitions apply. is -H, -(optionally substituted alkyl group) or -C(0)-(optionally substituted Ci_e alkyl group). R¹⁰ is preferably -H, -C(0)-C-i_6 alkyl group, wherein the alkyl group can be optionally substituted by one or more halogen atoms, or a -Ci_e alkyl group which may optionally be substituted by one or more halogen atoms. More preferably, R¹⁰ is -H, -Ci_6 alkyl group or -CCOy-C^ alkyl group. Even more preferably R¹⁰ is -H. is independently -H, a -C^ alkyl group, a C₃_₇ cycloalkyi group or a -Ci_6 alkyl group which is substituted by one or more halogen atoms; preferably R ¹ is -H. is independently a -C^ alkyl group, a -C^ alkenyl group or a C₃_₇ cycloalkyi group; or wherein two R¹² can be joined together to form a 3- to 7-membered cycloalkyi ring.

In one embodiment, R¹² is independently a -Ci_6 alkyl group, a -Ci_6 alkenyl group or a

C₃_₇ cycloalkyi group. Preferably, R¹² is independently a -C^ alkyl group.

In another embodiment, two R¹² are joined together to form a 3- to 7-membered cycloalkyi ring, preferably a 5- or 6-membered cycloalkyi ring.

R¹³ is independently -H, -halogen, -CN, -OH, -0-(Ci_e alkyl group, wherein the alkyl group is optionally substituted by halogen) or -(C^ alkyl group, wherein the alkyl group is optionally substituted by halogen). R¹⁴ is -H, -(optionally substituted d-s alkyl), -(optionally substituted C₃_₇ cycloalkyi), - (optionally substituted aryl), -(optionally substituted heterocycloalkyl), -(optionally substituted heteroaryl), -Ci_₄ alkyl— (optionally substituted C₃_₇ cycloalkyi), - _4 alkyl— (optionally substituted aryl), -C _-4 alkyl— (optionally substituted heterocycloalkyl), or -d-4 alkyl— (optionally substituted heteroaryl). R¹⁴ is preferably -(optionally substituted Ci_e alkyl). R¹⁴ is more preferably selected from -CH₃, CH(CH₃)₂ and CH(CH₃)(CF₃).

R ⁵ is selected from -H, -C1-6 alkyl, -OH and -O-C^ alkyl; preferably R^1S is -H. m is 1 , 2 or 3, preferably 1 or 2. n is 1 , 2 or 3, preferably 1 or 2. o is 0, 1 , 2, 3 or 4, preferably 0. 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)-d_6 alkyl, -Hal, -CF₃, -CN, -COOR**, -OR**, -S(0)R**, -S(0)₂R**, -(CH₂)_qNR**R***, -C(0)-NR**R*** and -NR**- C(0)-d_6 alkyl; wherein the optional substituent(s) of the optionally substituted cycloalkyi group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group and/or optionally substituted hydrocarbon group is one or more substituents R^b, wherein each R^b is independently selected from -Ci_e alkyl, -^OJ-d^ alkyl, -Hal, -CF₃, -CN, -COOR**, -OR**, -S(0)R**, -S(0)₂R**, -(CH₂)_qNR**R***, -C(0)-NR**R*** and -NR**- C(0)-C^ alkyl; wherein

R*** is selected from -H, and -Ci_₆ alkyl;

R** is selected from -H, -d-e 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 cycloalkyi 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 -O-C^ alkyl. Preferably the substituent of the optionally substituted alkyl group is -halogen, more preferably F.

wherein t is 1 to 5, preferably 1 to 3.

Non-limiting examples of the compounds are given in the examples section and further include the following compound:

The present inventors have surprisingly found that the compounds according to the present invention which have this type of bulky substituent at the pyrimidone ring exhibit improved pharmacological properties. Without wishing to be bound by theory it is assumed that these compounds provide improved cellular activity.

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 well 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 capslet, lozenge, a liposome, a suppository, a plaster, 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 injectionable 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 thimersal. 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, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl 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, alginic 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 stearyl 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 propellant, 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 propellant 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 daily.

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, Papillomaviridae, Polyomaviridae, Parvoviridae, Hepadnaviridae, Reoviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Hepeviridae, Caliciviridae, Astroviridae, Togaviridae, Flaviviridae, Deltavirus, Bornaviridae, and prions. Preferably viral diseases which are caused by Herpesviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, 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

Papillomaviridae 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

Junin virus,

Machupo virus

Sabia virus

Coronaviridae 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 thogotovirus. 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 dual-labelled 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 JM. Curr Protoc Microbiol. Influenza: propagation, quantification, and storage. 2006 Dec;Chapter 15:Unit 15G.1. doi: 10.1002/0471729256. mc15g01s3) 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 lung 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 1X 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 1X PBS and then infected with virus, MOI 0.1 in 10μΙ 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 Nano-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 CellTiter-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.mc15g01s3), and stocks frozen at -80°C. Viral infections were carried out using DMEM Glutamax supplemented with 0.3% BSA (Sigma), 25mM Hepes (Sigma), and 1X penicillin/streptomycin (Invitrogen).

IC50_S of viral replication inhibition in a celi-based Luciferase Reporter Assay (LRA)

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 (R² = H, Scheme 1) can be prepared by reaction of a substituted phenyl magnesium halogenide (halogen being CI, Br or I) with an alkyl 2-cyano-2- cyclopentylidenacetate or an alkyl 2-cyano-2-cyclohexylidenacetate in the presence of copper (I) cyanide and in a solvent such as ethers, e.g. diethyl ether or preferably tetrahydrofuran, at temperatures between -50°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 0°C, preferably at 0°C.

Amidines of formula 6 are prepared by the reaction of methylimidates 4 with piperazinones 5 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.

Compounds of formula 2 (R² = Me) can be prepared from compounds of formula 2 (R² = H) by deprotonation with sodium hydride followed by reaction with an alkyl iodide, e.g. methyl iodide, in a solvent such as e.g. dimethylacetamide at 0 to 22°C. Scheme 2

11 13

Piperazinones 5 can be prepared by various methods (Scheme 2). A first method starts with the reaction of sulfonamide acetic acid 7 and amines 8 (R = CH(Me)CF₃) in the presence of a coupling reagent, preferably S-(1-oxido-2-pyridinyl)-1 ,1 ,3,3-tetramethylthiouronium hexafluoro-phosphate (HOTT), and an amine, e.g. diisopropylamine, in a solvent such as dimethylformamide at room temperature to give the amides 9.

Cyclization of amides 9 can be accomplished with 1 ,2-dibromoethane and a base, preferably potassium carbonate, in a solvent such as acetonitrile at elevated temperature, e.g. at 110°C, yielding protected piperazinones 10.

Deprotection of 10 can be effected with thiophenol and a base, preferably potassium carbonate, in a solvent such as acetonitrile at room temperature to give piperazinones 5.

In another method, Boc protected piperazinone 11 was reacted with halogen substituted aromatic residues, preferably X = iodo substituted aromatic residues 12 (R¹ = 2,6- dichlorophenyl, 1-methylpyrazol-3-yl, 4-pyridyl and 1-methylimidazol-4-yl) in the presence of copper (I) iodide, potassium phosphate tribasic and a base, e.g. Ν,Ν'-dimethylethylenediamine in an ether, preferably dioxane, at 100°C to give the boc protected piperazinones 13.

Deprotection of 13 can be accomplished with trifluoroacetic acid or hydrochloric acid in dioxane and dichloromethane at room temperature to give the piperazinones 5. In an yet another method Boc protected piperazinone 11 was reacted with halogen substituted alkyl residues, preferably X = bromo substituted alkyl residues 12 (R¹ = tert- butyl(dimethyl)silyl]oxyethyl, 2-methoxyethyl and 2-(trifluoromethoxy)ethyl) in the presence of a hydride, preferably sodium hydride, in a solvent such as dimethylformamide at room temperature, to give boc protected piperazinones 13, which can be deprotected as described above.

Scheme 3

17 18 In an alternative route, compounds of formula I (Scheme 3) can be prepared from nitriles 14 and 1 ,4-dibromobutane or 1 ,5-dibromopentane in the presence of a hydride, e.g. sodium hydride, in a solvent mixture of dimethylsulfoxide and diethylether at room temperature to give the alkylated nitriles 15. Nitriles 15 are reduced to aldehyds 16 using an aluminium hydride reagents, preferably diisobutylaluminium hydride, in a solvent such as dichloromethane at low temperature, preferably at -70°C.

Aldehydes 16 can be converted to nitriles 3 (R³ = H) with toluenesulfonylmethyl isocyanide and a base, preferably potassium t-butoxide, in a solvent such as ethers, preferably tetrahydrofurane, at -50°C. Alternatively, aldehydes 16 might be reduced to the alcohols 17 activated to the mesylates 18 and subsituted with cyanide to give nitriles 3 (R³ = H).

In an alternative method (R² = OH) aldehydes 16 are reacted with cyanodiethylaluminum in an inert solvent such as toluene at 0°C affording the hydroxynitriles 3 (R³ = H). Scheme 4

25 (R³ or R⁴ or R⁵ = alkyl, alkenyl or cycloalkyl)

I (R³ or R⁴ or R⁵ = alkyl,

I (R³ or R⁴ or R⁵ = Br)

alkenyl or cycloalkyl)

In yet an alternative route, compounds of formula I (Scheme 4) can be prepared by reaction of nitriles 4 (R² = H, R³ or R⁴ or R⁵ = Br) with ammonium chloride in the presence of tri- methylaluminium in a solvent such as toluene at 0 to 80°C to give amidines 19.

The reaction of amidines 19 with 4-methyl (2E)-3-(benzyloxy)-2-hydroxybut-2-enedioate in the presence of a base such as sodium methoxide in a solvent like methanol at room temperature yields the pyrimidine derivatives 20. Pyrimidine derivatives 20 can be converted to the acids 21 with a base such as lithium hydroxide in a solvent mixture of water and tetrahydrofuran at elevated temperature, e.g. at 70°C. Coupling of the acids 21 to the amides 22 can be accomplished with a O-silyl protected hydroxyethylamine, e.g. {2-[(tertbutyldimethylsilyl)oxy]ethyl}(methyl)amine in the presence of an activating agent such as e.g. 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluoro-phosphate in the presence of a base, e.g. diisopropylethylamine, in a solvent such as dimethylformamide at room temperature.

The silyl protecting group of amides 22 can be cleaved by reaction with an acid, e.g. hydrochloric acid, in a solvent such as dioxane at room temperature to give the alcohols 23.

Alcohols 23 can be cyclized by the Mitsunobu reaction using diethylazodicarboxylate and triphenylphosphine in a solvent such as dichloromethane at room temperature affording the pyrazino-pyrimidines 24.

Compounds of formula I (R² = H, R³ or R⁴ or R⁵ = Br) can be obtained from benzyl protected compounds 24 by deprotection with an acid, e.g. sulfuric acid, in a solvent such as acetic acid at room temperature. Alternatively, hydrogenation in the presence of a palladium catalyst can be employed as well.

Compounds of formula I (R² = H, R³ or R⁴ or R⁵ = alkyl, alkenyl or cycloalkyl) can be prepared from compounds of formula I (R² = H, R³ or R⁴ or R⁵ = Br) by the Suzuki reaction with an alkyl, alkenyl or cycloalkyl boronic acid or ester in the presence of a catalyst, preferably 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichioride dichloromethane complex, and a base, e.g. sodium carbonate, in solvent mixture of dioxane and water at elevated temperature, e.g. at 80°C. Alternatively, the boronic acid or ester can be replaced by alkyl zinc bromide or dialkyl zinc reagents. Alkenyl residues can be reduced to the alkyl residue using hydrogenation with palladium as the catalyst.

In a further variant, benzyl protected compounds 24 can first be converted to the benzyl protected compounds 25 followed by deprotection to compounds of formula I (R² = H, R³ or R⁴ or R⁵ = alkyl, alkenyl or cycloalkyl). Example 1

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Ethyl 2-cyano-2-ri-(3-ethylphenyl)cvclopentyllacetate

To a suspension of copper (I) cyanide (4.32 g) in THF (28 ml) was added drop wise at 0°C a solution of (3-ethylphenyl)magnesium bromide in THF (1 M, 92 ml) and stirring was continued at 22°C for 1h. After cooling to 0°C, a solution of ethyl 2-cyano-2-cyclopentylideneacetate (6.0 g) in THF (14 ml) was added drop wise, the reaction mixture was allowed to warm to 22°C and stirring was continued for 16 h. The mixture was partitioned between aqueous half saturated sodium carbonate and ethyl acetate, the organic layer was dried, evaporation and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate, 5 : 1 ) to give the title compound (9.8 g) as an oil.

MS (ESI, m/z): 286.2 [(M-H)^"]. b) 2-f 1 -(3-Ethylphenvncvclopentyllacetonitrile

To a light yellow solution of ethyl 2-cyano-2-[1-(3-ethylphenyl)cyclopentyl]acetate (9.56 g) in dimethyl sulfoxide (130 ml) were subsequently added water (1.44 g) and sodium chloride (682 mg) and the mixture was heated to 160°C for 2 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 (4.88 g) as a light yellow oil, which was used without further purification.

MS (ESI, m/z): 214.2 [(M+H)⁺]. c) Methyl 2-H-(3-ethylphenyl)cvclopentyl1ethanimidate hydrochloride

To a light yellow solution of 2-[1-(3-ethylphenyl)cyclopentyl]acetonitrile (2.0 g) in Methanol (38 ml) was bubbled through at -15°C hydrogen chloride gas until the solution was saturated. The mixture was kept in the fridge for 3 d. In case of incomplete 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 colorless solid. In case that the residue does nor solidify it can be used directly. MS (ESI, m/z): 246.2 [(M+H)⁺]. d) To a solution of methyl 2-[1-(3-ethylphenyl)cyclopentyl]ethanimidate hydrochloride (2.0 g) and 1-methylpiperazin-2-one (1.62 g) in THF (150 ml) was added at 22°C diisopropylethyl amine (1.83 g) and after 5 min acetic acid (426 mg) and stirring was continued at 22°C for 16 h. The mixture can be further processed as described below or the intermediate 4-[2-[1-(3- ethylphenyl)cyclopentyl]ethanimidoyl]-1-methyl-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 cooled down to -30°C, a solution of lithium hexamethyldisilazide in THF (1 M, 50 ml) was added followed by diethyl oxalate (4.15 g) 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 22°C, partitioned between aqueous hydrochloric acid (1 N) and dichloromethane, the organic layer was dried, evaporated, the residue triturated with diethyl ether, filtered and the residue dried to give example 1 (1.40 g) as a white powder. Alternatively, the crude material can purified by preparative HPLC (RP-18, MeCN/H₂0 containing 0.23% of HCOOH).

MS (ESI, m/z): 382.3 [(M+H)⁺].

Example 2

Preparation of 9-Hydroxy-6-[[1-(3-methoxy-4-methyl-phenyl)cyclopentyl]methyl]-2- methyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 2 was prepared in analogy to example 1 starting with 4-bromo-2-methoxy-1 -methyl- benzene in step a to give the product as an off-white solid. MS (ESI, m/z): 398.3 [(M+H)⁺]. Example 3

Preparation of 6-[[1-(3,4-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 3 was prepared in analogy to example 1 starting with 4-bromo-1 ,2-dimethyl-benzene in step a to give the product as an off-white solid. MS (ESI, m/z): 382.3 [(M+H)⁺].

Example 4

Preparation of 9-Hydroxy-2-methyl-6-[(1-tetralin-6-ylcyclopentyl)methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 4 was prepared in analogy to example 1 starting with 6-bromotetralin in step a to give the product as an off-white powder.

MS (ESI, m/z): 408.4 [(M+H)⁺]. Example 5

Preparation of 9-hydroxy-6-[(1-indan-5-ylcyclopentyl)methyl]-2-methyl-3,4 dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 5 was prepared in analogy to example 1 starting with 5-bromoindane in step a to give the product as an off-white powder. MS (ESI, m/z): 394.3 [(M+H)⁺].

Example 6

Preparation of 9-hydroxy-2-methyl-6-[(1-tetralin-5-ylcyclopentyl)methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 1-Tetralin-5-ylcvclopentanecarbonitrile

To a suspension of NaH (60% suspension in oil, 1.00 g) in dimethylsulfoxide (10ml) was added a 0°C a solution of 2-tetralin-5-ylacetonitrile (2.00g, preparation: Kuendig, E.P. et al., Helvetica Chimica Acta (1991), 74(8), 2009-23) and 1 ,4-dibromobutane (2.52g) in diethylether (20 ml) and dimethylsulfoxide (20ml) and stirring was continued at 22°C for 16 h. The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate, 95 : 5) to give the title compound (1.80 g) as a greenish gum.

MS (ESI, m/z): 225.0 [(M)⁺]. b) 1 -Tetralin-5-ylcyclopentanecarbaldehvde

To a solution of 1-tetralin-5-ylcyclopentanecarbonitrile (800 mg) in dichloromethane (30ml) was added at -70°C diisobutylaluminium hydride (1 M, 7.1 ml) and stirring was continued at - 70°C for for 30 min. The mixture was quenched with saturated aqueous sodium potassium tartarate solution (100 ml) at -70°C and extracted with dichloromethane. The organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, n- heptane/ethyl acetate, 97 : 3) to give the title compound (550 mg) as a greenish gum.

MS (ESI, m/z): 228.0 [(M)⁺]. c) 2-(1-Tetralin-5-ylcyclopentyl)acetonitrile

To a stirred solution of potassium t-butoxide (1 M, 3.3 ml) in tetrahydrofurane (5 ml) was added at -50°C toluenesulfonylmethyl isocyanide (654 mg) in tetrahydrofurane (5 ml). After 15 min a solution of 1-tetralin-5-ylcyclopentanecarbaldehyde (450 mg) ) in tetrahydrofuran (10 ml) was added and stirring was continued at -50°C for 1 h. The mixture was warmed to 22°C. Methanol (2.5 ml) was then added and stirring was continued at 60°C for 16 h and at 80°C for 1 h. The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate, 97 : 3) to give the title compound (550 mg) as a colorless gum. MS (ESI, m/z): 239.0 [(M)⁺]. d) 2-(1-Tetralin-5-ylcyclopentyl)acetonitrile was converted in analogy to example 1c - d to example 6, which was obtained as an off-white solid. MS (ESI, m/z): 408.3 [(M+H)⁺].

Example 7

Preparation of 9-hydroxy-2-methyl-6-[[1-(p-tolyI)cyclopentyl]methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 2-ΙΊ -(4-Bromophenyl)cvclopentyllacetamidine hydrochloride

To a suspension of ammonium chloride (3.61 g) in dry toluene (150 ml) was added at 5°C tri- methylaluminium (2M in toluene, 34 ml) and stirring was continued at 22°C for 2 h. A solution of 2-[1-(4-bromophenyl)cyclopentyl]acetonitrile (6.00 g, preparation: Wolkerstorfer, A. et al., US patent application 2014/0194431 ) in toluene (30 ml) was added and stirring was continued at 80°C for 14 h. A suspension of silica gel (24 g) in chloroform (24 ml) was added at 0°C, stirring was continued at 22°C for 30 min and the suspension was filtered through a short bed of celite The residue was washed with methanol, the combined filtrates were evaporated, the residue was triturated with a solution of dichloromethane (180 ml) and methanol (20 ml) and the suspension was filtered and the filtrate evaporated to give the title compound (2.50 g) as a white solid.

MS (ESI, m/z): 280.8 [(M+H)⁺]. b) tert-Butyl 5-benzyloxy-2-rri-(4-bromophenvncvclopentyl1methvn-6-hvdroxy-pyrimicline-4- carboxylate

To a solution of 2-[1-(4-bromophenyl)cyclopentyl]acetamidine hydrochloride (2.50 g) and 1- tert-butyl 4-methyl (2E)-3-(benzyloxy)-2-hydroxybut-2-enedioate (2.68g, preparation: Wolkerstorfer, A. et al., US patent application 2014/0194431) in methanol (100 ml) was added at 0°C sodium methoxide solution (25% in methanol, 5.1 ml) and stirring was continued at 22°C for 16h. The mixture was diluted with hydrochloric acid (1 N, 50 ml) and evaporated, the residue partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate, 5 : 1) to give the title compound (2.50 g) as a yellow solid.

MS (ESI, m/z): 540.0 [(M)^*].

5-Benzyloxy-2-[[1-(4-bromophenvncvclope

To a solution tert-butyl 5-benzyloxy-2-[[1-(4-bromophenyl)cyclopentyl]methyl]-6-hydroxy- pyrimidine-4-carboxylate (2.50 g) in tetrahydrofuran (65 ml) and water (35 ml) was added at 22°C lithium hydroxide monohydrate (3.89 g) and stirring was continued at reflux temperature for 48h. The mixture was evaporated, the residue partitioned between water and ethyl acetate, the aqueous layer was acidified to pH 5 - 6 using aqueous hydrochloric acid (1 N), the suspension was filtered and the filtrate dried to give the title compound (1.50 g) as a white solid.

d) 5-Benzyloxy-2-fri-(4-bromophenyl)cvclopentvnmethyll-N-f2-rtert-butyl(dimethvnsilyl1oxy- ethyll-6-hvdroxy-N-methyl-pyrimidine-4-carboxamide

To a solution of 5-benzyloxy-2-[[1-(4-bromophenyl)cyclopentyl]methyl]-6-hydroxy-pyrimidine-4- carboxylic acid (1.50 g) and {2-[(tertbutyldimethylsilyl)oxy]ethyl}(methyl)amine (1.17 g) in dimethylformamide (30 ml) were added at 22°C diisopropylethylamine (1.5 ml) and 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1.48 g) and stiring was continued for at 22°C for 1h. The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane/ethyl acetate, 3 : 2) to give the title compound (2.50 g) as a yellow solid.

e) 5-Benzyloxy-2-f[1-(4-bromophenyl)cvclopentyllmethyll-6-hvclroxy-N-(2-hvdroxyethvn-N- methvl-Dvrimidine-4-carboxamide

To a solution of 5-benzyloxy-2-[[1-(4-bromophenyl)cyclopentyl]methyl]-N-[2-[tert- butyl(dimethyl)silyl]oxy-ethyl]-6-hydroxy-N-methyl-pyrimidine-4-carboxamide (1.50 g) in dioxane (40 ml) was added a solution of hydrochloric acid in dioxane (4M, 24 ml) and stirring was continued at 22°C for 1 h. The mixture was evaporated, the residue triturated with n- hexane/ethyl acetate, 95 : 5 and dried to give the title compound as a white solid.

MS (ESI, m/z): 540.1 [(M+H)^*].

f) 9-Benzyloxy-6-rri-(4-bromophenv0cvclop

clpyrimidine-1 ,8-dione

To a solution of 5-benzyloxy-2-[[1-(4-bromophenyl)cyclopentyl]methyl]-6-hydroxy-N-(2- hydroxyethyl)-N-methyl-pyrimidine-4-carboxamide (1.00 g) in dichloromethane (50 ml) were subsequently added triphenyl phosphine (0.73 g) and diethylazodicarboxylate (0.48 g) and stirring was continued at 22°C for 20 min. The mixture was evaporated and the residue purified by flash chromatography (silica gel, 2% methanol in dichloromethane) to give the title compound (0.50 g) as a white solid.

MS (ESI, m/z): 521.9 [(M+H)⁺]. g) 6-ff1-(4-Bromophenyl)cvclopentyllmethyll-9-hvdroxy-2-methyl-3,4-dihvdropyrazinon ,2- clpyrimidine-1 ,8-dione

To a solution of 9-benzyloxy-6-[[1-(4-bromophenyl)cyclopentyl]methyl]-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (600 mg) in acetic acid (7 ml) was added at 10°C sulfuric acid (338 mg) and stirring was continued at 22°C for 1.5 h. The mixture was partitioned between water and dichloromethane, the organic layer was dried, evaporated to a volume of 3 ml, diethyl ether was added and stirring was continued at 0°C for 16 h. The suspension was filtered, the residue washed with diethyl ether and dried to give the title compound (437 mg) as a colorless solid.

MS (ESI, m/z): 532.0 [(M)⁺]. h) To a mixture of 6-[[1-(4-bromophenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (50 mg), methylboronic acid (11 mg), 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (5 mg) in dioxane (0.4 ml) were subsequently added at 22°C water (0.25 ml) and aqueous sodium carbonate (2 N, 0.17 ml) and stirring was continued at 80°C for 20 h. The mixture was treated with acetic acid (52 mg)and filtered through a glass fiber paper The residue was washed with water and dichloromethane, the filtrate was evaporated and the residue purified by preparative HPLC (RP-18, MeCN/H₂0 containing 0.23% of HCOOH) to give example 7 as a colorless powder.

MS (ESI, m/z): 368.2 [(M)⁺]. Example 8

Preparation of 9-hydroxy-6-[[1-(4-isopropylphenyl)cyclopentyl]methyl]-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

^a) 9-Hvdroxy-6-fri-(4-isopropenylphenyl)cvclopentynmethyll-2-methyl-3^-dihydro- pyrazinof 1 ,2-c1pyrimidine-1 ,8-dione

To a mixture of 6-[[1-(4-bromophenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (50 mg), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1 ,3,2-dioxaborolane (31 mg) and 1 ,1'-bis(diphenylphosphino)ferrocene-paliadium(ll)dichloride dichloromethane complex (5 mg) were subsequently added at 22°C dioxane (0.35 ml), water (0.25 ml) and an aqueous sodium carbonate solution (2 N, 0.2 ml) and stirring was continued at 80°C for 20 h. The mixture was treated with aqueous hydrochloric acid, filtered through a glass fiber paper, the residue was washed with dichloromethane and the filtrate was evaporated to give the crude title compound as an orange solid, which was used without further purification.

MS (ESI, m/z): 394.2 [( +H)^*]. b) A mixture of 9-hydroxy-6-[[1-(4-isopropenylphenyl)cyclopentyl]methyl]-2-methyl-3,4-dihydro- pyrazino[1 ,2-c]pyrimidine-1 ,8-dione (50 mg) and palladium on carbon (10%, 10 mg) in methanol (10 ml) was hydrogenated at 22°c and under normal pressure for 3 h. The mixture was filtered through a glass fiber paper, the residue washed with methanol and dichloromethane, the filtrate evaporated and the residue purified by preparative HPLC (RP-18, MeCN/H₂0 containing 0.23% of HCOOH) to give example 8 as a colorless powder.

MS (ESI, m/z): 396.2 [(M+H)⁺]. Example 9

Preparation of 6-[[1 -(4-cyclopropylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4 dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 9 was prepared in analogy to example 7h but using cyclopropylboronic acid to give the compound as an off-white solid. MS (ESI, m/z): 394.2 [(M+H)⁺].

Example 10

Preparation of 9-hydroxy-6-[[1-(3-isopropenylphenyl)cyclopentyl]methyl]-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

6-[[1-(3-Bromophenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4-dihydropyrazino[1 ,2- c]pyrimidine-1 ,8-dione (prepared in analogy to example 6a - d but using 2-(3- bromophenyl)acetonitrile in step a) was converted in analogy to example 8a to give example 10 as an off-white powder. MS (ESI, m/z): 394.2 [(M+H)⁺].

Example 11

Preparation of 9-hydroxy-6-[[1-(3-isopropylphenyl)cyclopentyl]methyI]-2-methyl-3,4' dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 11 , prepared from example 10 in analogy to example 8b, was obtained as an off- white solid.

MS (ESI, m/z): 396.0 [(M+H)⁺]. Example 12

Preparation of 9-hydroxy-6-[[1 -(2-isopropenylphenyl)cyclopentyl]methyl]-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 12, prepared in analogy to example 10, was obtained as an off-white solid. MS (ESI, m/z): 394.0 [(M+H)⁺]. Example 13

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

Example 13, prepared in analogy to example 7, was obtained as an off-white solid. MS (ESI, m/z): 368.2 [(M+H)⁺3. Example 14

Preparation of 9-hydroxy-2-methyl-6-[[1-(o-tolyl)cyclopentyl]methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 14, prepared in analogy to example 7, was obtained as an off-white solid. MS (ESI, m/z): 368.0 [(M+H)⁺]. Example 15

Preparation of 9-hydroxy-2-rnethyI-6-[[1-(2,4,6-trimethylphenyl)cyclopentyl]methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 15, prepared in analogy to example 6, was obtained as an off-white solid.

MS (ESI, m/z): 396.3 [(M+H)⁺].

Example 16

Preparation of 6-[[1-(4-tert-butylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 16, prepared in analogy to example 6 starting with 2-(4-tert-butylphenyl)acetonitrile, was obtained as a white solid. MS (ESI, m/z): 410.3 [(M+H)⁺]. Example 17

Preparation of 6-[[1-(2,4-dimethylphenyl)cyclopentyl]methyI]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 17, prepared in analogy to example 6 starting with 2-(2,4-dimethylphenyl)acetonitrile, was obtained as a colorless powder.

MS (ESI, m/z): 382.3 [(M+H)⁺].

Example 18

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

Example 18, prepared in analogy to example 6 starting with 2-(2,5-dimethylphenyl)acetonitrile, was obtained as a colorless powder.

MS (ESI, m/z): 382.3 [(M+H)⁺]. Example 19

Preparation of 6-[[1-(2,3-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 19, prepared in analogy to example 6 starting with 2-(2,3-dimethylphenyl)acetonitrile, was obtained as a colorless powder. MS (ESI, m/z): 382.3 [(M+H)⁺].

Example 20

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

Example 20, prepared in analogy to example 6 starting with 2-(3,5-dimethylphenyl)acetonitrile, was obtained as a colorless powder.

MS (ESI, m/z): 382.3 RM+H)⁺]. Example 21

Preparation of 9-hydroxy-6-[[1-(3-isobutylphenyl)cyclopentyI]methyl]-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 21 , prepared in analogy to example 1 , was obtained as a light red powder.

MS (ESI, m/z): 410.4 [(M+H)⁺].

Example 22

Preparation of 9-hydroxy-2-methyl-6-[[1 -(3-propylphenyl)cyclopentyl]methyi]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 22, prepared in analogy to example 11 , was obtained as an off-white powder. MS (ESI, m/z): 396.4 [(M+H)⁺]. Example 23

Preparation of 6-[[1-(3-cyclobutylphenyl)cyclopentyl]methyI]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1,2-c]pyrimidine-1,8-dione

To a mixture of 6-((1-(3-bromophenyl)cyclopentyl)methyl)-9-hydroxy-2-methyl-3,4-dihydro-1 H- pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (40 mg, prepared in analogy to 7g), [1 ,1 - bis(diphenylphosphino)ferrocene]-dichloropalladium(ll), complex with dichloromethane (15 mg) and dioxane (0.4 ml) was added at 22°C cyclobutylzinc(ll) bromide (0.37 ml) and stirring was continued at 80°C for 4 d. The mixture was partitioned between aqueous hydrochloric acid (1 N) and ethyl acetate, the organic layer was dried, evaporated and the residue purified by preparative HPLC (RP-18, MeCN/H₂0 containing 0.23% of HCOOH) to give the title compound (1 mg) as a light brown solid.

MS (ESI, m/z): 408.2 [(M+H)⁺]. Example 24

Preparation of 6-[[1-(3-fluoro-5-methyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 24, prepared in analogy to example 1 but using bromo-(3-fluoro-5-methyl- phenyl)magnesium in step a, was obtained as a brown solid.

MS (ESI, m/z): 386.2 [(M+H)⁺].

Example 25

Preparation of 9-hydroxy-2-isopropyI-6-[[1-(m-tolyl)cyclopentyl]methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 25, prepared in analogy to example 6a - d but using 2-(3-bromophenyl)acetonitrile in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one) and example 7h, was obtained as a colorless powder.

MS (ESI, m/z): 396.3 [(M+H)⁺]. Example 26

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

Example 26, prepared in analogy to example 18 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a colorless powder.

MS (ESI, m/z): 410.3 [(M+H)⁺].

Example 27

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-isopropyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 27, prepared in analogy to example 1 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white powder. MS (ESI, m/z): 410.3 [(M+H)⁺].

Example 28

Preparation of 9-hydroxy-2-isopropyl-6-[[1-(3-propylphenyl)cyclopentyl]methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 28, prepared in analogy to example 22 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a colorless powder.

MS (ESI, m/z): 424.4 [(M+H)⁺].

Example 29

Preparation of 9-hydroxy-2-isopropyl-6-[(1-tetralin-6-ylcyclopentyl)methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 29, prepared in analogy to example 4 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white powder.

MS (ESI, m/z): 436.4 [(M+H)⁺].

Example 30

Preparation of 9-hydroxy-6-[(1-indan-5-ylcyclopentyI)methyl]-2-isopropyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 30, prepared in analogy to example 5 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a white powder. MS (ESI, m/z): 422.4 [(M+H)⁺].

Example 31

Preparation of 9-hydroxy-2-isopropyl-6-[(1-tetralin-5-ylcyclopentyl)methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 31 , prepared in analogy to example 6 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white solid.

MS (ESI, m/z): 436.0 [(M+H)⁺]. Example 32

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

Example 32, prepared in analogy to example 3 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white solid. MS (ESI, m/z): 410.3 [(M+H)⁺].

Example 33

Preparation of 6-[[1-(3-fluoro-5-methyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2- isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 33, prepared in analogy to example 24 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as an off-white powder.

MS (ESI, m/z): 414.3 [(M+H)⁺]. Example 34

Preparation of 9-hydroxy-6-[[1-(3-isopropenylphenyl)cyclopentyl]methyl]-2-isopropyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 34, prepared in analogy to example 10 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a light red powder. MS (ESI, m/z): 422.3 [(M+H)⁺].

Example 35

Preparation of 9-hydroxy-2-isopropyl-6-[[1 -(3-isopropylphenyl)cyclopentyl]methyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 35, prepared in analogy to example 11 (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a colorless powder.

MS (ESI, m/z): 424.3 [(M+H)⁺]. Example 36

Preparation of 6-[[1-(3-bromo-5-methyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2- isopropyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 36, prepared in analogy to example 6 but using 2-(3-bromo-5-methyl- phenyl)acetonitrile in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2- one), was obtained as a white solid.

MS (ESI, m/z): 474.2 [(M+H)⁺].

Example 37

Preparation of 6-[[1-(3-chloro-5-methyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2- isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 37, prepared in analogy to example 1 starting with 1-bromo-3-chloro-5- methylbenzene in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a colorless solid.

MS (ESI, m/z): 430.2 [(M+H)⁺]. Example 38

Preparation of 9-hydroxy-2-isopropyl-6-[[1-(3-methyl-5-vinyl- phenyl)cyclopentyl]methyl]-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 38, prepared from example 36 by reaction with 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2- dioxaborolane (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a light brown solid.

MS (ESI, m/z): 422.3 [(M+H)⁺].

Example 39

Preparation of 6-[[1-(3-ethyl-5-methyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2- isopropyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 39, prepared from example 38 by hydrogenation (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a light brown solid.

MS (ESI, m/z): 424.3 [(M+H)⁺]. Example 40

Preparation of 6-[[1-(3,5-diethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-isopropyI-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 2-[1-(3,5-Diethylphenyl)cyclopentvnacetonitrile

To a mixture of 2-[1-(3,5-dibromophenyl)cyclopentyl]acetonitrile (200 mg, prepared in analogy to example 6 but using 2-(3,5-dibromophenyl)acetonitrile in step a) in dry dioxane (2.7 ml) were added subsequently 1 ,1'-bis(diphenylphosphino)ferrocene dichloropalladium(ll) complex with dichloromethane (33 mg) and diethylzinc (1 M in hexane, 624 μΙ) and stirring was continued at 60°C for 1.5 h. The mixture was quenched by the addition of aqueous ammonium chloride and methanol, evaporated and the residue partitioned between water and dichloromethane The organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, 0 - 20% ethyl acetate in n-heptane) to give the title compound (94 mg) as a light yellow liquid.

MS (ESI, m/z): 242.2 [(M)⁺]. b) 2-[1-(3,5-Diethylphenyl)cyclopentyl]acetonitrile was converted in analogy to example 1c - d (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one) to give example 40 as a white powder. MS (ESI, m/z): 438.3 [(M+H)⁺].

Example 41

Preparation of 6-[[1 -(4-f luoro-3,5-dimethyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2- isopropyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 41 , prepared in analogy to example 1 but using (4-fluoro-3,5- dimethylphenyl)magnesium bromide in step a (1-methylpiperazin-2-one replaced by 1- isopropylpiperazin-2-one), was obtained as a white solid.

MS (ESI, m/z): 428.3 [(M+H)⁺]. Example 42

Preparation of 6-[[1-(3-ethyl-4-fluoro-phenyl)cyclopentyl]methyl]-9-hydroxy-2-isopropyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 42, prepared in analogy to example 1 but using 4-bromo-2-ethyl-1-fluoro-benzene (preparation: Chu, X. et al., patent WO 2003097048) in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a white powder. MS (ESI, m/z): 428.3 [(M+H)⁺].

Example 43

Preparation of 6-[[1-(3-ethyl-5-fluoro-phenyl)cyclopentyl]methyl]-9-hydroxy-2-isopropyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 1 -Bromo-3-ethyl-5-fluoro-benzene

A mixture of 1-bromo-3-ethenyl-5-fluorobenzene (1.80 g, preparation: Buettelmann, B. et al., patent application WO 2003/097637), acetic acid (1.0 ml) in ethyl acetate (20 ml) and Pd-C (10%, 180mg) was hydrogenated at 22°C and normal pressure for 2 h. The mixture was filtered through a

celite bed. The filtrate washed with aqueous sodium hydrogen carbonate and brine, dried, evaporated and the residue purified by flash chromatography (silica gel, n-heptane) to give the title compound ( .60 g) as a light yellow liquid. b) 1-Bromo-3-ethyl-5-fluoro-benzene was converted in analogy to example 1 (1- methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one) to give example 43 as an off- white powder. MS (ESI, m/z): 428.3 [(M+H)⁺]. Example 44

Preparation of 9-hydroxy-2-isopropyl-6-[[1-[3-methyI-5-

(trifluoromethyl)phenyl]cyclopentyl]methyl]-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8- dione

Example 44, prepared in analogy to example 1 but using 1-bromo-3-methyl-5- (trifluoromethyl)benzene in step a (1-methylpiperazin-2-one replaced by -isopropylpiperazin- 2-one), was obtained as a white powder.

MS (ESI, m/z): 464.3 [(M+H)⁺]. Example 45

Preparation of 6-[[1-(5-ethyl-2-fluoro-phenyl)cyclopentyl]methyl]-9-hydroxy-2-isopropyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 45, prepared in analogy to example 1 but using 2-bromo-4-ethyl-1-fluoro-benzene (preparation: Zhang, X. et al., patent WO 2006076246) in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a colorless powder.

MS (ESI, m/z): 428.3 [(M+H)⁺].

Example 46

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

Example 46, prepared in analogy to example 1 but using 1-bromo-3,5-dimethyl-benzene in step a (1-methylpiperazin-2-one replaced by 1-isopropylpiperazin-2-one), was obtained as a colorless powder.

MS (ESI, m/z): 410.4 [(M+H)⁺].

Example 47

Preparation of 9-hydroxy-6-[[1-(m-tolyl)cyclopentyl]methyl]-2-(2,2,2-trifluoroethyl)-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 47, prepared in analogy to example 1d from methyl 2-[1-(m- tolyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2,2,2-trifluoroethyl)piperazin-2-one (preparation: Bayrakdarian, M. et al., patent WO 2008136756), was obtained as a solid.

MS (ESI, m/z): 436.2 [(M+H)⁺].

Example 48

Preparation of 9-hydroxy-6-[[1-(m-tolyl)cyclopentyl]methyl]-2-(2-phenylethyl)-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 48, prepared in analogy to example 1d from methyl 2-[1-(m- tolyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-phenylethyl)piperazin-2-one (preparation: Chambers, M. S. et al., Journal of Medicinal Chemistry (1999), 42(4), 691-705)), was obtained as a solid.

MS (ESI, m/z): 458.2 [(M+H)⁺].

Example 49

Preparation of 9-hydroxy-6-[(1-tetralin-5-ylcyclopentyl)methyI]-2-[(1S)-2,2,2-trifluoro-1- methyl-ethyl]-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) 2-[(4-Nitrophenyl)sulfonylamino1-N-r(1S)-2.2,2-trifluoro-1-methyl-ethyllacetamide

To a suspension of (2S)-1,1 ,1-trifluoropropan-2-amine hydrochloride (3.49 g) in dimethylformamide (35 ml) was added diisopropylamine (9.5 ml) and stirring was continued at 22°C for 10 min. 2-[(4-Nitrobenzene)sulfonamido]acetic acid (6.00 g) and S-(1-oxido-2- pyridinyl)-1 ,1 ,3,3-tetramethylthiouronium hexafluorophosphate (HOTT, 10.27 g) were added and stirring was continued for 2 h. The mixture was partitioned between water and ethyl acetate The organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, 10 - 30% ethyl acetate in n-heptane) to give the title compound (6.85 g) as an off-white solid.

MS (ESI, m/z): 353.9 [(M-H) ]. b) 4-(4-Nitrophenv0sulfonvH-rnS)-2,2,2-trifluoro-1-m

To a solution of 2-[(4-nitrophenyl)sulfonylamino]-N-[(1S)-2,2,2-trifluoro-1-methyl- ethyl]acetamide (2.20 g) in acetonitrile (20 ml) in a sealed tube were added subsequently potassium carbonate (2.57 g) and 1 ,2-dibromoethane (1.1 ml) and stirring was continued at 110°C for 22 h. The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, 5 - 17% ethyl acetate in n-heptane) to give the title compound (1.35 g) as an off-white solid. c) 1 -f( 1 S)-2.2.2-Trifluoro-1 -methyl-ethvnpiperazin-2-one

To a solution of 4-(4-nitrophenyl)sulfonyl-1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]piperazin-2-one (3.25 g) in acetonitrile (50 ml) were added at 22°C potassium carbonate (3.54 g) and thiophenol (2.6 ml) and stirring was continued at 22°C for 17 h. The mixture was filtered through a ceiite bed, the filtrate was evaporated and the residue was purified by flash chromatography (silica gel, 3% methanol in dichloromethane) to give the title compound (1.21 g) as a brown liquid.

MS (ESI, m/z): 196.0 [(M)⁺]. d) Example 49, prepared in analogy to example 1d from methyl 2-(1-tetralin-5- ylcyclopentyl)ethanimidate-hydrochloride and 1-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]piperazin-2- one, was obtained as an off-white solid.

MS (ESI, m/z): 490.0 [(M+H)⁺]. Example 50

Preparation of 9-hydroxy-6-[(1-tetralin-5-ylcyclopentyl)methyl]-2-[(1R)-2,2,2-trifluoro-1- methyl-ethyl]-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 50, prepared in analogy to example 1d from methyl 2-(1-tetralin-5- ylcyclopentyl)ethanimidate-hydrochloride and 1-[(1 R)-2,2,2-trifluoro-1-methyl-ethyl]piperazin- 2-one (prepared according to example 49a - c but using (2R)-1,1 ,1-trifluoropropan-2-amine hydrochloride in step a), was obtained as an off-white solid.

MS (ESI, m/z): 490.2 [(M+H)⁺].

Example 51

Preparation of 6-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-(2,2,2- trifluoroethyl)-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 51 , prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(2,2,2-trifluoroethyl)piperazin-2- one (preparation: Bayrakdarian, M. et al., patent WO 2008136756), was obtained as an off- white solid.

MS (ESI, m/z): 450.2 [(M+H)⁺].

Example 52

Preparation of 6-[[1-(3,5-dirnethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 52, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -[( 1 S)-2,2,2-trifluoro-1 -methyl- ethyl]piperazin-2-one, was obtained as a white solid.

MS (ESI, m/z): 464.3 [(M+H)^*].

Example 53

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

Example 53, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-[(1 R)-2,2,2-trifluoro-1-methyl- ethyl]piperazin-2-one, was obtained as a white solid.

MS (ESI, m/z): 464.3 [(M+H)⁺].

Example 54

Preparation of 2-cyclopropyl-6-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 54, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-cyclopropylpiperazin-2-one, was obtained as an off-white solid. MS (ESI, m/z): 408.0 [(M+H)⁺].

Example 55

Preparation of 2-(2,6-dichlorophenyl)-6-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-9- hydroxy-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 55, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(2,6-dichlorophenyl)piperazin-2- one (prepared in analogy to example 56), was obtained as an off-white solid.

MS (ESI, m/z): 512.1 pl+H)⁺].

Example 56

Preparation of 6-[[1-(3,5-dimethylphenyl)cyciopentyl]methyI]-9-hydroxy-2-(1- methylpyrazol-3-yl)-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

a) tert-Butyl 4-(1-methylpyrazol-3-yl)-3-oxo-piperazine-1-carboxylate

To an argon flushed suspension of tert-butyl 3-oxopiperazine-1-carboxylate (800 mg) and 3- iodo-1-methyl-1 H-pyrazole (997 mg) in dioxane (30 ml) at 22°C were subsequently added potassium phosphate tribasic (1.87 g), copper (I) iodide (76 mg) and Ν,Ν'- dimethylethylenediamine (70 mg) and stirring was continued at reflux temperature for 19 h. The mixture was filtered, the filtrate evaporated and the residue purified by flash chromatography (silica gel, 0 - 2.5% methanol in dichioromethane) to give the title compound (914 mg) as a light yellow oil.

MS (ESI, m/z): 281.2 [(M+H)⁺]. b) 1 -( 1 -Methylpyrazol-3-yl)piperazin-2-one

tert-Butyl 4-(1-methylpyrazol-3-yl)-3-oxo-piperazine-1-carboxylate (914 mg) dissolved in a solution of hydrochloric acid in dioxane (4 M, 8 ml) and dichioromethane (7.5 ml) was stirred at 22°C for 4 h. The mixture was evaporated and the residue treated with aqueous ammonium hydroxide, which was followed by chromatography (NH₂-Si0₂, 5% methanol in dichioromethane) to give the title compound (406 mg) as a light yellow solid. MS (ESI, m/z): 181.1 [(M+H)⁺]. c) Example 56, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(1-methylpyrazol-3-yl)piperazin- 2-one, was obtained as an off-white solid. MS (ESI, m/z): 448.3 [(M+H)⁺].

Example 57

Preparation of 6-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-(2- hydroxyethyl)-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) tert-Butyl 4-f2-rtert-butyl(dimethvnsilyl1oxyethvn-3-oxo-piperazine-1 -carboxylate

To solution of tert-butyl 3-oxopiperazine-1-carboxylate (1.00 g) in dimethylformamide (20 ml) was added at 0°C sodium hydride (240 mg) in three portions and stirring was continued at 22°C for 30 min. (2-Bromoethoxy)(tert-butyl)dimethylsilane (1.43 g) was added at 0°C and stirring was continued at 22°C for 4 h. The mixture was partitioned between water and ethyl acetate, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, 0 - 5% methanol in dichloromethane) to give the title compound (6.85 g) as a light yellow oil.

MS (ESI, m/z): 359.2 [(M+H)⁺]. b) 1-(2-Hvdroxyethyl)piperazin-2-one

tert-Butyl 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-oxo-piperazine-1-carboxylate (1.12 g) dissolved in a solution of hydrochloric acid in dioxane (4 M, 8 ml) and dichloromethane (6 ml) was stirred at 22°C for 5 h. The mixture was evaporated and the residue treated with aqueous ammonium hydroxide, which was followed by chromatography (NH₂-Si0₂, 5% methanol in dichloromethane) to give the title compound (168 mg) as a yellow solid. c) Example 57, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-hydroxyethyl)piperazin-2- one, was obtained as an off-white solid

MS (ESI, m/z): 412.3 [(M+H)⁺]. Example 58

Preparation of 6-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-2-[(4-fluorophenyl)methyl]- 9-hydroxy-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 58, prepared in analogy to example 1d from methyl 2-[1-(3,5- dimethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -[(4-fluorophenyl)methyl]- piperazin-2-one (preparation: Kim, H. et al., Bioorganic & Medicinal Chemistry Letters (2011), 21(12), 3809-3812), was obtained as a light brown solid.

MS (ESI, m/z): 476.4 [(M+H)⁺].

Example 59

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-(1-methylpyrazol-3- yl)-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 59, prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(1-methylpyrazol-3-yl)piperazin-2- one (from example 56b), was obtained as an off-white solid.

MS (ESI, m/z): 448.3 [(M+H)⁺].

Example 60

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-(4-pyridyl)-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 60, prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(4-pyridyl)piperazin-2-one (prepared in analogy to example 56a - b but using 4-iodopyridine in step a, white solid, MS (ESI, m/z): 178.1 [(M+H)⁺]), was obtained as a light yellow solid.

MS (ESI, m/z): 445.3 [(M+H)⁺]. Example 61

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-(2-methoxyethyl)- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 61 , prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-methoxyethyl)piperazin-2-one (prepared in analogy to example 57a - b but using 1-bromo-2-methoxyethane in step a, yellow oil, MS (ESI, m/z): 159.1 [(M+H)⁺]), was obtained as a white solid.

MS (ESI, m/z): 426.3 [(M+H)⁺].

Example 62

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyI]-9-hydroxy-2-(1-methylimidazol- 4-yl)-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

Example 62, prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1-(1-methylimidazol-4-yl)piperazin-2- one (prepared in analogy to example 56a - b but using 4-iodo-1-methyl-1 H-imidazole in step a, light yellow solid, MS (ESI, m/z): 181.1 [(M+H)⁺]), was obtained as an off-white solid.

MS (ESI, m/z): 448.3 [(M+H)⁺].

Example 63

Preparation of 6-[[1 -(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-(2-hydroxyethyl)- 3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 63, prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-hydroxyethyl)piperazin-2-one (from example 57b), was obtained as an off-white solid.

MS (ESI, m/z): 412.2 [(M+H)⁺].

Example 64

Preparation of 6-[[1-(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-[2-

(trifluoromethoxy)ethyl]-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione

Example 64, prepared in analogy to example 1d from methyl 2-[1-(3- ethylphenyl)cyclopentyl]ethanimidate-hydrochloride and 1 -(2-hydroxyethyl)piperazin-2-one (prepared in analogy to example 57a - b but using 1-[2-(trifluoromethoxy)ethyl]piperazin-2- one in step a, light yellow oil, MS (ESI, m/z): 213.1 [(M+H)⁺]), was obtained as an off-white solid.

MS (ESI, m/z): 480.3 RM+H)⁺].

Example 65

Preparation of 6-[[1-(3-ethylphenyl)cyclohexyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1,2-c]pyrimidine-1,8-dione

To a mixture of 6-[[1-(3-bromophenyl)cyclohexyl]methyl]-9-hydroxy-2-methyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (10 mg, prepared in analogy to example 6 but using 2-(3-bromophenyl)acetonitrile and 1 ,5-dibromopentane in step a, yellow solid, MS (ESI, m/z): 446.7 [(M+H)⁺]) and [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (5 mg) in tetrahydrofuran (0.1 ml) was added at 22°C under argon diethylzinc (45 μΙ) and stirring was continued at 80°C for 2 h. The mixture was evaporated and the residue purified by preparative HPLC (RP-18, MeCN/H₂0 containing 0.23% of HCOOH) to give the title compound (2.4 mg) as a brown solid.

MS (ESI, m/z): 396.3 [(M+Hf]. Example 66

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

Example 66, prepared in analogy to example 1 but using 1-bromo-3,5-dimethyl-benzene and ethyl 2-cyano-2-cyclohexylideneacetate in step a, was obtained as a light brown solid. MS (ESI, m/z): 424.3 [(M+H)⁺].

Example 67

Preparation of 9-hydroxy-2-methyl-6-[1 -[1 -(m-tolyl)cyclopentyl]ethyl]-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione

a) Ethyl 2-cyano-2-f 1 -(m-tolvDcyclopentyllpropanoate

To a solution of ethyl 2-cyano-2-(1-(m-tolyl)cyclopentyl)acetate (150 mg, prepared according to example 1a starting with 1-bromo-3-methyl-benzene) in dimethylacetamide (2.6 ml) was added at 0°C sodium hydride (dispersion in oil, 24 mg) and stirring was continued at 0°C for 30 min. Methyl iodide (86 mg) was added and stirring was continued at 0°C for 15 min and at 22°C for 16 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried, evaporated and the residue purified by flash chromatography (silica gel, 0 - 20% ethyl acetate in n-heptane) to give the title compound (113 mg) as a colorless oil.

MS (ESI, m/z): 286.2 [(M+Hf] b) Ethyl 2-cyano-2-[1-(m-tolyl)cyclopentyl]propanoate was converted in analogy to example 1 b - d to give example 67 which was obtained as a colorless powder.

MS (ESI, m/z): 382.3 [(M+H)⁺],

Example 68

Preparation of 6-[[1-(3,5-dimethylphenyl)cyclopentyl]-hydroxy-m

fluorophenyl)methyl]-9-hydroxy-3,4-dihydropyrazino[1,2-c]pyrsmidine-1,8-dione

To a solution of 1-(3,5-dimethylphenyl)cyclopentanecarbaldehyde (1.00 g, prepared according to example 6a - b but using 2-(3,5-dimethylphenyl)acetonitrile in step a, preparation: Wu, G. et al., Angewandte Chemie, International Edition (2014), 53(39), 10510-10514) in toluene (30 ml) was added at 0°C a solution of cyanodiethylaluminum (1 M in toluene, 7.4 ml) and stirring was continued at 0°C for 3 h. The mixture was quenched by the addition of a saturated solution of Rocheller salt (potassium sodium tartrate heptahydrate, 40 ml) and stirring was continued at 22°C for 16 h. The organic layer was separated, the aqueous layer extracted with dichloromethane, the combined organic layers dried, evaporated and the residue purified by flash chromatography (silica gel, ethyl acetate/n-heptane) to give the title compound (1.05 g) as a light yellow solid. MS (ESI, m/z): 492.3 [(M+H)⁺] b) 2-[1-(3,5-Dimethylphenyl)cyclopentyl]-2-hydroxy-acetonitrile was converted to example 68 in analogy to example 1c - d, using 1-[(4-fluorophenyl)methyl]piperazin-2-one (preparation: Kim, H. J. et al., Bioorganic & Medicinal Chemistry Letters (2011), 21 (12), 3809-3812) in step d, to give the title compound as an off-white solid.

MS (ESI, m/z): 492.3 [(M+H)⁺]

Claims

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

wherein

R is selected from -H, -(optionally substituted d_6 alkyl group) and -C(O)- (optionally substituted d-6 alkyl group);

R¹¹ is independently -H, a -d_6 alkyl group, a C₃_₇ cycloalkyi group or a -d-6 alkyl group which is substituted by one or more halogen atoms; is independently a -Ci_₆ alkyl group, a -d-6 alkenyl group or a C₃_₇ cycloalkyi group; or

wherein two R¹² can be joined together to form a 3- to 7-membered cycloalkyi ring; R is independently -H, -halogen, -CN, -OH, -0-{C^ alkyl group, wherein the alkyl group is optionally substituted by halogen) or -(C^ alkyl group, wherein the alkyl group is optionally substituted by halogen);

R¹⁴ is -H, -(optionally substituted alkyl), -(optionally substituted C₃_₇ cycloalkyl), - (optionally substituted aryl), -(optionally substituted heterocycloalkyi), -(optionally substituted heteroaryl), -C^ alkyl— (optionally substituted C₃_₇ cycloalkyl), -Ci_4 alkyl— (optionally substituted aryl), -Ci_ alkyl— (optionally substituted heterocycloalkyi), or alkyl-(optionally substituted heteroaryl);

R ⁵ is selected from -H, -Ci_e alkyl, -OH and -O-C^ alkyl, m is 1, 2 or 3; n is 1 , 2 or 3; o is 0, 1 , 2, 3 or 4; 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_e alkyl, -Hal, -CF₃, -CN, -COOR**, - OR^**, -S(0)R^**, -S(0)₂R^**, -(CH₂)_qNR*^*R***, -C(0)-NR**R*** and -NR**-C(0)- C_1-J3 alkyl; wherein the optional substituent(s) of the optionally substituted cycloalkyl group, optionally substituted heterocycloalkyi group, optionally substituted aryl group, optionally substituted heteroaryl group and/or optionally substituted hydrocarbon group is one or more substituents R^b, wherein each

R^b is independently selected from -Ci_e alkyl, -C{0)-C^ alkyl, -Hal, -CF₃, -CN, - COOR^**, -OR^**, -S(0)R*^*, -S(0)₂R^**, -(CH₂)_qNR**R**^*, -C(0)-NR**R*** and - NR^**-C(0)-C₁_6 alkyl; wherein R*** is selected from -H, and -C^ alkyi;

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

r 1 to 3; and

q is 0 to 4.

The compound according to claim 1 , wherein R is -H, -CiOJ-C^ alkyi group, wherein the alkyi group can be optionally substituted by one or more halogen atoms, or a -C^ alkyi group which may optionally be substituted by one or more halogen atoms.

The compound according to claim 1 or 2, wherein R¹² is independently a -Ci_e alkyi group, a -C^ alkenyl group or a C^.₇ cycloalkyl group.

The compound according to claim 1 or 2, wherein two R ² are joined together to form a 3- to 7-membered cycloalkyl ring.

The compound according to any of claims 1 to 4, wherein n is 1 .

The compound according to any of claims 1 to 5, wherein R¹⁴ is iso-propyl.

The compound according to any one of claims 1 to 6, wherein the compound having the general formula (I) is a compound having the following general formula (la)

wherein the same definitions as in claim 1 apply. The compound according to any one of claims 1 to 7, wherein at least one R¹² phenyl ring is in a meta-position th respect to the position at which the group

is attached to the phenyl ring.

9. The compound according to any of claims 1 to 8, wherein R¹⁴ is methyl and at least one R¹³ on the phenyl ring is halogen in a meta-position with respect to the position at which the group

is attached to the phenyl ring.

10. A pharmaceutical composition comprising:

a compound having the general formula (I) as defined in any of claims 1 to 9, 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).

11. A compound having the general formula (I) as defined in any of claims 1 to 9, 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 9, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.

13. A compound having the general formula (I) as defined in any of claims 1 to 9, 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.

14. 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 9, optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof.