ew PCT-patent application

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

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

Background of the invention Influenza viruses belong to the Orthomyxoviridae family of RNA viruses. Based on antigenic differences of viral nucleocapsid and matrix proteins, influenza viruses are further divided into three types named influenza A, B, and C viruses. All influenza viruses have an envelope, and their genomes are composed of eight or seven single-stranded, negative-sensed RNA segments. These viruses cause respiratory diseases in humans and animals with a significant morbidity and mortality. The influenza pandemic of 1918, Spanish flu, is thought to have killed up to 100 million people. The reassortment of avian flu RNA fragments with circulating human viruses caused the other two pandemics in 1957 H2N2 "Asian influenza" and 1968 H3N2 "Hong Kong influenza". Now, people around the world face the challenges of influenza from various angles: seasonal influenza epidemics affect about 5-15% of the world's population with an annual mortality ranging from 250,000 to 500,000. Infections of avian flu strains, mostly H5N1 , have been reported in many Asian countries. Although no frequent human-to- human spreading has been observed, avian flu infection is serious and associated with a high mortality of up to 60% of infected persons. In 2009, an H1 N1 swine flu infection appeared initially in North America and evolved into a new pandemic. Currently, seasonal trivalent influenza vaccines and vaccines specific for H5N1 or swine flu are either available or in the phase of clinical trials. The prophylaxis is an effective method, at least in some populations, for preventing influenza virus infection and its potentially severe complications. However, continuous viral antigenicity shifting and drafting makes future circulating flu strains unpredictable. Furthermore, due to the limitations of mass production of vaccines within a relatively short period of time during a pandemic, other anti-flu approaches such as anti-flu drugs are highly desirable. On the market, there are two types of anti-flu drugs available: neuraminidase inhibitors such as oseltamivir phosphate (Ta ilf!u) and zanamivir (Re!enza); 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 happenend 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, 1 1 , 946-951 ), but their use is limited due to side effects (Furuta et al., Antimicrobial Agents and Chemotherapy 2005, 981- 986).

Influenza viruses being Orthomyxoviridae, as described above, are negative-sense ssRNA viruses. Other examples of viruses of this group include Arenaviridae, Bunyaviridae, Ophioviridae, Deltavirus, Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae and Nyamiviridae. These viruses use negative-sense RNA as their genetic material. Single- stranded RNA viruses are classified as positive or negative depending on the sense or polarity of the RNA. Before transcription, the action of an RNA polymerase is necessary to produce positive RNA from the negative viral RNA. The RNA of a negative-sense virus alone is therefore considered non-infectious. The trimeric viral RNA-dependent RNA polymerase, consisting of polymerase basic protein 1 (PB1 ), polymerase basic protein 2 (PB2) and polymerase acidic protein (PA) subunits, is responsible for the transcription and replication of the viral RNA genome segments. Structural data of the two key domains of the polymerase, the mRNA cap-binding domain in the PB2 subunit (Guilligay et al., Nature Structural & Molecular Biology 2008, 15(5), 500-506) and the endonuclease-active site in the PA subunit (Dias et al., Nature 2009, 458, 914-918) has become available.

The ribonucleoprotein represents the minimal transcriptional and replicative machinery of an influenza virus. During transcription, the viral RNA polymerase synthesizes capped and polyadenylated mRNA using 5 ^' capped RNA primers. During replication, the viral RNA polymerase generates a complementary RNA (cRNA) replication intermediate, a full-length complement of the vRNA that serves as a template for the synthesis of new copies of vRNA. The nucleoprotein is also an essential component of the viral transcriptional machinery. The polymerase complex which is responsible for transcribing the single-stranded negative-sense viral RNA into viral mRNAs and for replicating the viral mRNAs, is thus a promising starting points for developing new classes of compounds which may be used in order to treat influenza (Fodor, Acta virologica 2013, 57, 1 13-122). This finding is augmented by the fact that the polymerase complex contains a number of functional active sites which are expected to differ to a considerable degree from functional sites present in proteins of cells functioning as hosts for the virus (Magden et al., Appl. Microbiol. Biotechnol. 2005, 66, 612-621 ). As one example, a substituted 2,6-diketopiperazine has been identified which selectively inhibits the cap- dependent transcriptase of influenza A and B viruses without having an effect on the activities of other polymerases (Tomassini et al., Antimicrob. Agents Chemother. 1996, 40, 1 189-1 193). In addition, it has been reported that phosphorylated 2'-deoxy-2'-fluoroguanosine reversibly inhibits influenza virus replication in chick embryo cells. While primary and secondary transcription of influenza virus RNA were blocked even at low concentrations of the compound, no inhibition of cell protein synthesis was observed even at high compound concentrations (Tisdale et al., Antimicrob. Agents Chemother. 1995, 39, 2454-2458).

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

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

WO 2012/039414 relates to compounds which are described as having antiviral effects, particularly having growth inhibitory activity on influenza viruses. WO 2014/108406 discloses certain pyrimidone derivatives and their use in the treatment, amelioration or prevention of a viral disease. It is an object of the present invention to identify further compounds which are effective against viral diseases and which have improved pharmacological properties.

Summary of the invention

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

(I)

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

A further embodiment of the present invention relates to a pharmaceutical composition comprising a compound having the general formula (I) and optionally one or more pharmaceutically acceptable excipient(s) and/or carrier(s).

The compounds having the general formula (I) are useful for treating, ameliorating or preventing viral diseases. Detailed description of the invention

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

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (lUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kolb!, 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. The term "heterocycloalkyl" represents a version of "cycloalkyl" in which one or more CH _{2 g} roups are independently replaced by O, NH, N(C _1-6 -alkyl) or S. Unless specified otherwise, the heterocycloalkyl group can have 3 to 12 carbon atoms and 1 to 3 atoms selected from O, N and S. "Hal" or "halogen" represents F, CI, Br and I.

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

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

The term "heteroaryl" preferably refers to a five-or six-membered aromatic ring wherein one or more of the carbon atoms in the ring have been replaced by 1 , 2, 3, or 4 (for the five- membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S. Examples of the heteroaryl group include pyrrole, pyrrolidine, oxolane, furan, imidazolidine, imidazole, pyrazole, oxazolidine, oxazole, thiazole, piperidine, pyridine, morpholine, piperazine, and dioxolane.

The term "hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring" refers to any group having 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and 2 as long as the group contains at least one ring. The term is also meant to include bicyclic, tricyclic and polycyclic versions thereof. If more than one ring is present, they can be separate from each other or be annelated. The ring(s) can be either carbocyclic or heterocyclic and can be saturated, unsaturated or aromatic. The carbon atoms and heteroatoms can either all be present in the one or more rings or some of the carbon atoms and/or heteroatoms can be present outside of the ring, e.g., in a linker group (such as -(CH ₂ ) _P - with p = 1 to 6). Examples of these groups include -(optionally substituted C ₃ _ ₇ cycloalkyl), -(optionally substituted aryl) wherein the aryl group can be, for example, phenyl, -(optionally substituted biphenyl), adamantyl, -(C ₃ . ₇ cycloalkyl)-aryl as well as the corresponding compounds with a linker.

If a compound or moiety is referred to as being "optionally substituted", it can in each instance include 1 or more of the indicated substituents, whereby the substituents can be the same or different.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Suitable pharmaceutically acceptable salts include acid addition salts which may, for example, be formed by mixing a solution of compounds of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, 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 R ¹⁰ is replaced by P(0)(0)OR ¹⁹ ; C(0)OR ¹⁹ ; C(0)R ¹⁹ ; C(R) ₂ -R ¹⁹ or R ¹⁹ ; wherein R ¹⁹ is selected from C ₁₀ aryl, alkylene-C _M0 aryl, Ci_e alkyl, C-,_ ₆ alkylene(-0-Ci_ ₆ alkyl) _n (with n = 1 to 30), C _M alkylene-C(0)OR, C^ ₁₀ arylene-C(0)OR, C,. alkylene-0-C(0)OR and d_6 alkylene-0-C(0)R. The group R is H or C _M alkyl.

In the prodrugs of the present invention, the "R ¹⁰ " group in -OR ¹⁰ 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 ^0a ,

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-R ^10b ,

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

g) -C(=O)-O-R ¹⁰ °,

h) -C(=O)-N(R ^10c ) ₂ ,

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

j) -CH ₂ -R ^10d ,

k) -CH ₂ -O-L'-O-R ^0d ,

I) -CH ₂ -O-C(=O)-R ^10d ,

m) -CH ₂ -O-C(=O)-Q-R ^10d ,

n) -CH(-CH ₃ )-O-C(=O)-O-R ^10d ,

o) -CH ₂ -O-C(=O)-N(-K)-R ^0c ,

p) -CH ₂ -O-C(=O)-O-L'-O-R ^10d ,

q) -CH ₂ -O-C(=O)-O-L'-N(R ^10d ) ₂ ,

r) -CH ₂ -O-C(=O)-N(-K)-L'-O-R ^10d ,

s) -CH ₂ -O-C(=O)-N(-K)-L'-N(R ^10d ) ₂ ,

t) -CH ₂ -O-C(=O)-O-L'-O-L'-O-R ^10d ,

u) -CH ₂ -O-C(=O)-O-L'-N(-K)-C(=O)-R ^10d ,

v) -CH ₂ -0-P(=0)(-OH) ₂ ,

w) -CH ₂ -0-P(=0)(-OBn) ₂ ,

x) -CH ₂ -R ^10e

y) -C(=N ⁺ R ^0f ₂ )(-NR ^10f 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 ¹ ° ⁹ , or lower alkenyl optionally substituted with one or more R ¹ ° ⁹ , R ^10b is a carbocyclic group optionally substituted with one or more R ¹ ° ⁹ , a heterocyclic group optionally substituted with one or more R ¹ ° ⁹ , lower alkyi amino optionally substituted with one or more R ¹⁰⁹ , or lower alkylthio optionally substituted with one or more R ¹ ° ⁹ ,

R ^10c is lower alkyi optionally substituted with one or more R ^10g , a carbocyclic group optionally substituted with one or more R ¹ ° ⁹ , or a heterocyclic group optionally substituted with one or more R ° ⁹ ,

R ^10d is lower alkyi optionally substituted with one or more R ¹ ° ⁹ , a carbocyclic group optionally substituted with one or more R ^10s , a heterocyclic group optionally substituted with one or more R ^0g , lower alkyi amino optionally substituted with one or more R ¹ ° ⁹ , carbocycle lower alkyi optionally substituted with one or more R ¹ ° ⁹ , heterocycle lower alkyi optionally substituted with one or more R ¹ ° ⁹ , or lower alkylsilyl,

R ^10e is carbocyclic group optionally substituted with one or more R ^10g , or heterocyclic group optionally substituted with one or more R ¹ ° ⁹ , and

R ^0f is lower alkyi optionally substituted with one or more R ¹ ° ⁹ ,

R ¹ ° ⁹ is selected from oxo, lower alkyi, hydroxy lower alkyi, amino, lower alkylamino, carbocycle lower a!ky!, lower a!kylcarbony!, halogen, hydroxy, carboxy, lower alkylcarbonylamino, lower aikylcarbonyloxy, lower alkyloxycarbonyl, lower alkyloxy, cyano, and nitro.

In the above definitions of R ^10a to R ^10s , the term "lower" refers to C-, .γ, except for lower alkenyl and alkenylene, where it refers to C ₂ .7-

As the group to form a prodrug, the "R ⁰ " group in -OR ¹⁰ group in the formula (I) is preferably a group selected from the following b), I), m), and n).

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

I) -CH ₂ -O-C(=O)-R ^10d ,

m) -CH ₂ -O-C(=O)-O-R ^10d ,

n) -CH(-CH ₃ )-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).

(I)

The present invention provides a compound having the general formula (I) in which the following definitions apply.

R ⁰ is -H, -(optionally substituted Ci_6 alkyl group) or -C(0)-(optionally substituted d_e alkyl group). R ¹⁰ is preferably -H, -C(0)-d„ ₆ alkyl group, wherein the alkyl group can be optionally substituted by one or more halogen atoms, or a -d-6 alkyl group which may optionally be substituted by one or more halogen atoms. More preferably, R ¹⁰ is -H, -Ci_6 alkyl group or -C(0)-Ci_6 alkyl group. Even more preferably R ¹⁰ is -H.

R ¹¹ is -H, -OH, -CH2-OH, a -d-6 alkyl group, or a -C^ alkyl group which is substituted by one or more halogen atoms; preferably R ¹ is -H, or -OH, -CH ₂ -OH. R is -H, -OH, -CH2-OH, a -d-e alkyl group, or a -Ci_ ₆ alkyl group which Is substituted by one or more halogen atoms; preferably R ¹² is -H.

In one embodiment R ¹¹ and R ¹² can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring.

R ¹³ is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring). Preferably, the at least one ring is aromatic such as an aryl or heteroaryl ring. More preferably, R ¹³ is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms and which contains at least two rings, wherein the hydrocarbon group can be optionally substituted. Even more preferably, at least one of the at least two rings is aromatic such as an aryl or heteroaryl ring. Preferred examples of R ¹³ can be selected from the group consisting of

More preferably R is selected from

X is absent, CH ₂ , NH, C(0)NH, S or O. Furthermore,

Y is CH ₂ .

In an alternative embodiment, X and Y can be joined together to form an annulated, carbo- or heterocvlic 3- to 8-membered ring which can be saturated or unsaturated. Specific examples of X-Y include -CH ₂ -, -CH ₂ -CH ₂ -, -0-, and -NH-.

Z is O or S.

R is independently selected from -C^ alkyl, -C, ₆ alkenyl, , -Ci_ ₆ alkinyl, -CF ₃ , - halogen, -CN, -OH, -CH ₂ C(0)OH, -CH ₂ C(0)OCi_6 alkyl, -O-d ₆ alkyl, -C _{3 7} cycloalkyl, -(CH ₂ ) ₁ . ₄ -0-C^ ₆ alkyl, -(CH ₂ ) _1-4 -CN, -(CH ₂ ) _1-4 -OH, -(CHz^-O-iC^ alkyl), alkyl, -aryl, -heterocycloalkyi or -heteroaryl.

R ^e is independently selected from -H, -d_ ₆ alkyl, -C $ alkenyl, , -C _t _6 alkinyl, -CF ₃ , -halogen, -CN, -OH, -CH ₂ C(0)OH, -CH ₂ C(0)OC^ alkyl, -O-d ₆ alkyl, -C ₃ _ ₇ cycloalkyl, -(CH^^-O-C,^ alkyl, -(CH ₂ ) ₁ .4-CN, -(CH ₂ ) _1-4 -OH, -{CH ₂ ) _{r 4} -0-(C, ₆ alkyl), alkyl, -aryl, -heterocycloalkyi or -heteroaryl. t is 0 to 5, preferably 0 to 3. is -H, -(optionally substituted d ₆ alkyl), -(optionally substituted C ₃ _ ₇ cycloalkyl), - (optionally substituted aryl), -(optionally substituted heterocycloalkyi), -(optionally substituted heteroaryl), -Ci_4 alkyl— (optionally substituted C ₃ _ ₇ cycloalkyl), -C^ alkyl— (optionally substituted aryl), -C^ alkyl— (optionally substituted heterocycloalkyi), or -C-,_ ₄ alkyl— (optionally substituted heteroaryl). R is preferably -(optionally substituted Ci_6 alkyl). R ¹⁴ is more preferably selected from -CH ₃ , CH(CH ₃ ) ₂ and CH(CH ₃ )(CF ₃ ).

R is -R or -d_4 alkyl-R, wherein R is selected from -XH, -COOH, -COO-(optionally substituted Ci_ ₆ alkyl), -(optionally substituted d-e alkyl), -(optionally substituted C ₃ _ ₇ cycloalkyl), -(optionally substituted aryl), -(optionally substituted heteroaryl), -(optionally substituted heterocycloalkyl), -X-(optionally substituted Ci_e alkyl), -X-(optionally substituted C ₃ ^ ₇ cycloalkyl), -X-(optionally substituted aryl), -X-(optionally substituted heterocycloalkyl), or -X-(optionally substituted heteroaryl), wherein X is O or S.

In one embodiment R ¹⁴ and R ⁷ can be joined together to form an optionally substituted 3- to 7-membered (e.g., 5 or 6-membered) heterocyclic ring which can include one or more additional heteroatoms selected from N, O and S in addition to the nitrogen atom to which R ¹⁴ is attached. This optionally substituted 3- to 7-membered heterocyclic ring may optionally be benzannulated, wherein benzannulated preferably indicates that a benzene ring is attached in such a manner that two neighboring carbon atoms in the 3- to 7-membered heterocyclic ring are at the same time two neighboring carbon atoms in the benzene ring.

The optional substituent(s) of the optionally substituted alkyl group is one or more substituents R ^a , wherein each R ^a is independently selected from -C(0)-Ci_e alkyl, -Hal, -CF ₃ , -CN, - COOR**, -(CH ₂ ) _q -OR ^* *, -S(0)R ^** , -S(0) ₂ R ^** , -(CH ₂ ) _q NR ^** R ^*** , -C(0)-NR ^** R ^*** and - NR**-C(0)-Ci_6 alkyl;

The optional substituent(s) of the optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted hydrocarbon group and/or an optionally substituted 3- to 7- membered heterocyclic ring is one or more substituents R ^b , wherein each R ^b is independently selected from -d_ ₆ alkyl, -C(0)-d_6 alkyl, -Hal, -CF ₃ , -CN, -COOR ^** , -(CH ₂ ) _q -OR ^** , - S(0)R* ^* , -S(0) ₂ R**, -(CH ₂ ) _q NR ^** R* ^** , -C(0)-NR ^** R ^*** and -NR ^** -C(0)-d_ ₆ alkyl;

The optional substituent(s) of the optionally substituted hydrocarbon group is one or more substituents R ^d , wherein each R ^d is independently selected from -d-e alkyl, -C ₁ -6 alkenyl, - d_e alkinyl, -C(0)-C, ₆ alkyl, -Hal, -CF ₃ , -CN, -OH, -CH ₂ C(0)OH, -CH ₂ C(0)Od_6 alkyl, - G-d- _€ alkyl, -C ₃ _ ₇ cycloalkyl, -COOR ^** , -(CH ₂ ) _q -OR ^** , -(CH ₂ ) _q -CN, -S(0)R ^** , -S(0) ₂ R ^** , - (CH ₂ ) _P NR**R***, -C(0)-NR**R***, -NR**-C(0)-C ₁ _ ₆ alkyl, alkyi, -aryl, - heterocycloalkyl and -heteroaryl; wherein

R*** is selected from -H, and -Ci_ ₆ alkyl;

R** is selected from -H, -C^ alkyl which is optionally substituted with one or more halogen atoms, and -<CH ₂ CH ₂ 0) _r H;

r 1 to 3; and

q is 0 to 4.

Furthermore, the optional substituent(s) of any group which is indicated as being "optionally substituted" in the present specification may be one or more substituents R ^a as defined above, unless other substituents are defined for this group. Preferably, the optional substituent(s) of the optionally substituted cycloalkyl group, optionally Rnhstiti ited heterocvc!oa!kv! group, optionally substituted aryl group, optionally substituted heteroaryl group and/or optionally substituted hydrocarbon group is -halogen (preferably F), -OCH ₃ or -CN. Preferably, the optional substituent of the optionally substituted alkyi 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.

The present inventors have surprisingly found that the compounds according to the present invention which have the additional substituent R ¹⁷ which may be linked with substitutent R ¹⁴ exhibit improved pharmacological properties. Without wishing to be bound by theory it is assumed that these compounds exhibit improved cellular potency.

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, containinn fnr e amnie water-buffered aaueous solutions, e.a. biocomoatible buffers, ethanol, po!yol, 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, phenoi, 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 propeilant 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

Hendra virus 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

Puumaia 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

Delta virus Hepatitis deltavirus

Bornaviridae Bornavirus

Pnons

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 (inciuding 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 endonuciease 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. md 5 g01 s3) and contains the extremely bright luciferase variant, NanoLuc (Promega), which has been appended to the C-terminus of the polymerase subunit, PA. The reporter virus replicates with near native properties both in cell culture and in vivo. Thus, NanoLuc luciferase activity can be used as a readout of viral infection. In order to identify small molecule inhibitors of influenza A virus, A549 (human non-small cell 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 (DME , 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% C0 ₂ overnight. The following day, cells were washed once with 1X PBS and then infected with virus, MOI 0.1 in 10 μΙ of infection media for 60 min. 15 μΙ 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% C0 ₂ . 15 μΙ 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). EC ₅₀ and CC ₅₀ 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. md 5 g01 s3), and stocks frozen at -80°C. Viral infections were carried out using DMEM Glutamax supplemented with 0.3% BSA (Sigma), 25mM Hepes (Sigma), and 1 X penicillin/streptomycin (Invitrogen). ICmg of viral replication inhibition in a cell-based Luciferase Reporter Assay (LRA)

LRA

Structure IC ₅₀ [μΜ]

Example 1

0.128

Example 2

0.08

Example 3

0.616

Example 4

0.043 



42

Abbreviations:

9-BBN 9-borabicyclo[3.3.1]nonane

AcCN acetonitrile

AcOH acetic acid

AcOK potassium acetate

AIBN azobisisobutyronitrile

BBr ₃ boron tribromide

Bn Benzyl

Bu ₃ SnH tributyl tin hydride

DAST diethylaminosulfur trifluoride

DBU 1 ,8-diazabicycloundec-7-ene

DCC Ν,Ν'-dicyclohexylcarbodiimide

DCM dichloromethane

DEAD diethylazodicarboxylate

DIBAL-H diisobuty!a!uminium hydride

DIPEA NN-diisopropyl ethy! amine

DMF dimethylformamide

dppf 1 , 1 '-bis(diphenylphosphino)ferrocene

EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide

ESI electrospray ionization

Et ₂ 0 diethyl ether

EtOAc or EA ethyl acetate

h hour

HATU (1-[Bis(dimethylamino)methyiene]-1 H-1 ,2,3-triazoio[4,5- bjpyridinium 3-oxid hexafluorophosphate)

HV, hv high vacuum

KHC0 ₃ potassium bicarbonate

LC/MS liquid chromatography / mass spectromety

LHMDS lithium bis(trimethylsilyl)amide

MeOH methanol

MgSO magnesium sulfate

min minute

MTBE methyl ieri-butyl ether

Na ₂ S0 ₄ sodium sulfate NaCI sodium chloride

NaHC0 ₃ sodium bicarbonate

NBS N-bromosuccinimide

NH ₄ CI ammonium chloride

NMP N-methyl-2-pyrrolidone

NOESY nuclear Overhauser effect spectroscopy

Pd(dppf)CI ₂ [1 , 1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride

Pd/C palladium on activated carbon

PE petrol ether

PPh ₃ triphenylphosphine

RM, rm reaction mixture

RT, rt, r.t. room temperature

SFC supercritical fluid chromatography

Si-NH ₂ amino modified silica gel

TBME ferf-butyl methyl ether

TEMPO (2,2,6, 6-Tetramethy!piperidin-1 -y!)oxy!

THF tetrahydrofuran

TosMIC toluenesulfonylmethyl isocyanide

triflic anhydride trifluoromethanesuifonic anhydride

TsOH p-toluenesulfonic acid

Xantphos 4,5-dis(diphenylphosphino)-9,9-dimethylxanthene

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

2a

^ fotmation/cyclization 5

Compounds of general structure I (Scheme 1 ) can be prepared starting from unsaturated cyano esters of general formula 1 and Grignard reagents of general formula 2 which are reacted in the presence of metal salts such as CuCN or Cul in THF to give cyano esters of general formula 3. Grignard reagents of general structure 2 can be purchased from commercial vendors or prepared from compounds of general structure 2a by using Mg in solvents such as THF or Et ₂ 0. The nitrile building blocks of general formula 4 may then be obtained via Krapcho decarboxylation preferentially with NaCI in DMSO at 120 °C or higher temperatures. Imino ether hydrochlorides of general formula 5 can then be prepared via common Pinner reaction conditions - namely saturated HCI in MeOH. Amidine intermediates of general formula 7 can be obtained by coupling of immino ether hydrochloride salt of general formula 5 with a suitable piperazinone of general formula 6 in the presence of AcOH and a tertiary amine such as DIPEA in a solvent such as THF. Compounds of general structure la can finally be obtained via cyclization of amidine of general formula 7 in the presence of reagents such as diethyl oxalate and LHMDS in solvents such as THF. Alternatively, compounds of general formula la can be obtained in a one-pot amidine formation / cyclization procedure in analogy to the above described two-step procedure. Scheme 2

deprotection

Piperazinones of general structure 6 (Scheme 2) can be prepared starting from 2,2'-((tert- butoxycarbonyl)azanediyl)diacetic acid 9 by formation of the corresponding Weinreb amide of structe 10 using any of the commen peptide coupling reagents such as DCC preferentially in DMF. Intermediates of general structure 11 can then be obtained via addition of suitable Grignard reagents in solvents such as THF. Boc-protected intermediates of general formula 12 can then be obtained by reaction with a suitable primary amine in a one-pot reductive amination/piperazinone formation step using reagents such as BH(OAc) ₃ and AcOH in solvents such as THF followed by piperazinone formation via the use of coupling agents such as EDC in solvents such as DMF. Piperazinones of general structure 6 can then be obtained by using conditions such as TFA in DCM or HCI in dioxane.

Scheme 3

up

Alternatively, piperazinones of general structure 6 (Scheme 3) can be prepared starting from enantiomerically pure amino acid derivatives of general structure 13. After reduction, preferentially using BH ₃ in solvents such as THF, oxidation, preferably using sodium hypochlorite in combination with TEMPO in solvent mixtures such as DCM/water, generates aldehydes of general structure 14. Amino esters of general structure 15 can then be obtained via reductive amination using reagents such as NaHB(OAc) ₃ in solvents such as DCM. Piperazinones of general structure 6 can then be obtained via deprotection under hydrogenation using catalysts such as 10% Pd/C in solvents such as MeOH which is followed by in-situ cyclization.

Alternatively compounds of general structure 6a can be obtained via deprotection, preferentially by using HCI in dioxane, followed by in-situ cyclization and protection, preferentially by using di-tert-butyl dicarbonate in THF and NaOH as base. Compounds of general structure 6 can then be obtained via alkylation, preferentially using alkyl halides in presence of bases such as NaH in DMF, or, alternatively via Buchwald couplings using methods well-known to people trained in the art, followed by deprotection using preferentially HCI in dioxane. Scheme 4

In addition to Scheme 1 , nitrile building blocks of general formula 4 can be prepared by alternative synthetic routes as outlined in Scheme L4. Benzylic nitri!es of general formula 16 can be alkylated with a suitable electrophile such as 1 ,4-dibromobutane (n=1 ), in the presence of a base such as KO'Bu or NaH in a solvent such as THF or DMSO/Et ₂ 0 mixtures to give products of general formula 17. Aldehydes of general formula 18 can then be obtained by treatment with DIBAL preferentially in DCM. Nitrile building blocks of general formula 4 can then be obtained by treatment with TosMIC in the presence of a base such as KO'Bu in a solvent such as THF followed by refluxing in presence of MeOH.

Alternatively, aldehydes of general structure 18 can be transformed into the corresponding nitrile of general structure 4 by reduction preferentially with NaBH ₄ in MeOH followed by mesylation preferentially with MsCI in presence of a base such as NEt ₃ in DCM and nucleophilic substitution preferentially with KCN in the presence of Kl in DMSO at 140 °C.

Alternatively, intermediates of general structure 17 can be obtained via decarboxylative coupling of compounds of general formula 21 with potassium cyano carboxylate 22 catalyzed preferentially by Pd ₂ (allyl) ₂ Cl ₂ and Xantphos in mesitylene at 140 °C. Scheme 5

Compounds of general structure 26 (Scheme 5) can be obtained from aryl halide building blocks such as general structure 23 by carbonyiation preferentially with Mo(CO) ₆ catalyzed by Pd(OAc) ₂ in solvents such as DMF in presence of EtOH. After hydrolysis preferentially with NaOH, reduction preferentially with BH ₃ in THF, oxidation preferentially with Mn0 ₂ and transformation with DAST in DCM, compounds of general formula 26 can be obtained.

Benzylic fluorides of general structure 28 can be obtained by coupling of 23 with 30 catalyzed by Pd(PPh ₃ ) ₄ followed by reduction preferentially with NaBH ₄ in DCM/water followed by transformation with DAST preferentially in DCM.

Ethyl benzene derivatives of general formula 33 (Scheme 6) can be prepared from bromo- benzaldehydes of general structure 31 by Wittig reaction using preferentially PPh ₃ Mel in presence of KO'Bu in THF followed by hydrogenation using preferentially 10% Pd/C in EtOAc/AcOH as solvent mixture. Scheme 7 = CI R _3.7 = CN

NiC

Suzuki

R _{3 7} = alkyl, cycloalkyl,

aryl, heteroaryl, vinyl

Compounds of general structure Sb (Scheme 7 can be further functionalized if any R ₃ . ₇ = halide, preferentially bromide. Via Suzuki reactions catalyzed preferentially by Pd(dppf)CI ₂ in solvents such as dioxane/water mixtures aryl-, alkyl-, cycloalkyl-. heteroaryl- and vinyl- substituents can be introduced. By Treatment with NiCI ₂ in DMF at 160 °C chlorides can be introduced. By treatment with CuCN in NMP at 190 °C cyano groups can be introduced. By using boronic acid 34 catalyzed by Pd(dppf)CI ₂ in solvent mixtures such as dioxane/water benzylic nitriles can be introduced. The benzylic nitriles can be transformed into the corresponding carboxilic acids by HCI at 80 °C or into the corresponding amides by HCI at room temperature.

Scheme 8

Ic Id

Compounds of general formula 35a (Scheme 8) can be obtained via alkylation by using preferentially NaH as base in DMF and Mel as alkylation agent. In analogy to Scheme 1 compounds of general formula 36 can be obtained starting from compounds of general formula 35b. Then, compounds of general formula 37 can be obtained by nucleophilic substitution by a suitable nucleophile, as for example alcohols or amines, preferentially in solvents such as MeOH or THF in presence of a base such as NaOH or NaOMe.

Scheme 9

R _g =

aryl, h

38

Compounds of general structure 39 (Scheme 9) can be obtained via Suzuki reactions starting from compounds of general structure 38. Compounds of general structure 40 can be obtained via Negishi reactions catalyzed by Pd(dppf)CI ₂ in dioxane using Et ₂ Zn or by Suzuki reaction followed by hydrogenation starting from 38.

Scheme 10

Compounds of general formula 2a (Scheme 10) can be prepared from the corresponding compounds of general formula 41 via Sandmeyer reactions by standard conditions known by people trained in the art. Compounds of general structure 43 can be obtained by triflation of compounds of general structure 42 by using triflic anhydride in solvents such as DCM in the presence of bases such as NEt ₃ . Scheme 1

Compounds of general structure 44 (Scheme 1 1 ) can be obtained by compounds of general structure 18 by using Et ₂ AICN preferentially in toluene. Compounds of general structure ie can then be obtained following Scheme L1 starting from compounds of general structure 44.

Compounds of general structure 45 (Scheme 12) can be obtained by lithiation of compounds of general structure 2a, preferentially by using "BuLi in THF followed by addition of DMF. Compounds of general structure 46 can be obtained starting from compounds of general structure 45 by reduction, preferentially using NaBH,, in MeOH, followed by mesylation, preferentially by using MsCI in DCM and bases such as NEt ₃ . Compounds of general structure 16 can then be obtained by substitution using KCN in solvents such as DMF. Scheme 13

R _{3 7}

aryl, ^Et

17 Compounds of general structure 47 (Scheme 13) can be obtained via Suzuki reactions starting from compounds of general structure 17 having and R ₃ . ₇ = Br. Compounds of general structure 48 can be obtained via Negishi reactions catalyzed by Pd(dppf)CI ₂ in dioxane using Et ₂ Zn or by Suzuki reaction followed by hydrogenation starting from 17.

Scheme 14

Compounds of general structure 50 (Scheme 14) can be obtained from compounds of general structure 49 by deprotection, preferentially via hydrogention using Pd(OH) ₂ in EtOH, followed by treatment with DAST in a solvent such as DCM.

Scheme 15

52

Compounds of general structure 53 (Scheme 15) can be obtained by condensation of aldehyde 51 with an amino alcohol of general structure 52 preferably in presence of AcOH in DCM under microwave irradiation. Compounds of general structure 54 can then be obtained by deprotection, preferably by hydrogenation using 10% Pd/C in MeOH.

Compounds of genera! structure 57 (Scheme 16) can be prepared by condensing cyano ethyl acetate 55 with ketones of general structure 56, preferentially by refluxing in toluene in presence of ammonium acetate and AcOH using a Dean-Stark apparatus. Compounds of general structure 57 can then be further transformed by using Grignard reagents of general formula 2 in the presence of metal salts such as CuCN or Cul in THF to give cyano esters of general formula 58. The nitriie building blocks of general formula 59 may then be obtained via Krapcho decarboxylation preferentially with NaCI in DMSO at 120 X or higher temperatures. Imino ether hydrochlorides of general formula 60 can then be prepared via common Pinner reaction conditions - namely saturated HCI in MeOH. Amidine intermediates of general formula 61 can be obtained by coupling of imino ether hydrochloride salt of general formula 60 with a suitable piperazinone of general formula 6 in the presence of AcOH and a tertiary amine such as DIPEA in a solvent such as THF. Compounds of general structure If can be finally obtained via cyclization of amidine of general formula 61 in the presence of reagents such as diethyl oxalate and LHMDS in solvents such as THF. Alternatively, compounds of general formula If can be obtained in a one-pot amidine formation / cyclization procedure in analogy to the above described two-step procedure. Scheme 17

Compounds of genera! structure 1 (Scheme 17) can be prepared by condensing cyano ethyl acetate 55 with ketones of general structure 62, preferentially by refluxing in toluene in presence of ammonium acetate and AcOH using a Dean-Stark apparatus.

Scheme 18

Compounds of general structure Ih (Scheme 18) can be prepared from compounds of general structure Ig by de-methylation, preferentially by using BBr ₃ in presence of Nal and 15-crown-5 in DCM.

Scheme 19

6 ³ 64 65

Compounds of general structure 65 (Scheme 19) can be prepared by reduction of compounds of general structure 63, preferentially by using NaBH ₄ in EtOH, to give compounds of general structure 64, followed by benzylation using standard conditions well-aware by people trained in the art. Scheme 20

i) hydroboration ii) Appel reaction radical

cyclization

Compounds of general structure li (Scheme 20) can be prepared starting from compounds of general structure 66 via allylalion, preferentially by using LHMDS and ally! bromide in THF, to give compounds of general structure 67. Compounds of general structure 68 can then be obtained by Horner-Wadsworth-Emmons reactions by using conditions well aware to people trained in the art. Compounds of general structure 69 can then be obtained by hydroboration, preferentially by using 9-BBN in THF followed by oxidation with NaBO,,, followed by Appel reaction by using conditions well aware to people trained in the art. Compounds of general structure 70 can then be obtained via radical cyclization, preferentially using Bu ₃ SnH and AIBN in solvents such as benzene. Compounds of general structure li can then be obtained following the corresponding steps of Scheme 1.

Compounds of general structure Ij (Scheme 21 ) can be prepared starting from compounds of general structure 72 via a nucleophilic substitution reaction using electrophile 71. Compounds of general structure 74 can be obtained via Horner-Wadsworth-Emmons reactions by using conditions well aware to people trained in the art. Compounds of general structure 75 can then be obtained via radical cyclization, preferentially using Bu ₃ SnH and A!BN in solvents such as benzene. Compounds of general structure Ij can then be obtained following the corresponding steps of Scheme 1.

cheme 22

Compounds of general structure Ik (Scheme 22) can be prepared starting from acids of general formula 76 which are reacted with amino alcohols 77 using common amide coupling conditions such as HATU, DMF, DIPEA to give amides of general structure 78. The alcohol of 77 may be protected with a suitable protective group, for example a silyl protective group such as TES, which is cleaved in situ after the amide coupling step.

One phenolic OH of 76 is protected with a suitable protective group such as benzyl. Amides 78 can be then cyclized to intermediates 79 using Mitsunobu conditions such as DEAD/PPh ₃ /DCM, preferentially at room temperature or higher reaction temperatures. Deprotection, for example cleavage of a benzyl protective group using hydrogenation with a suitable solvent such as MeOH and catalyst such as Pd/C gives compounds Ik. Alternatively the benzyl protective group can be cleaved with other methods, for example by treatment with cone, aq HCI in MeOH at temperatures from 5 °C to room temperature. Chiral compounds can be obtained starting from chiral starting materials such as chiral, optionally protected amino alcohols 77 or by separation of racemic mixtures to the chiral components using suitable methods such as chromatography with a chiral stationary phase, preferentially with intermediates 79.

Halogen substituted derivatives such as R ⁴ = (Br, CI or I) can be converted to alkene derivatives 80 with palladium catalyzed reactions (Suzuki reaction), for example using 4,5,5- tetramethyl-2-vinyl-1 ,3,2-dioxaborolane, Pd(PPh ₃ ) ₄ , Na ₂ C0 ₃ in THF/H ₂ 0 at 70-80 °C. Alkenes 80 can then be deprotected as described above to derivatives II or reduced to alkyl substituted derivatives 81 , for example by hydrogenation in presence of Pd/C and a solvent such as EtOAc at room temperature. Derivatives 81 can then be deprotected as described above. Methyl groups can be introduced in analogy using a suitable reagent such as 2,4,6-trimethyl- 1 ,3,5,2,4,6-tn ^' oxatriborinane without the hydrogenation step.

Isopropyl groups can be introduced in analogy using a suitable reagent such as prop-1 -en-2- ylboronic acid with the hydrogenation step.

Scheme 23

reductive

Protected and unprotected amino alcohols 77 can be prepared by various routes. For example, as illustrated in Scheme 23, an amine 82 can be reacted with ketones 83 under reductive amination conditions such as NaBH(AcO) ₃ , AcOK in DCE, at temperatures ranging from 0°C to room temperature.

cheme 24

N-Me substituted amino alcohols 77b can be prepared from suitable, N protected, for example Boc protected, amino acids 84, which are converted to esters 85 (Scheme 24). For the conversion to esters, acids 84 can be treated with an alkylating agent like methyl iodide, a base such as potassium carbonate in a solvent such as acetone, preferentially at a iemperature above room temperature such as 60 °C. Alternatively, an amino acid 86 can be esterified, for example using SOCI ₂ in MeOH to give 87, preferentially at temperatures between 0 °C and 70 °C, followed by protection to give 85, for example using Boc ₂ 0 and TEA in MeOH at temperatures preferentially between 0 °C and room temperature.

Reduction of both, the ester and NHBoc group with a suitable reducing agent such as lithium aluminum hydride in a solvent such as THF, preferentially at temperatures between 0 °C and THF reflux temperature gives amino alcohols 77b. Scheme 25

DPEA PG = TBS

Amino alcohols 88 can be selectively O protected to give intermediates 89 (Scheme 25), for example by reaction with TBS-CI in presence of a base such as DIPEA and solvent such as DCM at temperatures preferentially between 5 °C and room temperature. Amines 89 can be converted to intermediates 77c by reductive amination with acetone, a reducing agent such as NaBH(OAc) ₃ at temperatures preferentially between 5 °C and room temperature. cheme 26

77d

Amino alcohols 88 can be converted to N-benzyl derivatives 90 by treatment with PhCHO and a suitable reducing agent such as NaBH(OAc) ₃ at temperatures preferentially between 5 °C and room temperature (Scheme 26). A methyl group can be introduced by treating derivatives 90 with CH ₂ 0 and a suitable reducing agent such as NaBH(OAc) ₃ at temperatures

preferentially between 5 °C and room temperature. Cleavage of the Bn group, for example by hydrogenation in presence of Pd(OH) ₂ in a solvent such as MeOH preferentially at temperatures between 5 °C and room temperature gives amino alcohols 77d.

Alternatively, an N-benzyl protected ester 92 can be reacted with CH ₂ 0 and a suitable reducing agent such as NaBH(OAc) ₃ at temperatures preferentially between 5 °C and room temperature to give derivatives 93. The ester group of 93 is then reduced to aicohols 91 with a reducing agent such as NaBH ₄ in the presence of LiCi and a solvent such as THF/EtOH, preferentially between 5 °C and room temperature.

Scheme 27

77e

Treatment of ester 94 with a strong base such as LDA in a solvent such as THF at low temperature, e.g. -78 °C, followed by addition of a brominating agent such as NBS gives bromide 95 (Scheme 27). Substitution with MeNHBn in a solvent like MeCN preferentially at temperatures between 5 °C and room temperature gives intermediate 96, which is then reduced with a suitable reducing agent like LAH in a solvent like THF, preferentially at temperatures close to 0 °C to an alcohol. The benzyl group of can then be cleaved for example by hydrogenation in the presence of Pd(OH) ₂ /C in MeOH, preferentially at a pressure of 50 psi and room temperature to give 77e.

Scheme 28

¹⁰ 102

Compounds of general formula I can be obtained from acids 76 as shown in Scheme 28. Esterification of acids 76 with an activated diol 97 to esters 98, followed by cyclization gives intermediates 99. Sulfonates such as mesyl are suitable as activating groups. Esterification can be performed using HATU or other suitable reagents, a suitable base such as DIPEA and a suitable solvent such as DCM, at preferred temperatures ranging from 0 °C to room temperature. For cyclization to intermediate 99, esters 98 are treated with a suitable base such as Cs ₂ C0 ₂ in a solvent such as DMF. Treatment of 99 with an amine that may be dissolved in a suitable solvent such as ethanol gives intermediates 100. Treatment with an oxidizing agent such as Dess Martin periodinane in a solvent such as DCM, preferentially at temperatures ranging 25-40 °C gives intermediates 101. Deprotection gives compounds In. Treatment of intermediates 101 with alcohols such as methanol preferentially in the presence of an acid such as TsOH, gives compounds 102, which can be deprotected to compounds lo.

Scheme 29

Intermediate acids 76 can be obtained as outlined in Scheme 29. A nitrile of general formula 103 can be converted to amidinium salts 104, for example by treatment with NH ₄ CI in a solvent such as toluene and trimethyl aluminum at temperatures ranging preferentially from 0 °C to 80 °C. Amidinium salts 104 can be reacted with intermediate 105, in a solvent such as methanol and a suitable base such as sodium methoxide, preferentially at room temperature to give terf-butyl esters 106, which can then be cleaved to acids 76, for example by hydrolysis with aqueous LiOH in THF at reflux temperature.

Scheme 30

A compound of general formula Ip (Scheme 30) can be prepared from intermediate 107, which can be prepared by the methods outlined above, by treatment with MeOH and cone. aq. HCI at temperatures between 5 °C and room temperature.

Treatment of 107 with acids such as HCI in water and a solvent such as THF at temperatures between 5 °C and room temperature can give acids Iq. Alternatively, esters 107 can be hydrolyzed with a mineral base such as LiOH in a mixture of water and a solvent such as methanol, preferentially at room temperature. Acids Iq can be converted to amides Ir by treatment with NH ₄ CI and a suitable coupling reagent such as HATU in a solvent such as DMF in presence of a base such as DIPEA, preferentially at a temperature between 10 °C and room temperature. Amides Ir can be converted to nitriles Is by treatment with Burgess reagent in a solvent such as THF, preferentially a temperature between 15 °C and room temperature. cheme 31

79 108 It

Compounds of general structure It can be obtained as illustrated in Scheme 31. Intermediates 79 can be deprotonated with a strong base like LHMDS in a solvent such as THF,

preferentially at low temperature such as -65 °C and then reacted with paraformaldehyde to give intermediates 108 which can then be deprotected as described above. Dlastereoisomers of 108 can be separated by chromatography.

Scheme 32

deorotection

deprotection

lu

Thioethers of general formula 79b (Scheme 32) can be oxidized with m-CPBA in a solvent such as DCM, preferentially at a temperature close to 0 °C to sulfoxides 79c and sulfones 79d which can be deprotected to compounds It and compounds lu.

Scheme 33

Alcohols of general structure Iv (Scheme 33), obtained with the methods described above can be oxidized to acids Iw with an oxidizing agent such as Phl(OAc) ₂ in the presence of catalytic amounts of TEMPO in a solvent mixture such as DCM/water, preferentially at temperatures between 15 °C and 30 °C. Acids Iw can be converted to amides Ix by treatment with an amine or ammonium salt and a suitable coupling reagent such as HATU in a solvent such as DMF in presence of a base such as DIPEA, preferentially at a temperature between 10°C and room temperature.

Scheme 34

laa

As shown in Scheme 34, intermediates 79 can be chlorinated selectively to intermediates 79e by treatment with a suitable chlorinating agent such as 1 ,3,5-trichloro-l ,3,5-triazinane-2,4,6- trione in a solvent such as chloroform, preferentially at temperatures ranging from 5 °C to 75 "C. Deprotection as outlined above gives compounds ly. The chlorine group can be substituted with acetate to give Iz, for example by treatment with NaOAc, Nal in a solvent such as DMF, preferentially at room temperature. The acetate group of Iz can be hydrolyzed to give alcohols laa, by standard ester hydrolysis methods well known in the art such as treatment with NaOH in a solvent such as MeOH, preferentially at temperatures between 0°C and room temperature. Example 1

3-Ethyl-9-hvdroxy-2-methyl-6-((1 -phenylcyclopentyl)methyl)-3,4-dihvdro-1 H- clpyrimidine-1 ,8(2H)-dione

a) Ethyl 2-cvano-2-(1-phenylcvclopentyl)acetate

In a 100 mL three-necked flask, copper (I) cyanide (790 mg, 8.82 mmol, Eq: 1 .58) in THF (2 ml) was cooled in an ice bath to 0°C. Then phenylmagnesium bromide 1 M in THF (16.7 ml, 16.7 mmol, Eq: 3.00) was added at this temperature and the mixture was allowed to warm to room temperature to give a light green suspension. After 30 min the reaction mixture was cooled to -30°C and a solution of ethyl 2-cyano-2-cyclopentylideneacetate (1 g, 5.58 mmol, Eq: 1.00) in THF (1.40 ml) was added slowly. Then the mixture was allowed to warm to room temperature and stirred for 3.5 h Saturated NH ₄ CI was added, the aqueous layer was separated and extracted twice with diethyl ether. The combined organic layers were washed with saturated NaCI, dried over MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to give the title compound as a colorless oil (1.0 g, 70 % yield).

MS (ESI, m/z): 256.2 [(M-H) ^" ]. b) 2-(1 -PhenylcvclopentvDacetonitrile N in a 10 mL flask, ethyl 2-cyano-2-( 1 -phenylcyclopentyl )acetate (505 mg, 1.96 mmoi, Eq: 1.00), sodium chloride (39 mg, 667 mol, Eq: 0.34) and water (73 mg, 73 μΙ, 4.03 mmol, Eq: 2.05) were combined with dimethyl sulfoxide (6.6 ml) to give a colorless solution. The reaction mixture was heated to 160 °C and stirred for 100 min. The reaction mixture was allowed to cool down to room temperature and water was added. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed once with H ₂ 0 and once with saturated aq. NaCI, dried over MgS0 ₄ and concentrated in vacuo. The residue was filtered over a plug of silica gel eluting with ethyl acetate. After evaporation and drying on high vacuum the title compound was obtained as a brown oil (270 mg, 74 % yield) and used as such in the next step.

c) Methyl 2-(1-phenylcyclopentyl)ethanimidate hydrochloride

H-CI

In a 25 ml flask 2-(1 -phenylcyclopentyl)acetonitrile (500 mg, 2.7 mmol, Eq: 1 ) was dissolved in dry methanol (9.37 ml). The solution was saturated with dry HCI at -10°C under a stream of dry HCI-gas. The solution was tightly stoppered with a greased glass stopper and a metal clip. The flask was left in the fridge for 4 days. The crude reaction mixture was concentrated in vacuo at room temperature and dried on high vacuum. The residue was triturated with MTBE to give a thick, white suspension, which was filtered through sintered glass, washed with MTBE and dried on high vacuum to give the title compound as a white powder (621 mg, 91 % yield).

MS (ESI, m/z): 218.2 [(M+H) ⁺ ].

d) 2-((tert-Butoxycarbonyl)(2-(methoxy(methyl)amino)-2-oxoethyl )amino)acetic acid

2,2'-((tert-Butoxycarbonyl)azanediyl)diacetic acid (9 g, 37 mmol, Eq: 1 ) in dimethylformamide (60 ml) was treated with 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (8.9 g, 46.4 mmol, Eq: 1.25) in four portions over 30 min at 0°C, then warmed to room temperature and stirred for 1 h. The mixture was cooled to 0°C, treated drop wise with a premixed solution of Ν,Ο-Dimethy!hydroxylamine hydrochloride (4.5 g, 45.2 mmol, Eq: 1 .22) and N,N- diisopropylethylamine (5.92 g, 8 ml, 45.8 mmol, Eq: 1.24) in dimethylformamide (20 ml) and stirred for 18 h at room temperature. The reaction mixture was poured on ice (100 g) mixed with 2M HCI (120 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were washed with 2M HCI (2 x 120 mL), brine (1 x 100 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The light yellow oil was dissolved in ether and stirred slowly under cooling to receive a thick white suspension which was filtered through sintered glass, washed twice with ether and dried on high vacuum to give the title compound as a white solid (4.1 g, 40 % yield).

MS (ESI, m/z): 275.3 [(M-H)] e) 2-((tert-Butoxycarbonvn(2-oxobutyl)amino)acetic acid

In a 100 ml_ three-necked flask, a solution of 2-((tert-butoxycarbonyl)(2- (methoxy(methyl)amino)-2-oxoethyl)amino)acetic acid (1.0 g, 3.62 mmol, Eq: 1 ) in tetrahydrofuran (25.5 m!) was cooled to Q°C and treated with ethylmagnesium bromide 3.2 M in tetrahydrofuran (2.49 ml, 7.96 mmol, Eq: 2.2) drop wise over 15 min, via syringe. The mixture was allowed to warm to room temperature and it was stirred for 1 h. Then the solution was cooled in an ice bath to 0°C, saturated NH ₄ CI (10 ml) and H ₂ 0 (10 ml) were added dropwise over 20 min at 0°C and the mixture was stirred for 3 h at room temperature. Diethyiether (50 mi) was added and the mixture was extracted with 2M NaOH (30 ml). The aqueous layer was acidified by the addition of concentrated HCI (4.5 ml) at 0°C and then extracted twice with diethyl ether (100 ml and 50 ml). The organic layers were dried over Na ₂ S0 ₄ and concentrated in vacuo to give the title compound as a yellow oil (0.8 g). This material was contaminated with starting material but was used in the next reaction without further purification.

MS (ESI, m/z): 244.3 [(M-HV]

f) tert- Butyl 3-ethvl-4-methvl-5-oxo-piperazine-1 -carboxylate

In a 100 mL round-bottomed flask, 2-((tert-butoxycarbonyl)(2-oxobutyl)amino)acetic acid (765 mg, 3.12 mmol, Eq: 1 ) was combined with 1 ,2-dichloroethane (15.75 ml) to give a white solution. It was treated with methylamine 2M in tetrahydrofuran (1.56 ml, 3.12 mmol, Eq: 1 ), acetic acid (187 mg, 179 μΙ, 3.12 mmol, Eq: 1 ) and sodium triacetoxyborohydride (860 mg, 4.06 mmol, Eq: 1.3). The resulting suspension was stirred at room temperature for 30 h. The solvent was removed under vacuo, the residue was dissolved in dimethylformamide (13.5 ml) and treated with 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (598 mg, 3.12 mmol, Eq: 1 ). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (2 x 70 ml). The organic layers were combined, washed with 2M HCI (4 x 15 mL), saturated NaHC0 ₃ (4 x 15 mL), saturated NaCI (1 x 15 mL) and dried over MgS0 ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM) to give the title compound as a white powder (0.25 g, 33 % yield over two steps).

MS (ESI, m/z): 243.1 [(M+H) ⁺ ].

g) 6-Ethyl-1-methyl-piperazin-2-one

In a 10 mL round-bottomed flask, tert-butyl 3-ethyl-4-methyl-5-oxopiperazine-1 -carboxylate (234 mg, 966 μιηοΙ, Eq: 1 ) was combined with methylene chloride (1.04 ml), then 2,2,2- trifluoroacetic acid (1 10 mg, 520 μΙ, 966 prnol, Eq: 1 ) was added to give a colorless solution. The reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated in vacuo. The residue was neutralized (ca pH 8) with saturated KHC0 ₃ and concentrated in vacuo. The reaction mixture was filtered through silica gel (methylene chloride : methanol 4:1 ). The solvent was evaporated to give The crude material was concentrated in vacuo to give the title compound as a yellow oil (161 mg) which was used in the next step without further purification.

MS (ESI, m/z): 243.2 [(M+H) ⁺ ] h) 3-Ethyl-9-hvdroxy-2-methyl-6-((1-phenylcyc[opentyl)methyl)-3 ,4-dihvdro-1 H-pyrazinoH ,2- clpyrimidine-1 ,8(2H)-dione

In a 50 mL three-necked flask, methyl 2-(1-phenylcyclopentyl)acetimidate hydrochloride (287 mg, 1.13 mmol, Eq: 1 .34) and 6-ethyl-1 -methylpiperazin-2-one (120 mg, 844 μπιοΙ, Eq: 1 ) were combined with THF (17.5 ml) and N,N-diisopropylethylamine (293 mg, 396 μΙ, 2.27 mmol, Eq: 2.69) to give a light yellow solution. Then acetic acid (67.9 mg, 64.7 μΙ, 1 .13 mmol, Eq: 1 .34) was added and the mixture was stirred at room temperature for 2 days. The thick suspension was diluted with THF (3 ml) and was cooled to -30°C, then first lithium bis(trimethylsilyl)amide 1 M in THF (6.33 ml, 6.33 mmol, Eq: 7.5) was added at -30°C followed by diethyl oxalate (555 mg, 519 μΙ, 3.8 mmol, Eq: 4.5). The cooling bath was removed and the reaction was stirred for 3 h at room temperature. The reaction mixture was taken up in 1 M HCI and extracted four times with DCM. The combined organic layers were evaporated and the residue purified by reversed phase preparative HPLC to give the title compound as white powder (74 mg, 23 % yield).

MS (ESI, m/z): 382.2 [(M+H) ⁺ ].

Example 2 & Example 3

(3S)-3-Ethyl-9-hvdroxy-2-methyl-6-f(1-phenylcyclopen

clpyhmidine-1 ,8-dione

and

(3R)-3-ethyl-9-hydroxy-2-methyl-6-r(1-phenylcvclopentyl)m ethyll-3,4-dihvdropyrazinori ,2- clpyrimidine-1 ,8-dione

3-Ethyl-9-hydroxy-2-methyl-6-((1 -phenylcyclopentyl)methyl)-3,4-dihydro-1 H-pyrazino[1 ,2- c]pyrimidine-1 ,8(2H)-dione (64 mg) was submitted to chiral separation on the column Reprosil 100 AILIC-A (5 μητι) eluting with 20% acetonitrile in water to give the title compounds as white powders (23 mg for Example 2 and 22 mg for Example 3)

Example 2; MS (ESI, m/z): 382.3 [(M+H) ⁺ ].

Example 3: MS (ESI, m/z): 382.3 [(M+Hf].

The absolute configuration was tentatively assigned in analogy to Example 1 1 based on biological activity.

Example 4

3-Ethyl-6-rri -(3-ethylphenyl)cvclopentyllmethvn-9-hydroxy-2-methyl-3,4-di hv

clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyi)magnesium bromide instead of phenylmagnesium bromide in step a) to give the title compound as a white powder.

MS (ESI, m/z): 410.3 [(M+H) ⁺ ].

Example 5 & Example 6

(3S)-3-Ethyl-6-fi 1 -(3-ethylphenyl ^' )cvciopentvnmethvn-9-hvdroxy-2-methyl-3,4- dihvdropyrazinofl ,2-c|pyrimidine-1 ,8-dione

and

(3R)-3-ethvl-6-[[1 -(3-ethvlphenvl)cvclopentyllmethvll-9-hvdroxv-2-methyl-3,4- dihvdropyrazinon ,2-clpyrimidine-1 ,8-dione

3-Ethyl-6-[[1 -(3-ethylphenyl)cyclopentyl]methyl]-9-hydroxy-2-methyl-3,4-d

c]pyrimidine-1 ,8-dione (20 mg) was submitted to chiral separation using was submitted to chiral separation on the column Reprosil 100 AILIC-A (5 pm) eluting with 20% acetonitrile in water to to give the title compounds as white powders (7 mg for Example 5 and 6 mg for Example 6)

Example 5: MS (ESI, m/z): 410.3 [(M+H) ⁺ ],

Example 6: MS (ESI, m/z): 410.3 [(M+H) ⁺ ]. The absolute configuration was tentatively assigned in analogy to Example 1 1 based on biological activity.

Example 7

6-[n-(3,5-Dimethylphenyl)cvclopentyllmethyll-9-hvdroxy-2-iso propyl-3-methyl-3,4-

The title compound was prepared in analogy to Example 1 by using (3,5- dimethy!phenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and isopropylamine instead of methylamine in step f) to give the title compound as a white powder.

MS (ESI, m/z): 442.3 [(M+Hf]. Example 8

2-Cvc[opropyl-6-f[1-(3,5-dimethylphenvQ^

dihvdropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylpheny!)magnesium bromide instead of phenylmagnesium bromide in step a) and cyclopropylamine instead of methylamine in step f) to give the title compound as a white powder.

MS (ESI, m/z): 422 3 [(M+H) ⁺ ],

Example 9

6-iri-(3-Fiuoro-5-methyl-phenvncvclopentvnmethvn-9-hvdroxy-2 -isopropyl-3-methyl-3,4- dihvdropyrazinofl ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3-Fluoro-5- methylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and isopropylamine instead of methylamine in step f) to give the title compound as a white powder. MS (ESI, m/z): 428.3 [(M+H) ⁺ ].

Example 10

9-Hvdroxy-2,3-dimethyl-6-ff1-r3-(trifluoromethyl)phenyllc vclopentyllmeth

dihvdropyrazinofl ,2-clpyrimidine-1 ,8-dione

a) (3-Trifluoromoethvlpenvl)maqnesium bromide:

Mg turnings (1 .1 g, 46.7 mmol) were combined with a catalytic amount of iodine and heated in a two neck round-bottom flask at 80°C for 5mins followed by the addition of dry THF (20 mL). To this suspension, a solution of 1 -bromo-3-(trifluoromethyl)benzene ( 10. O g, 44.4 mmol) in THF (20 mL) was added slowly at refluxing condition with constant stirring until 1 0 mL of the solution was added. As the reaction started, the oil bath was removed and the rest of the solution was added drop wise. After the exotherm of the reaction ceased (after 2hrs) the mixture was heated at 80°C for another 5 minutes and then gradually cooled to room temperature. The solution of (3-trifluoromoethylpenyl)magnesium bromide (approximately 4.4 M in THF, yield was considered as quantitative) was used as such in the next step. b) 9-Hvdroxy-2,3-dimethyl-6-f[1-[3-(W^

dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- trifiuoromethylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) to give the title compound as a white powder.

MS (ESI, m/z): 436.2 [(M+H)+].

Example 11 & Example 12

(3S)-9-Hvdroxv-2,3-dimethvl-6-[( 1-phenvlcvclopentvl)methvn-3.4-dihydropyrazinof1 ,2- clpyrimidine-1 ,8-dione

and

(3R)-9-hydroxy-2,3-dimethyl-6-[(1-phenylcvclopentyl)methvn-3 ,4-dihvdropyrazinof1 ,2- clpyrimidine-1 ,8-dione

Example 1 19 (19 mg) was submitted to chiral separation on the column Reprosil 100 AILIC-A (5 pm) eiuting with 80% MeOH in water to to give the title compounds as white powders (6 mg for Example 1 1 and 6 mg for Example 12). The absolute stereochemistry was determined via X-ray co-crystallography.

Example 1 1 : MS (ESI, m/z): 368.3 [(M+H)+].

Example 2: MS (ESI, m/z): 368.3 [(M+H)+].

Example 13

(3S)-6-rri-(3-Fluoro-5-methyl-phenyl)cvclopentyllmethvn-9-hv droxy-2,3-dimethyl-3,4- dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

a) Benzyl N-f( 1 S)-2-hydroxy-1 -methvl-ethyll-N-methyl-carbamate

In a 200 mL four-necked flask, benzyloxycarbonyl-N-methyl-L-alanine (5 g, 21.1 mmol) was combined with THF (45 ml) to give a colorless solution. 1 M Borane tetrahydrofuran complex in THF (42.1 ml, 42.1 mmol) was added at 0 °C. The reaction mixture was stirred for 90 min at room temperature. LC/MS analysis after 90 min indicated completion of the reaction. H ₂ 0 (50 ml) and sat. Na ₂ C0 ₃ (50 ml) were added at 0 °C. The mixture was extracted with EtOAc and the organic phases were dried and concentrated to give the title compound as a yellow oil (5.6 g, quantitative yield). This material was used as such in the next step. b) Benzyl N-methyl-N-f(1 S)-1 -methyl-2-oxo-ethvncarbamate

In a 200 mL four-necked flask, Benzyl N-[(1 S)-2-hydroxy-1 -methyl-ethyl]-N-methyl-carbamate (4.7 g, 21.1 mmol), sodium bromide (217 mg, 2.11 mmol), NaHC0 ₃ (177 mg, 2.1 1 mmol) and TEMPO (65.8 mg, 421 Mmol, Eq: 0.02) were combined with DCM (45 ml) and H ₂ 0 (45 ml) to give a biphasic mixture. 15 % sodium hypochlorite (15.7 g, 13 ml, 31.6 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 15 min. Further 15% sodium hypochlorite (5.22 g, 4.33 ml, 10.5 mmol) was added at 0 °C. LC/MS analysis after 5 min indicated completion of the reaction. The reaction mixture was poured over water and extracted with DCM. The combined organic fractions were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as yellow oil (5.2 g, quantitative yield). The crude product was used immediately as such in the next step.

MS (ESI, m/z): 222.1 [(M+H)+].

c) Methyl 2-ff(2S)-2-fbenzvloxvcarbonyl(methvl)aminolpropvllaminolacet ate

In a 250 mL round-bottomed flask, Benzyl N-methyl-N-[(1 S)-1-methyl-2-oxo-ethyl]carbamate (4.5 g, 20.3 mmol) was combined with DCM (140 ml) to give a yellow solution. Glycine methyl ester (2.9 g, 32.5 mmol), DIPEA (3.15 g, 4.26 ml, 24.4 mmol, Eq: 1.2) and sodium triacetoxyborohydride (5.17 g, 24.4 mmol, Eq: 1.2) were added at room temperature. LC/MS analysis after 100 min indicated completion of the reaction. The reaction was quenched with sat. NaHC0 ₃ and extracted with DCM. The combined organic phases were reduced and dried in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 100% EtOAc in heptane) to give the title compound as yellow oil (2.82 g, 47 % yield).

MS (ESI, m/z): 295.2 [(M+H)+], d) (6S)-1 ,6-Dimethylpiperazin-2-one

In a 100 ml_ round-bottomed flask, methyl 2-[[(2S)-2-

[benzyloxycarbonyl(methyl)amino]propyl]amino]acetate (2.82 g, 9.58 mmol) was combined with Methanol (50 ml) to give a colorless solution. The flask was evacuated and purged with nitrogen and 10% Pd/C (277 mg, 2.61 mmol) was added. The flask was evacuated and purged with nitrogen and placed under a balloon atmosphere of H ₂ . LC/MS analysis after 4 h indicated completion of the reaction. The reaction material was filterered and the filtrate was concentrated and dried in vacuo to give the title compounds as a yellow oil ( .2 g, quantitative yield). The product was used as such in the next step.

MS (ESI, m/z): 129.1 [(M+H)+].

e) (3S)-6-ff1 -(3-Fluoro-5-methyl-phenyl)cvclopentyl1methvn-9-hvdroxy-2.3- dimethyl-3,4- dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3-fluoro-5- methylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)- 1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 400.2 [(M+H) ⁺ ].

5 Example 14

(3S)-9-Hvdroxy-2,3-dimethyl-6-rri-f3-methyl-5-(trifluorometh yl)phenyllcvclopen

dihydropyrazinoil ,2-c1pyrimidine-1 ,8-dione

i n

a) 3-Trifluoromethvl-5-methylpenvl)maqnesium bromide

15 In a 50 ml_ two-necked flask equipped with a reflux condenser, magnesium turnings (391 mg, 16.1 mmol) were combined with THF (7 ml). 1 -Bromo-3-methyl-5-(trifluoromethyl)benzene (3.85 g, 2.5 ml, 16.1 mmol) dissolved in THF (12.2 ml) was added drop wise during which the reaction initiated and warming up to 50°C. During the addition of the remaining solution the temperature was kept at kept at 38°C. The mixture was heated to 38°C for 1 h, then allowed to 0 cool down to room temperature. This solution was used as such. b) (3S)-9-Hydroxy-2,3-dimethyl-6-[ri-^

3,4-dihydropyrazinon ,2-clPyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3-trifluoromethyl-5- methylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)- 1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyi-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 450.3 [(M+H)+].

Example 15

(3S)-6-[(1 -Cvclohexvlcvclopentvl)methvll-9-hvdroxv-2.3-dimethyl-3,4-di hvdropvrazinoM ,2- clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using cyclohexyl magnesium chloride instead of phenylmagnesium bromide in step a) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 374.3 [(M+H)+].

Example 16

(3S)-9-Hvdroxy-6-f(1 -isopropylcyclopent

clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using isopropyl magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 334.3 [(M+H)+].

Example 17

(3S)-9-Hvdroxv-2,3-dimethvl-6-[[1-(m-tolyl)cvclopentvllmethy ll-3,4-dihvdropvrazino[1 ,2- clpvrimidine-1 ,8-dione acetic acid adduct

a) (6S)-1 ,6-Dimethyl-4- ^r 2-f1 -(m-tolyl)cvcto hydrochloride salt

In a 10 mL round-bottomed flask, methyl 2-(1 -(m-tolyl)cyclopentyl)acetimidate hydrochloride (48.1 mg, 180 μιηοΙ) - prepared in analogy to Example 1 steps a-c) using (3- methylphenyl)magnesium chloride instead of phenylmagnesium bromide in step a) - was combined with THF (1.5 ml) to give a light yellow solution. DIPEA (94.1 μΙ, 539 pmol) and (S)- 1 ,6-dimethy!piperazin-2-one (34.5 mg, 269 pmol) (see Example 13) were added. After 5 minutes, AcOH (10.3 pi, 180 pmol) was added. After stirring overnight LC/MS analysis indicated complete conversion. Et ₂ 0 was added to the thicken suspension and the solid obtained by filtration was washed with Et ₂ 0. After drying on high vacuum the title compound was obtained as a white solid (54 mg, 82 % yield) and was used in the next step as such.

MS (ESI, m/z): 328.3 [(M+H)+].

b) (3S)-9-Hvdroxy-2.3-dimethvi-6-fi1-(m-tolyl)cvclopentyl1methv n-3,4-dihvdropyrazinon ,2- c1pyrimidine-1 ,8-dione acetic acid adduct

In a 25 mL three-necked flask, (6S)-1 ,6-dimethyl-4-[2-[1 -(m- tolyl)cyclopentyl]ethanimidoyl]piperazin-2-one hydrochloride salt (50 mg, 137 μιηοΙ) was combined with THF (2.5 ml) to give a white suspension. After cooling to -30°C, diethyl oxalate (37 μΙ, 275 pmol) was added followed by the addition of 1 M LHMDS in THF (550 μΙ, 550 pmol). After stirring for 15 min at -30°C the reaction was warmed to 0°C. After 30 min the mixture was stirred at room temperature. After stirring for 1 h at room temperature LC/MS indicated complete conversion to product. The reaction was quenched by the addition of AcOH (787 μΙ, 13.7 mmol) at 0°C. After stirring while warming up to room temperature the reaction mixture was concentrated to dryness. The residue was dissolved in DCM and washed with 1 M HCI. The organic layer was concentrated to dryness and the title compound was obtained as a white solid (18 mg, 30 % yield) after recrystallisation with Et ₂ 0.

MS (ESI, m/z): 382.2 [(M+H)+].

Example 18

1 -ΓΗ -(3.5-Dimethvlphenvl)cyclopentyllmethyll-4-hydroxv-7,8,9.10, 10a, 11 - hexahvdropyridof3,4lpvrazino[3,5-b1pyrimidine-3,5-dione

The title compound was prepared in analogy to Example 1 by using (3.5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and octahydro-4h-pyrido[1 ,2-a]pyrazin-4-one instead of 6-ethyl-1-methyl-piperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 422.3 [(M+H)+j. Example 19

1-ΓΓ1 -(3-Ethylphenvncvclopentyl1methvn-4-hvciroxy-7,8,9, 10, 10a, 1 1 - hexahvdropyridof3,4lPyrazino[3,5-blpyrimidine-3,5-clione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and octahydro-4h-pyriuo[1 ,2-a]pyrazin-4-one instead of 6-ethyl-1 -methyl-piperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 422.2 [(M+H)+].

Example 20

1-fri-(3,5-Dimethylphenyl)cvclopentyllmethyll-4-hydroxy-8 ,9,9a,10-tetrahvdro-7H- pyrrolof3,4lpyrazinof3,5-blPyrimidine-3,5-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and hexahydro-pyrrolo[1 ,2-a]pyrazin-4-one instead of 6-ethyl-1-methyl-piperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 408.2 [(M+H)+].

Example 21

9-Hvdroxy-12-(( 1 -( m-tolyl)cvclopentyl)methyl)-5.6.14, 14a- tetrahvdropyrimidor ,6':4,51pyrazino[2,1 -a1isoquinoline-8,10-dione

The title compound was prepared in analogy to Example 17 by using 1 ,2,3,6,7,1 1 B- Hexahydro-4h-pyrazino(2, 1 -a)isoquinoline-4-one instead of (S)-1 ,6-dimethylpiperazin-2-one in step a) to give the title compound as a white powder.

MS (ESI, m/z): 456.2 [(M+H)+].

Example 22

12-(( 1 -(3,5-Dimethvlphenvl)cyclopentvl)methvl)-9-hvdroxv-5,6, 14, 14a- tetrahydropyrirriidoH ',6':4,5lpyrazino[2, 1 -alisoquinoline-8, 1 Q-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and 1 ,2,3,6,7,1 1 B-hexahydro-4h-pyrazino(2,1-a)isoquinoline-4-one instead of 6-ethyl-1 -methyl- piperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 470.2 [(M+H)+J.

Example 23

(3S)-6-rf1 -(3,5-Dimethylphenyl)cvclopentvnmethyll-9-hvdroxy-2,3-dimeth yl-3,4- dihvdropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 396.2 [(M+H)+j.

Example 24

(3S)-6-fri-i3-Chloro-5-methyl-phenyl)cvclopentvnmethyll-9-hv droxy-2,3-dimethyl-3,4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3-chloro-5- methy!phenyl)magnesium bromide (prepared in analogy to 3-trifluoromethyl-5- methyipenyl)magnesium bromide, see Example 14, by starting from 1-bromo-3-chloro-5- methylbenzene) instead of phenylmagnesium bromide in step a) and (6S)-1 ,6- dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 416.2 [(M+H)+].

Example 25

((3S)-6-rf1-(4-Fluoro-3,5-dimethyl-phenyl)cvclopentyllmethyl l-9-hvdroxy-2,3-dimethyl-3,4- dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5-dimethyl-4- fluorophenyl)magnesium bromide (prepared in analogy to 3-trifluoromethyl-5- methylpenyl)magnesium bromide, see Example 14, by starting from 1 -bromo-3,5-dimethyl-4- fluorobenzene) instead of phenylmagnesium bromide in step a) and (6S)-1 ,6- dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 414.2 [(M+H)+].

Example 26

(3S)-6-rri-r3-(Difluoromethyl)phenvncvclopentyl1methyll-9-hv droxy-2.3-dimethyl-3,4- dihvdropyrazino[1 ,2-clpyrimidine-l ,8-dione

a) 1-(3-Bromophenyl)cyclopentanecarbonitrile

In a four-neck round bottom flask 2-(3-bromophenyl)acetonitrile (20 g, 102 mmol) was dissolved in THF (100 ml) and cooled to 0 °C. KOtBu (25.2 g, 224 mmol) was added portionwise such that the internal temperature did not rise above 10 °C. After stirring the resulting suspension for 30 min at 0-5 °C, 1 ,4-dibromobutane (12.2 ml, 102 mmol) was added over 15 min and the resulting mixture was warmed up to rt. After two hours the reaction mixture was quenched by the addition of sat. NH ₄ CI (250 ml). The mixture was extracted with EtOAc (3 x 250 ml) and the combined organic phases were dried with Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by filtration over a plug of silica eluting with 10% EtOAc in heptane to give the title compound (19.3 g, 75 %) as a yellow oil. MS (El, m/z): 249.0 [M+]

b) 1 -(3-Bromophenyl)cvclopentanecarbaldehvde

To a solution of 1 -(3-bromophenyl)cyclopentanecarbonitrile (10 g, 40 mmol) in DCM (250 ml) was addded dropwise at -78 °C 1 M DIBAL-H in DCM (60 ml, 60 mmol) and stirring was continued at -78 °C for 2 h. The mixture was quenched by the drop wise addition of 25% HCI (1 16 ml) at -78 °C and stirring was continued at overnight while warming to rt. The organic layer was separated and the aqueous layer was extracted with DCM (2x100 ml). The combined organic layers were dried and evaporated to give the title compound (9.9 g, 98%) as light yellow oil. The product was used as such in the next step.

MS (El, m/z): 252.0 [M+]

c) 2-Γ 1 -(3-Bromophenyl)cvclopentvnacetonitrile

To a turbid solution of potassium terf-butoxide (17.6 g, 156 mmol) in THF (250 ml) was added dropwise -78 °C a solution of TOSMIC (15.3 g, 78.2 mmol) in THF (83 ml) and the resulting mixture was stirred at -78 °C for 20 min. A solution of 1 -(3- bromophenyl)cyclopentanecarbaldehyde (9.9 g, 39.1 mmol) in THF (56 ml) was added dropwise at -78 °C and stirring was continued for 1.5 h at that temperature. MeOH (83 ml) was added drop wise and the reaction was allowed to warm to room temperature and then heated to reflux for 2h. The mixture was cooled to room temperature and poured onto ice water (400 ml) and extracted with EtOAc (3 x 250 ml). The combined organic phases were dried and evaporated. The residue was purified by silica flash chromatography eluting with 10% - 20% EtOAc in heptane to afford the title compound (5.2 g, 50%) as light yellow oil.

MS (El, m/z): 263.0 [M+]

d) ethyl 3-f1-(Cvanometriv0cvclopentvHbenzoate

A solution of 2-[1 -(3-bromophenyl)cyclopentyl]acetonitrile (2.0 g, 7.57 mmol) in DMF (20 ml_) in a sealed tube was degassed by argon followed by the addition of Mo(CO) ₆ (999 mg, 3.79 mmol) and DBU (1.729 g, 1 1.36 mmol). Pd(OAc) ₂ (170 mg, 0.78 mmol), dibutyl-1 - adamantylphosphine (543 mg, 1.51 mmol) and ethanol (349 mg, 7.57 mmol) were added successively. The reaction mixture was sealed and heated at 125 °C for 17 h. The reaction mass was quenched with Ice water (120 mL) and extracted with EtOAc (2 x 100 ml_). The combined organic phases were washed with water (100 mL), brine (50 mL), dried and concentrated in vacuo. The crude mass was purified by combiflash using 5-10% EtOAc in hexane to get the title compound (1.62 g, 83%) as a brown sticky liquid. e) 3-[1 -(Cvanomethyl)cvclopentyl1benzoic acid

To a solution of ethyl 3-[1 -(cyanomethyl)cyclopentyl]benzoate (1.6 g, 6.22 mmol) in ethanol (56 mL) was added 1 N NaOH (18.7 mL). The mixture was heated at 80 °C for 1 h. Ethanol was removed in vacuo and the aqueous part layer was acidified with 1 N HCI to pH~1. The solid was separated by filtration, washed with water and dried to get the title compound (1.2 g, 84%) as a white solid.

MS (ESI, m/z): 228.1 [(M-H)-j.

f) 2-f 1 -i3-(Hvdroxvmethvl)phenvllcvclopentyllacetonitrile

A solution of 3-[1 -(cyanomethyl)cyclopentyl]benzoic acid (1 .15 g. 5.02 mmol) in THF (30 mL) was cooled to 0°C under argon and 1 M BH ₃ -THF in THF (25.1 mL, 25.1 mmol) was added slowly. After the addition was complete the reaction mixture was allowed to stir at RT for 3 h. The reaction mass was quenched with sat. NH ₄ CI solution and THF was removed in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (30 mL), dried and concentrated in vacuo to get the title compound (1.05 g, 97%) as a colorless sticky liquid which was used as such in the next step. MS (EI, m/z): 215 [M+].

g) 2-[1-(3-Formylphenyl)cyclopentyllacetonitrile

To a solution of 2-[1-[3-(hydroxymethyl)phenyl]cyclopentyl]acetonitrile (1000 mg, 4.65 mmol) in chloroform (50 mL) was added Mn0 ₂ (2.019 g, 23.22 mmol) and stirred at room temperature for 17 h. TLC analysis (20% EtOAc in hexane) indicated product formation along with unreacted starting material. The reaction mass was filtered through celite and concentrated in vacuo. The crude residue was purified by combifiash using 5-15% EtOAc in hexane to get the title compound (235 mg, 24%) as a light yellow sticky mass.

h) 2-[1-f3-(Difluoromethvl)phenvncvclopentyllacetonitrile

To a solution of 2-[1 -(3-formylphenyl)cyclopentyl]acetonitrile (230 mg, 1 .16 mmol) in DCM (10 mL) was slowly added diethylaminosulfur trifluoride (0.57 mL, 5.78 mmol) at 0°C and the resulting solution was stirred at room temperature for 18h. The reaction mass was diluted with DCM (50 mL), washed with water (2 x 30 mL), dried and concentrated in vacuo. The residue was purified by combifiash using 5-10% ethyl acetate in hexane to afford the title compound (250 mg, 92%) as a light yellow liquid. MS (El, m/z): 235 [M+],

i) (3S)-6-rri-r3-(Difluoromethyl)phe^

dihydropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1-[3- (difluoromethyl)phenyl]cyclopentyl]acetonitrile instead of 2-(1-phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 418.3 [(M+H)+].

Example 27

(3S)-9-Hvdroxy-6-iri-i3-(1-hvdroxyethyl)phenvncvclopentyllme thyll-2,3-dimethyl-3,4- dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

O H a) 2-H -O-AcetylphenvDcyclopentyllacetonitrile

A solution of 2-[1-(3-bromophenyl)cyclopentyl]acetonitrile (see Example 26) (2.0 g, 7.6 mmol) in toluene (20 mL) was de-gassed for 5 min. To this solution, tributyl(1- ethoxyethenyl)stannane (2.6 mL, 7.6 mmol) was added and de-gassing continued for another two minutes. Pd(PPh ₃ ) ₄ (875 mg, 0.76 mmol) was added and the mixture was refluxed for 4 h. The reaction mixture was filtered through a pad of Ceiite and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (150 mL) and washed with water (2 x 30 mL), dried and concentrated under reduced pressure. The residue was purified by combif!ash using 10% to 20% EtOAc in hexane to get the title compound (1.15 g, 69%) as a gummy liquid. b) 2-f1 -f3-(1 -Hvdroxyethyl)phenvncvclopentyllacetonitrile

A solution 2-[1-(3-acetylphenyl)cyclopentyl]acetonitrile in a mixture of DCM (60.0 mL), methanol (32.0) and water (3.2 mL) was cooled to 0°C followed by the addition of NaBH ₄ (316 mg, 8.4 mmol) in portions. The reaction mixture was allowed to stir for 20 minutes at the same temperature. The reaction was quenched with aq. NH CI and extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (30 mL), dried and concentrated in vacuo to afford the title compound (950 mg, 99%) as colorless liquid used as such in the next step. MS (ESI, m/z): 247.1 [(M+H+NH3)+].

c) 2-H -f3-( 1 -Fluoroethvnphenvncvclopentvnacetonitrile

To a solution of 2-[1 -[3-(1 -hydroxyethyl)phenyl]cyclopentyl]acetonitrile (940 mg, 4.1 mmol) in DCM (25 mL) was added DAST (0.5 mL, 4.9 mmol) at 0°C and the solution was stirred at room temperature for 18 h. The reaction was quenched with sat. NaHCOs and extracted with DCM (2 x 25 mL). The combined organic phases were dried, filtered and concentrated in vacuo. The residue was purified by combiflash using 5-10% ethyl acetate in hexane to afford the title compound (710 mg, 75%) as a colorless liquid.

MS (ESI, m/z): 249.2 [(M+H+NH ₃ )+].

d) Methyl 2-H -[3-( 1 -chloroethyDphenyllcyclopentyllethanimidate hydrochloride -CI

2-[1-[3-(1-Fluoroethyl)phenyl]cyclopentyl]acetonitrile (325 mg, 1.4 mmol) was dissolved in dry methanol (5 ml) and stirred under a stream of dry HCI gas at 0 °C for 45 min. The flask was tightly stoppered with a greased glass stopper and a metal clip. The flask was left at 4 °C for 3 days. The crude reaction mixture was concentrated in vacuo at room temperature and dried under high vacuum to afford the title compound (quantitative yield), which was used as such in the next step. MS (ESI, m/z): 280.1 [( +H)+].

e) (3SV9-Hvdroxy-6-rn 3-( 1 -hvdroxyethvnphenyllcvclopentyllmethvn-2,3-dimethyl-3,4- dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using methyl 2-[1 -[3-(1 - chloroethyl)phenyl]cyclopentyl]ethanimidate hydrochloride instead of methyl 2-(1- phenylcyclopentyl)ethanimidate hydrochloride and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 412.2 [(M+H)+].

Example 28

(3S)-6-rri-(3-Ethv[-4-fluoro-phenyl)cvclopentyl1methyl1-9-hv droxy-2,3-dimethyl-^

dihvdropyrazinofl ,2-c]pyrimidine-1 ,8-dione

a) 4-Bromo-2-ethyl-1 -fluoro-benzene

4-Bromo-2-ethenyl-1 -fluorobenzene (2.0 g, 9.2 mmol) (prepared according to Buettelmann, B. et al., PCT patent application WO 2003097637) was dissolved in EtOAc (4 ml_) and AcOH (0.2 mL). The reaction mixture was degassed with nitrogen and 10% Pd/C (200 mg) was added and the mixture was further degassed for 2 minutes. The reaction mixture was evacuated and back filled with hydrogen gas and the reaction mixture was stirred under an atmosphere of hydrogen for 1 h. Reaction mixture was filtered through Celite. The filtrate was diluted with EtOAc (30 mL) and washed with sat. NaHC0 ₃ solution (2 x 20 mL). The organic layer was dried and concentrated under reduced pressure at 25 °C. The obtained residue was purified by silica gel chromatography (100-200 mesh) using hexane to afford the title compound (1.2 g, 64%) as a colorless oil. b) (3S)-6-rf H3-Ethyl-4-fluoro-phen^)wcloDentyl1methvn-9-hvdroxy-2.3 limethyl-3

dihydropyrazinoM ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3-ethyl-4- fluorophenyi)magnesium bromide (prepared in analogy to 3-trifluoromethy!-5- methylpenyl)magnesium bromide, see Example 14, by starting from 4-bromo-2-ethyl-1 -f!uoro- benzene) instead of phenylmagnesium bromide in step a) and (6S)-1 ,6-dimethylpiperazin-2- one (see Example 13) instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 414.3 l(M+H)+].

Example 29

(3S)-6-r[1-(3-Ethvl-2-fluoro-phenvl)cvclopentvllmethvll-9-hy droxv-2.3-dimethvl-3.4- dihvdropyrazinofl ,2-clpyrimidine-l ,8-dione

a) 1 -Bromo-2-fluoro-3-vinyl-benzene

To an ice-cold stirred solution of PPh ₃ Mel (9.956 g, 24.63 mmol) in THF (70 mL), potassium-t- butoxide (2.76 g, 24.63 mmol) was added portion wise and the reaction mixture was stirred at that temperature for 30 minutes. A solution of 3-bromo-2-fluorobenzaldehyde (2.0 g, 9.85 mmol) in THF (5 mL) was added drop wise at 0°C. The reaction mixture was stirred for 10 minutes at room temperature. Cone. H.CI (1.2 mL) was added to the reaction mixture at 0°C and the mixture was evaporated at 25 °C under reduced pressure. Water was added to the residue and extracted with DCM (2 x 25 mL). The combined organic phases were washed with brine (30 mL), dried and evaporated to dryness. The residue was purified by silica gel column chromatography (100-200 mesh) eluting with hexane to afford the title compound (1 .2 g, 61 %) as light green liquid.

b) 1 -Bromo-3-ethyl-2-fluoro-benzene

The title compound was prepared in analogy to 4-bromo-2-ethyl-1-fluoro-benzene (see Example 28, step a) starting from 1 -bromo-2-fluoro-3-vinyl-benzene.

c) 1 -(3-Ethvl-2-fluoro-phenvl)cyclopentanecarbonitrile

In a sealed tube an argon purged stirred solution of 1 -bromo-3-ethyl-2-fluoro-benzene (1 g, 4.93 mmol) in mesitylene ( ml_) was prepared. Potassium 1 -cyanocyclopentane-1 - carboxylate (1.308 g, 7.39 mmol) (prepared according to: Rui Shang et al.; Angew. Chem. Int. Ed. 2011 , 50, 4470 - 4474,) Pd ₂ (allyl) ₂ CI ₂ (72 mg, 0.20 mmol) and Xantphos (285 mg, 0.49 mmol) were added and argon gas was purged for 15 minutes. This reaction mixture was stirred in a pre-heated plate at 140 °C for 15h. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh) eluting with 6% EtOAc in hexane to afford the title compound (370 mg, 35%).

MS (EI, m/z): 217 [M+].

d) 1-(3-Ethvl-2-fluoro-phenvl)cvclopentanecarbaldehyde

To a stirred solution of 1 -(3-ethyl-2-fluoro-phenyl)cyclopentanecarbonitrile (1.0 g, 4.6 mmol) in DCM (25 mL) at -78 °C, 25% DIBAL-H in toluene (6.6 mL, 11.5 mmol) was added drop wise and the reaction mixture was stirred at that temperature for 2 h. To this a saturated solution of sodium potassium tartarate was added and the mixture was stirred for 15h at room temperature. The reaction mixture was extracted with DCM (2 x 50 mL) and the combined organic phases were washed with brine (30 mL) and evaporated to dryness. The residue was purified by silica gel column chromatography (100-200 mesh) eluting with 5% EtOAc in hexane to afford the title compound (510 mg, 50%) as a brownish liquid.

e) [1 -(3-Ethyl-2-fluoro-phenyl)cyclopentyllmethanol

To an ice-cold stirred solution of 1-(3-ethyl-2-fluoro-phenyl)cyclopentanecarbaldehyde

(150 mg, 0.68 mmol) in methanol (10 mL), sodium borohyd ide (52 mg, 1.4 mmol) was added and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and water (20 mL) was added to the residue and extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with brine (20 mL), dried and evaporated to afford the title compound (140 mg, 92%) which was used as such in the next step

MS (El, m/z): 222 [M+].

f) Γ1 -(3-Ethyl-2-fluoro-phenyl)cvclopentvnmethyl methanesulfonate

To a stirred solution [1-(3-ethyl-2-fluoro-phenyl)cyclopentyl]methanol (1.0 g, 4.5 mmol) in DCM (30 mL) at 0 °C, triethylamine (1.6 mL, 1 1.3 mmol) was added followed by drop wise addition of mesyl chloride (0.4 mL, 5.4 mmol) and the mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture and extracted with DCM (2 x 30 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried and evaporated to under reduced pressure. The residue was purified by normal silica gel (100-200 mesh) column chromatography eluting with 8% EtOAc in hexane to afford the title compound (1 .0 g, 74 %) as colorless liquid. g) 2-f1-(3-Ethyl-2-fluoro-phenyl)cyclopentvnacetonitrile

To a stirred solution of compound [1-(3-ethyl-2-fluoro-phenyl)cyclopentyl]methyl methanesulfonate (1.0 g, 3.3 mmol) in DMSO (15 mL) potassium cyanide (480 mg, 7.3 mmol) and potassium iodide (40 mg, 0.3 mmol) was added and the mixture was heated at 140 °C for 2 h. Saturated ferrous sulphate solution (50 mL) was added and the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulphate and evaporated. The residue was purified by silica gel (100-200 mesh) column chromatography eluting with 3.5% EtOAc in hexane to afford the title compound (290 mg, 38%) as a colorless liquid.

MS (El, m/z): 231 [M+].

h) (3S)-6-ff1 -(3-Ethvl-2-fluoro-phenvl)cvclopentvllmethvll-9-hvdroxv-2.3- dimethyl-3,4- dihvdropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1 -(3-ethyl-2-fluoro- phenyl)cyclopentyl]acetonitrile instead of 2-( 1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 414.3 [(M+H)+].

Example 30

(3S)-6-ri1-(5-Ethyl-2-fluoro-phenyl)cvclopentyl1methyl1-9-hv droxy-2,3-dimethyl-3,^

dihydropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 29 by using 3-bromo-4- fluorobenzaldehyde instead of 3-bromo-2-fluorobenzaldehyde in step a) to afford the title compound as a white powder. MS (ESI, m/z): 414.3 [(M+H)+].

Example 31

(3S)-6-[[1 -(3-Ethvl-5-fluoro-phenvl)cyclopentvnmethvn-9-hydroxy-2,3-di methyl-3,4- dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 29 by using 3-bromo-5- fluorobenzaldehyde instead of 3-bromo-2-fluorobenzaldehyde in step a) to afford the title compound as a white powder. MS (ESI, m/z): 414.3 [(M+H)+].

Example 32

(3S)-6-rri -(3-Ethyl-2-fluoro-phenyl)cvclopentyllmethvn-9-hvdroxy-2,3-d imethyl-3.4- dihydropyrazinoM ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 29 by using 1 -bromo-2-fluoro-3,5- dimethyl-benzene instead of 1 -bromo-3-ethyl-2-fluoro-benzene in step a) to afford the title compound as a white powder.

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

Example 33

(3SV9-Hvdroxy-2,3-dimethyl-6-rri-(3,4,5-trimethylphenyl)cvcl opentyl1methv^

dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

a) (3,4,5-Trimethylphenyl) trifluoromethanesulfonate

To a solution of 3,4,5-trimethylphenol (2.0 g, 14.68 mmol) and triethylamine (5.1 mL, 36.7 mmol) in DCM (80 mL) at -15°C was added trifflic anhydride (2.9 ml, 17.6 mmol) drop wise. After the addition was complete the reaction was stirred at room temperature for 15 h. The reaction was cooled to -15°C, quenched with sat. NH ₄ CI solution and diluted with DCM (100 mL). The organic layer was separated, washed with water (100 mL), dried and concentrated in vacuo. The residue was purified by combiflash using hexane to 5% EtOAc in hexane to get the title compound (3.02 g, 77%) as a colorless liquid.

b) (3S)-9-Hvdroxv-2,3-dimethvl-6-fn-(3.4.5-trimethvlphenvl)cvcl opentvllmethyl1-3.4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 29 by using (3,4,5-trimethylphenyl) trifluoromethanesulfonate instead of 1-bromo-3-ethyl-2-fluoro-benzene in step c) to afford the title compound as a white povvd MS (ESI, m/z): 410.4 [(M+H)+].

Example 34

(3S)-6-rri-(3-Bromo-5-methyl-phenyl)cvclopentvnmethvn-9-hvdr oxy-2,3-dimethyl-3,4- dihydropyrazinofl ,2-c1pyrimidine-1 ,8-dione

a) 2-f 1 -(3-Bromo-5-methvi-phenvDcvciopentyllacetonitrile

The title compound was prepared in analogy to 2-[1 -(3-bromophenyl)cyclopentyl]acetonitrile (see Example 26) by using 2-(3-bromo-5-methyl-phenyl)acetonitrile (prepared according to Guo Hongyan et al. PCT patent application WO 2009/005674 instead of 2-(3- bromophenyl)acetonitrile in step a).

b) (3SV6-rri -(3-Bromo-5-methyl-phenyl)cvclopentyllmethyll-9-hvdroxy-2,3- dimethyl-3,4- dihydropyrazinoH ,2-clpy midine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1-(3-bromo-5-methyl- phenyl)cyclopentyl]acetonitrile instead of 2-(1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 460.1 [(M+H)+].

Example 35

(3S)-9-Hvdroxy-2,3-dimethyl-6-if1 -(3-methyl-5-vinyl-phenyl)cvclopentvnmethvn-3,4- dihydropyrazinoH ,2-c1pyrimidine-1 ,8-dione

In a 5 mL sealed tube, (3S)-6-[[1-(3-bromo-5-methyl-phenyl)cyclopentyl]methyl]-9-hy droxy-2,3- dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (50 mg, 109 pmol), 4,4,5,5- tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (25.1 mg, 163 pmol), 2N sodium carbonate (163 μΙ, 326 pmol,) and 1 ,1 '-bis(diphenylphosphino)ferrocenedichloro palladium(ll) dichloromethane complex (5 mg, 6.83 pmol) were combined with dioxane (600 pi) and water (400 pi) to give a light yellow suspension. The reaction mixture was stirred at 120°C. After completion of the reaction as judged by LC/MS analysis the reaction mixture was concentrated in vacuo and diluted in DMSO. The solution was filtered using a syringe filter and submitted to reversed phase preparative HPLC purification to afford the title compound (19 mg, 42%) as a red solid.

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

Example 36

(3SV6-rri-(3-Ethyl-5-methyl-phenyl)cvclopentyllmethvn-9-hvdr oxy-2.3-dimethyl-3,4- dihydropyrazinofl ,2-clpyrimidine-1.8-dione

In a 5 mL round-bottomed flask, (3S)-9-hydroxy-2,3-dimethyl-6-[[1 -(3-methyl-5-vinyl- phenyl)cyclopentyl]methyl]-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 , 8-dione (15 mg, 36.8 pmol) was combined with methanol (1 ml) to give a colorless solution. The flask was degassed and purged with argon. 10% Pd/C (1 ,0 mg, 10 pmol) was added. The flask was degassed and purged with argon and placed under a balloon atmosphere of hydrogen. The reaction mixture was stirred for 3 days. Further 10% Pd/C (10 mg, 100 pmol) and 1 ml Methanol was added and the reaction mixture was stirred under an atmosphere of hydrogen for 1 h. LC/MS showed that the reaction was complete. The reaction mixture was filtered, reduced in vacuo and purified by reversed phase HPLC to afford the title compound (1.7 mg, 1 1 %) as a grey product. MS (ESI, m/z): 408.3 [(M+H)+].

Example 37

(3S)-9-Hydroxy-2.3-dimethyl-6-fM-(3-m^

dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was optained in analogy to Example 35 by using phenylboronic acid instead of 4 _l 4,5 _I 5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane to give the title compound as brown solid. MS (ESI, m/z): 458.3 [(M+H)+j.

Example 38

3-ri-[[(3S)-9-Hvdroxv-2,3-dimethyl-1.8-dioxo-3.4-dihvdropyra zino[1 ,2-clpvrimidin-6- vnmethvllcvclopentvll-5-methvl-benzonitrile

In a sealed vial (3S)-6-[[1-(3-bromo-5-methyl-phenyl)cyclopentyl]methyl]-9-hy droxy-2,3- dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (20 mg, 43 pmol) and copper (I) cyanide (8 mg, 89 μιηοΙ) were combined with NMP (1 ml) to give a yellow solution. The reaction mixture was stirred at 190 °C for 7 h, then overnight at 120 °C, and then 6 h at 190 °C. A further 8 mg copper (I) cyanide was added and the reaction mixture was stirred at 190 °C for 3 h. The mixture was purified by reversed phase preparative HPLC to afford the title compound (2 mg, 1 1 %) as a light brown solid. MS (ESI, m/z): 407.2 [(M+H)+j.

Example 39

(3S)-6-if1 -(3-Cyclopropyi-5-methyl-ph

dihvdropyrazinofl .2-c]pvrimidine-1 ,8-dione

The title compound was obtained in analogy to Example 35 by using 4.5 equivalents cyclopropyl boronic acid instead of 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaboro!ane to give the title compound as a light brown solid.

MS (ESI, m/z): 422.2 [(M+H)+j. Example 40

vnrnethyllcvclopentyll-5-methyl-phenyllacetonitrile

To a solution of (3S)-6-[[1-(3-bromo-5-methyl-phenyl)cyclopentyl]methyl]-9-hy droxy-2,3- dimethyl-3,4-diriydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (25 mg, 54 pmol) In DMSO (500 μ!) were added 4-isoxazoleboronic acid pinacol ester (13 mg, 65 pmol) and 1 M potassium fluoride (163 μΙ, 163 μιηοΙ) at room temperature and argon was bubbled through the solution for 10 min. Then 1 ,1'-bis(diphenylphosphino)ferrocenedichloro palladium(ll) dichloromethane complex (4 mg, 5 μιηοΙ) was added and the mixture was heated in a sealed tube to 130 °C for 16h.The mixture was cooled to room temperature, acetic acid (23 μΙ, 407 pmol) was added and the mixture was filtered through a membrane filter (Sartorius) and washed with DCM (5 ml). The volatiles were removed in vacuo and the resulting solution was purified by reversed phase preparative HPLC to give the title compound (13 mg, 57 %) as a light yellow solid.

MS (ESI, m/z): 421 .1 [(M+H)+],

Example 41

1-rf1-(3-Bromo-5-methyl-phenyl)cvclopentyl1methyll-4-hvdroxy -8,9,9a 0-tetrah

Pyrrolor3,4lPVrazino[3,5-blpyrimidine-3,5-dione

The title compound was prepared in analogy to Example 34 by using hexahydropyrrolo[1 ,2- a]pyrazin-4(1 H)-one instead of octahydro-4h-pyrido[1 ,2-a]pyrazin-4-one in step b) to give the title compound as a white powder.

MS (ESI, m/z): 474.1 [(M+H)+].

Example 42

1-rri-(3-Ethyl-5-methyl-phenyl)cyclopentyllmethyl]-4-hvdr oxy-8,9,9a,10-tetrahydro-7H- pyrrolo[3,4lPyrazinor3,5-blpyrimidine-3,5-dione

The title compound was prepared in analogy to Example 36 starting from 1-[[1 -(3-bromo-5- methyl-phenyl)cyclopentyl]methyl]-4-hydroxy-8,9,9a,10-tetrah ydro-7H- pyrrolo[3,4]pyrazino[3,5-b]pyrimidine-3,5-dione to give the title compound as light brown solid.

MS (ESI, m/z): 422.3 [(M+H)+]. Example 43 a) 1 -Bromo-3-(methoxyiTiethyl)-5-methyl-benzene

(3-Bromo-5-methy!phenyl)methanol (1.4 g, 7.0 mmo!) was dissolved In DMF (13 ml) and 60% NaH in mineral oil (334 mg, 14 mmol) was added slowly over 15 min (gas formation), followed by the addition of Mel (871 μΙ, 14 mmol). The reaction mixture was stirred for 2 h, excess NaH was carefully quenched with 1 N HCI, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water (2 x), and the combined organic layers were dried over Na ₂ S0 ₄ and evaporated. The residue was purified by silica gel column chromatography eluting with 0-80% EtOAc in heptane to afford the title compound (1 .4 g, 6.4 mmol) as a colorless oil.

b) 2-[1 -[3-(Methoxvmethvl)-5-methvl-phenyllcvclopentvllacetonitrile

The title compound was prepared in analogy to 2-(1 -phenylcyclopentyl)acetonitrile (see Example 1 , steps a-b) by using [3-(methoxymethyl)-5-methyl-phenyl]magnesium bromide (prepared in analogy to 3-trifluoromethyl-5-methylpenyl)magnesium bromide, see Example 14, by starting from 1-bromo-3-(methoxymethyl)-5-methyl-benzene) instead of phenylmagnesium bromide in step a) to give the title compound as a colorless oil. c) Methyl 2-ri-[3-(chloromethyl)-5-methyl-phenvncvclopentyllethanimida te hydrochloride

H-Cl

2-[1 -[3-(Methoxymethyl)-5-methyl-phenyl]cycloperityl]acetonitril e (473 mg, 1.9 mmol) was dissolved in anhydrous MeOH (7.8 ml) and stirred at -5 °C under a stream of dry HCI gas at for 35 min. The flask was removed from the apparatus, tightly stoppered with a greased glass stopper and a metal clip and stored at 4 °C for 5 days. The solvent was evaporated at room temperature to afford the title compound as a sticky white solid which was used as such in the next step.

MS (ESI, m/z): 280.2 [(M+H)+].

d) (3S)-6-ff1-r3-(Chloromethyl)-5-methyl-phenvncvclopentynmethv n-9-hvdroxy-2,3-dimethyl-

3,4-dihydropvrazinoH ,2-clpvrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using methyl 2-[1 -[3- (chloromethyl)-5-methyl-phenyl]cyclopentyl]ethanimidate hydrochloride instead of methyl 2-(1- phenylcyclopentyl)ethanimidate hydrochloride and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white solid. MS (ESI, m/z): 430.3 [(M+H)+].

Example 44

(3S)-9-Hvdroxy-6-rf1 -[3-(methoxymethyl)-5-methyl-phenyllcvclopentyl1methyll^

3,4-dihydropyrazino[1 ,2-c1pyrimidine-1 ,8-dione

A solution of (3S)-6-[[1-[3-(chloromethyl)-5-methyl-phenyl]cyclopentyl]met hyl]-9-hydroxy-2,3- dimethyl-S^-dihydropyrazinotl ^-^pyrimidine-l ,8-dione (31 mg, 72.1 prnol) in methanol (2 ml) was treated with 30% sodium methoxide in methanol (80 μΙ, 433 pmol) and stirred at room temperature for 3 days. The solvent was evaporated and the residue was treated with 1 N HCI and extracted with DCM (4x). The organic layers were evaporated and the residue purified by reversed phase preparative HPLC to give the title compound (7 mg, 21 %) as a white solid.

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

Example 45

(3S)-6-[f1 -r3-(Ethoxymethyl)-5-methyl-phenyl1cvclopentvnmethyll-9-hydr oxy-2,3-dimethyl-3,4- dihvdropyrazinof 1 ,2-clpvrimidine-1 ,8-dione

To a solution of (3S)-6-[[1 -[3-(chloromethyl)-5-methyl-phenyl]cyclopentyl]methyl]-9-hyd roxy- 2,3-dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (104 mg, 242 pmol) in ethanol (6 ml) was added sodium ethoxide (98.8 mg, 1.45 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was heated to 76 °C and refluxed for 6 h. The solvent was evaporated and the residue was taken up in 1 N HCI and extracted with DCM (4 x). The combined organic layers were evaporated and the residue was purified by reversed phase preparative HPLC to give the title compound (12 mg, 11 %) as a white solid. MS (ESI, m/z): 440,4 [(M+H)+].

Example 46

(3S)-9-Hvdroxv-2,3-dimethvl-6-[[1-[3-methvl-5-(pvrazoi-1-vlm ethyl)phenvllcvclopentvllmethvl1- 3,4-dihydropyrazino[1 ,2-clpyrimidine-1 ,8-dione

To a solution of 1 H-pyrazole (19 mg, 279 pmol) in THF (0.5 ml) was added NaOH pellets (90 mg, 2.25 mmol) and the mixture was stirred at room temperature for 3 h. Then a solution of (3S)-6-[[1-[3-(chloromethyl)-5-methyl-phenyl]cyclopentyl]met hyl]-9-hydroxy-2,3-dimethyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (100 mg, 233 μιηοΙ) in THF (1 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured onto an aqueous HCI solution (pH 4) and extracted with DCM (4x). The organic layers were dried over Na ₂ S0 ₄ and evaporated. The residue was purified by reversed phase preparative HPLC to give the title compound (16 mg, 15 %) as a white solid.

MS (ESI, m/z): 462.3 [(M+H)+). Example 47

(3S)-9-Hvdroxy-6-ri1 -f3-(hvdroxyme

dihydropyrazinon ,2-c1pyrimidine-1 ,8-dione

(3S)-6-[[1 -[3-(Chloromethyl)-5-methyl-phenyl]cyclopentyl]methyl]-9-hyd roxy-2,3-d

dihydropyrazinotl ^-cjpyrimidine-I .e-dlone (l OO mg, 233 μηΊθ!) in AcCN (0.5 m!) was transferred into a sealed vial loaded with water (3 ml), NaOH (9 mg, 233 pmoi) and tetrabutylammonium bromide (300 mg, 930 pmol). The mixture was heated to 1 10 °C for 5 min. The reaction was quenched with 1 N HCI, DCM was added and the mixture was extracted with DCM (4x). The combined organic phases were evaporated. The residue was purified by reversed phase preparative HPLC to give the title compound (13 mg, 14 %) as a white solid.

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

Example 48

(3S)-6-[ri-(3.5-Dibromophenyl)cvclopentyllmethvn-9-hvdrox y-2.3- ^■ idimethyl-3,4- dihydropyrazinof 1 ,2-c)pvrimidine-1 ,8-dione

a) 2-[1-(3,5-dibromophenyl)cvclopentyllacetonitrile

The title compund was prepared in analogy to 2-[1-(3-bromophenyl)cyclopentyl]acetonitrile (see Example 26, steps a-c) by using 2-(3,5-dibromophenyl)acetonitrile instead of 2-(3- bromopheny!)acetonitrile in step a) to give the title compound as a light yellow solid.

b) (3S)-6-rri-(3,5-Dibromophenvncvclopentvnmethvn-9-hvdroxy-2,3 -dimethyl-3,4- dihvdropyrazinoM ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1-(3,5- dibromophenyl)cyclopentyl]acetonitrile instead of 2-( 1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methy!piperazin- 2-one in step h) to give the title compound as a white solid.

MS (ESI, m/z): 526.0 [(M+H)+]. Example 49

(3S)-6-[f1-(3-Bromo-5-cyclopropyl-phenyl)cvclo^

dihvdropyrazinof ,2-clpyrimidine-1 ,8-dione

In a sealed vial (3S)-6-[[1 -(3,5-dibromophenyl)cyclopentyl]methyl]-9-hydroxy-2,3-dimeth yl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (100 mg, 190 μιηοΙ), cyclopropylboronic acid (16 mg, 190 pmol) and 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (8 mg, 9 μιηοΙ) were combined with dioxane (563 μΙ), water (408 μΙ) and 2N sodium carbonate (286 μΙ, 571 μmol). The reaction mixture was heated to 80° overnight. 1 ,1 '-bis(diphenyiposphino)ferrocene-palladium(ll)dichloride dichloromethane complex (8 mg, 9 pmol) and cyclopropylboronic acid (16 mg, 190 pmol) was added and the reaction mixture was heated to 90 °C overnight. 1 N HCI was added and the reaction mixture was extracted with DCM (3 x). The combined organic layers were dried over Na ₂ S0 ₄ , evaporated and the residue was purified by reversed phase preparative HPLC to give the title compound (2 mg, 2 %) as an off-white solid.

MS (ESI, m/z): 488.2 [(M+H)+]

Example 50 & Example 51

Example 50:

3-Bromo-5-[1 -f[(3S)-9-hvdroxy-2,3-dimethyl-1 ,8-dioxo-3,4-dihydropyrazinof1 ,2-clpyrimidin-e- vHmethyncyclopentynbenzonitrile

and Example 51 :

yllmethyllcyclopentyllbenzene-1 ,3-dicarbonitrile

In a sealed tube, to (3S)-6-[[1 -(3,5-dibromophenyl)cyclopentyl]methyl]-9-hydroxy-2,3-dimeth yl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (200 mg, 381 pmol) in NMP (2.6 ml) was added copper (I) cyanide (34 mg, 381 pmol). The reaction mixture was heated to 190 °C and stirred for 4h. The reaction mixture was taken up in H ₂ 0 and the mixture was extracted with DCM (4 x). The combined organic phases were dried over Na ₂ S0 ₄ and evaporated. The residue was purified by reversed phase preparative HPLC to give the two title compounds (Example 50: 1 1 mg, 6 % and Example 51 : 9 mg, 6 %) as brown solids.

MS (ESI, m/z): 473.1 [(M+H)+] (Example 51 ). MS (ESI, m/z): 418.2 [(M+H)+] (Example 50).

Example 52

(3S)-6-rri-(3.5-Dichlorophenyl)cvcloDentyllmethyll-9-hvdr oxy-2.3-dimethyl-3.4- dihvdropyrazinon ,2-c1pyrimidine- ,8-dione

In a sealed tube, (3S)-6-[[1-(3,5-dibromophenyl)cyclopentyl]methyl]-9-hydroxy- 2,3-dimethyl- 3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (200 mg, 381 Mmol) and nickel(ll) chloride (247 mg, 2 mmol) were combined in DMF (16,5 ml). The reaction mixture was heated to 170°C overnight. The reaction mixture was filtered through glass fiber paper, washed with DCM and water and the filtrate was coevaporated with toluene. The residue was purified by reversed phase preparative HPLC to give the title compound (24 mg, 14 %) as an off-white solid.

MS (ESI, m/z): 436.2 [(M+H)+]

Example 53

(3S)-6-rf1-(3-Bromophenvl)cvclopentvl1methvll-9-hvdroxv-2.3- dimethyl-3.4- dihydropyrazinoH ,2-clpvrimidine-1 ,8-dione

a) Methyl 2-ri-(3-bromophenyl)cvclopentvnethariimidate hydrochloride - Cl

The title compound was prepared in analogy to methyl 2-(1-phenylcyclopentyl)ethanimidate hydrochloride (see Example 1 , step c) starting from 2-[1-(3- bromophenyl)cyclopentyl]acetonitrile (see Example 26, steps a-c) instead of 2-(1 - phenylcyclopentyi)acetonitrile to afford the title compound as a light brown solid.

MS (ESI, m/z): 296.1 [(M+H)+]

b) (6S)-4-[2-f 1 -(3-Bromophenyl)cyclopentvnethanimidoyll-1 ,6-dimethyl-piperazin-2-one hydrochloride

To a solution of methyl 2-[1 -(3-bromophenyl)cyclopentyl]ethanimidate hydrochloride (1.2 g, 3.6 mmol) in THF (70 ml) were added at room temperature DIPE (1.9 ml, 10.8 mmol) and (S)- 1 ,6-dimethylpiperazin-2-one (555 mg, 4.33 mmol, Eq: 1.2) (see Example 13) and stirred for 15 min. Acetic acid (207 μΙ, 3.6 mmol) was added and stirring was continued for 48 h. The suspension was diluted with Et ₂ 0 (50 ml), stirred at room temperature for 15 min and filtered. The filter cake was washed three times with Et ₂ 0 (3 x 50 ml) and dried under high vacuum to give the title compound (1.20 g, 78%) as white solid MS (ESI, m/z): 392.1 [(M+H)+]

c) (3S)-6-rri-(3-Bromophenyl)cvclopentvnmethyll-9-hvdroxy-2,3-d imethyl-3.4- dihvdropyrazirioH ,2-c1pyrimidine-1 ,8-dione

A suspension of (6S)-4-[2-[1 -(3-bromophenyl)cyclopentyl]ethanimidoyl]-1 ,6-dimethyl- piperazin-2-one hydrochloride (1.3 g, 3.0 mmol) in THF (60 ml) was cooled to -30 °C and 1 M LHMDS in THF (12.1 ml, 12.1 mmol) was added drop wise (over 5 minutes) and stirred at -30 °C for 15 minutes. Diethyl oxalate (823 μΙ, 6.1 mmol) was added slowly and stirring was continued at -30 °C for 15 min. The resulting solution was allowed to warm to room temperature and the mixture was stirred for total 1.5 h. The mixture was slowly quenched with acetic acid (17 ml) at 0 °C, stirred for 15 min. The solvent was removed under reduced pressure and high vacuum and the residue was partioned between DCM (200 ml) and H ₂ 0 (200 ml). The aqueous layer was extracted once with DCM (200 ml). The combined organic layers were dried with Na ₂ S0 ₄ , filtered and evaporated to give a foam. Purification by crystallization from Et ₂ 0 (50 ml) afforded the title compound (1.0 g, 74%) as a light yellow solid.

MS (ESI, m/z): 446.1 [(M+H)+] Example 54

(3S)-9-Hvdroxy-2,3-dimethyl-6-r[1-r3-(3-thienyl)phenyllcvclo pentyllmethvn-3,4- dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 37 starting from (3S)-6-[[1-(3- bromopheny!)cyclopentyl]methyl]-9-hydroxy-2,3-dimethy!-3,4-d ihydropyrazino[1 ,2- c]pyrimidine-1 ,8-dione by using thiophene-3-boronic acid pinacol ester instead of phenylboronic acid to afford to title compound as a white solid.

MS (ESI, m/z): 450.2 [(M+H)+]

Example 55

2-Γ3-Π -[f(3S)-9-Hvdroxy-2,3-dimethyl-1 ,8-dioxo-3,4-dihydropyrazinof 1 ,2-c1pyrimidin-6- yllmethyncyclopentyllphenyllacetonitrile

To a suspension of (3S)-6-[[1-(3-bromophenyl)cyclopentyl]methyl]-9-hydroxy-2,3- dimethyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (50 mg, 1 12 pmol) in dioxane (0.36 ml) and water (0.26 ml) were added 2M Na ₂ C0 ₃ (168 μΙ, 336 pmol) and 4-isoxazoleboronic acid pinacol ester (33 mg, 168 μιηοΙ) at room temperature and argon was bubbled through the solution for 10 min. 1 ,1'-Bis(diphenylphosphino)ferrocenedichloro palladium(ll) dichloromethane complex (9 mg, 1 1 rnol) was added and the mixture was heated in a sealed tube to 80 °C for 4h. The mixture was cooled to room temperature, acetic acid (48 μΙ, 840 μιηοΙ) was added and filtered through a membrane filter (Sartorius) and washed with DCM (10 ml). The filtrate was concentrated in vacuo and the residue was purified by reversed phase preparative HPLC to give the title compound (10 mg, 22 %) as a light brown solid.

MS (ESI, m/z): 407.2 [(M+H)+]

Example 56

(3S)-6-ff1 -f3-(3-Furvl)phenvncvclopentvllmethvll-9-hvdroxv-2.3-dimethy l-3.4- dihydropyrazlnoi 1 ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 54 by using 3-furanboronic acid pinacol ester instead of thiophene-3-boronic acid pinacol ester to afford the title compound as off-white solid.

MS (ESI, m/z): 434.2 [(M+H)+] Example 57

(3S)-9-Hydroxy-2,3-dimethyl-6-rrW

dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The titie compound was prepared in analogy to Example 54 by using 1 -methyl-1 H-pyrazole-5- boronic acid pinacol ester instead of thiophene-3-boronic acid pinacol ester to afford the title compound as off-white solid.

MS (ESI, m/z): 448.2 [(M+H)+]

Example 58

(3S)-9-Hvdroxy-2,3-dimethyl-6-rn-r3-(1-methylpyrazol-3-yl )phenvncvclopentyllmethvn-3,4- dihydropyrazinoH ,2-c1pyhmidine-1 ,8-dione

The title compound was prepared in analogy to Example 54 by using 1 -methyl-1 H-pyrazole-3- boronic acid pinacol ester instead of thiophene-3-boronic acid pinacol ester to afford the title compound as an off-white solid. MS (ESI, m/z): 448.2 [(M+H)+]

Example 59

(3S)-6-rri-r3-r(E)-2-Ethoxyvinyl1phenvncvclopentvnmethyl1-9- hvdroxy-2,3-dimeth

dihydropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 54 by using trans-2- ethoxyvinylboronic acid pinacol ester instead of thiophene-3-boronic acid pinacol ester to afford the title compound as a light brown oil. MS (ESI, m/z): 438.2 [(M+H)+]

Example 60

(3S)-6-rri-r3-r(E)-2-Ethoxvvinvl1phenvllcvclopentvllmethvll- 9-hvdroxv-2.3-dimethvl-3.4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 54 by using 4-isoxazoleboronic acid pinacol ester instead of thiophene-3-boronic acid pinacol ester to afford the title compound as off-white solid. MS (ESI, m/z): 435.2 [(M+H)+]

Example 61

(3S)-6-rri-r3-(2-Ethoxyethyl)phenyl1cvclopentvnmethvn-9-hvdr oxy-2,3-dimethyl-3,4- dihydropvrazinoH ,2-c1pyrimidine-1 ,8-dione

To a solution of (3S)-6-[[1 -[3-[(E)-2-ethoxyvinyl]phenyl]cyclopentyl]methyl]-9-hydroxy- 2,3- dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (20 mg, 46 pmol) in MeOH (1 ml) was added 10 % Pd/C (2 mg, 46 pmol) and the mixture was stirred at room temperature under an atmosphere of hydrogen for 3 h. The catalyst was filtered off, washed with MeOH and the filtrate was concentrated in vacuo to give the title compound (15 mg, 75 %) as a light brown oil.

MS (ESI, m/z): 440.2 [M + H]+

Example 62

2-f3-ri-rr(3S)-9-Hvdroxy-2,3-dimethyl-1.8-dioxo-3.4-dihvdrop yrazinori .2-clpyrim

yllmethyllcvclopentyllphenvnacetamide

To a solution of 2-[3-[1-[[(3S)-9-hydroxy-2,3-dimethyl-1 ,8-dioxo-3,4-dihydropyrazino[1 ,2- c]pyrimldin-6-y!]methyl]cyclopentyl]phenyl]acetonitrile (30 mg, 74 pmol) in THF (0.5 ml) was added 37 % HCI (1.5 ml) and the mixture was stirred at room temperature for 16h. The mixture was concentrated in vacuo and the residue was crystallized from Et?0 ( 3 ml) to afford the title compound (22 mg, 70 %) as an off-white solid.

MS (ESI, m/z): 425.2 [M + H]+

Example 63

2-r3-f1-ff(3S)-9-Hvdroxy-2.3-dimethyl-1.8-dioxo-3,4-dihvdrop yrazinon .2-clpyrimidin-6- yllmethyncyclopentynphenvnacetic acid

A solution of 2-[3-[1-[[(3S)-9-hydroxy-2,3-dimethyl-1 ,8-dioxo-3,4-dihydropyrazino[1 ,2- c]pyrimidin-6-yl]methyl]cyclopentyl]phenyl]acetonitrile (30 mg, 73.8 pmol, Eq: 1) in 37 % HCI (1 .5 ml) was stirred at 90°C for 3h. The mixture was concentrated in vacuo and the residue crystallized from Et ₂ 0 (3 ml) to give the title compound (25 mg, 80 %) as an off-white solid.

MS (ESI, m/z): 426.2 [M + H]+

Example 64

(3S)-6-rri-(3,5-Diethylphenyl)cvclopentyl]methyll-9-hvdroxy- 2,3-dimethyl-3.4- dihvdropyrazinofl ,2-c1pyrimidine-1 ,8-dione

a) 2-f1-(3,5-Diethvlphenvl)cvclopentyllacetonitrile

To 2-[1 -(3,5-dibromophenyl)cyclopentyl]acetonitrile (200 mg, 583 pmol) (see Example 48, step a) in dry dioxane (2.7 ml) was added 1 ,1 '-bis(dipheny!phosphino)ferrocene dichloropalladium(ll) dichloromethane complex (33 mg, 41 pmol) and 1 M diethylzinc in hexane (624 μΙ, 624 pmol). The mixture was heated at 60°C for 90 min. The reaction mixture was cooled to room temperature and methanol (0.5 ml) and sat. NH ₄ CI (0.1 ml) were carefully added. The volatile solvents were evaporated in vacuo and the remaining mixture was extracted with DCM and water. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried with Na ₂ S0 and evaporated. The residue was purified on silica gel eluting with 0-20% EtOAc in heptane to afford the title compound (94 mg, 66 %) as a light yellow liquid. b) (3S)-6-rri-(3,5-Diethylphenyl)cvclopentyllmethyll-9-hvdroxy- 2,3-dimethyl-3,4- dihydropyrazinon ,2-clpyrimidine-1 ,8-dione

The titie compound was prepared in analogy to Example 1 by using 2-[1-(3,5- diethylphenyl)cyclopentyl]acetonitrile instead of 2-(1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin- 2-one in step h) to give the title compound as a white solid.

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

Example 65

(3S)-6-rri-(3-Bromo-5-ethyl-phenvncvclopentyl1methvn-9-hvdro xy-2,3→ dimethyl-3,4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

a) 2-[1 -(3-Bromo-5-ethvl-phenvl)cvclopentyllacetonitrile

In a sealed tube, to 2-[1-(3,5-dibromophenyl)cyclopentyl]acetonitrile (500 mg, 1.5 mmol) (see Example 48) in dry dioxane (6.7 ml) was added 1 ,1 '-bis(diphenylphosphino)ferrocene dichloropalladium(ll) dichloromethane complex (83 mg, 102 μιτιοΙ) and 1 M diethylzinc in hexane (729 μΙ, 729 pmol). The mixture was heated at 60°C for 90min. The reaction mixture was cooled to room temperature and methanol (1 ml) and sat. NH ₄ CI (0.2 ml) were carefully added. The volatile solvents were evaporated in vacuo and the remaining mixture was extracted with DCM and water. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried with Na ₂ S0 ₄ and evaporated. The residue was purified on silica gel eluting with 0-20% EtOAc in heptane to afford the title compound (146 mg, 34 %) as light yellow liquid.

b) (3S -6-rn-i3-Bromo-5-ethyl-phenyl)cvclopentyllmethvn-9-hvdroxy-2 ,3-dimethyl-3,4- dihvdropvrazinofl ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1 -(3-bromo-5-ethyl- phenyl)cyclopentyl]acetonitrile instead of 2-(1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white solid. MS (ESI, m/z): 476.2 [M + H]+ Example 66

(3S)-6-rr -(3-Chloro-5-ethyl-phenyl)cvclopentvnmethyll-9-hvdroxy-2,3-d imeth

dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

!n a sealed tube, (3S)-6-[[1 -(3-bromo-5-ethyi-phenyi)cyciopentyi]methyl]-9-hyd dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (18 mg, 38 μιηοΙ) and nickel(ll) chloride (10 mg, 76 pmol) were combined in DMF (1.6 ml). The reaction mixture was heated to 170°C and stirred overnight. The mixture was filtered, washed with DCM and water and the filtrate was concentrated in vacuo. The residue was extracted with 1 N HCI and DCM. The combined organic layers were dried with Na ₂ S0 ₄ , evaporated and the residue was purified by reversed phase preparative HPLC to afford the title compound (6 mg, 35 %) as a white solid.

MS (ESI, m/z); 430.3 [M + H]+

Example 67

3-Ethyl-5-ri-ri(3S)-9-hvdroxy-2.3-dimethyl-1 ,8-dioxo-3.4-dihvdropyrazinof1.2-c1pyrimidin-6- yllmethvncyclopentyllbenzonitrile

In a sealed tube, to (3S)-6-[[1 -(3-bromo-5-ethyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2,3- dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (30 mg, 63 μιηοΙ) in NMP (442 μΙ) was added copper (I) cyanide (12 mg, 130 μιτιοΙ). The reaction mixture was heated to 190 °C for 5 h. The reaction mixture was taken up in H ₂ 0 and extracted with DCM (4 x). The combined organic layers were dried over Na ₂ S0 ₄ and evaporated. The residue was purified by preparative reversed phase HPLC to afford the title compound (1 1 mg, 41 %) as a white solid.

MS (ESI, m/z): 421.3 [M + H]+

Example 68

2-[3-Ethvl-5-[1-[f(3S)-9-hydroxy-2,3-dimethyl-1 ,8-dioxo-3,4-dihydropvrazinoi 1 ,2-clpvrimidin-6- vHmethvHcvc!opentvliphenvnacetonitrile

The title compound was prepared in analogy to Example 40 starting from (3S)-6-[[1 -(3-bromo- 5-ethyl-phenyl)cyclopentyl]methyl]-9-hydroxy-2,3-dimethyl-3, 4-dihydropyrazino[1 ,2- c]pyrimidine-1 ,8-dione to afford the title compound as light brown solid.

MS (ESI, m/z): 435.3 [M + H]+ Example 69 & Example 70

Example 69:

(3S)-9-Hvdroxy-6-r(S)-hvdroxy-(1-phenylcvclopentyl)methyl1-2 ,3-dimethyl-3,4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

(The stereochemical configuration at the position of the benzylic alcohol may be reverted respectively)

and Example 70:

(3S)-9-Hvdroxy-6-r(R)-hvdroxy-(1-phenylcvclopentyl)methvn-2, 3-dimethyl-3,4- dihydropyrazinofl ,2-clpy midine-1 ,8-dione

(The stereochemical configuration at the position of the benzylic alcohol may be reverted respectively)

a) 2-Hydroxy-2-(1 -phenylcyclopentyl)acetonitrile

1 -Phenylcyclopentanecarbaldehyde (500 mg, 2.8 mmol) was combined with toluene (16 ml) and cooled in an ice bath. 1 M Diethylaluminum cyanide in toluene (4.25 ml, 4.25 mmol) was added slowly at 0°C and the reaction mixture was stirred at 0°C for 3 h. The reaction mixture was quenched with sat. sodium potassium tartrate (20 ml) and the mixture was stirred at room temperature for 2 h. The layers were separated and the aqueous layer was extracted with DCM (2 x). The combined organic layers were dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0% to 40% EtOAc in heptane to give the title compound (486 mg, 87 %) as a white solid.

b) Methyl 2-hvdroxv-2-(1 -phenvlcvclopentvl)ethanimidate hydrochloride -CI

The title compound was prepared in analogy to methyl 2-(1 -phenylcyclopentyl)ethanimidate hydrochloride (see Example 1 , step c) by starting from 2-hydroxy-2-(1- phenylcyclopentyl)acetonitrile to afford the title compound as a white solid.

MS (ESI, m/z): 234.1 [M + H]+ c) (3S)-9-Hvdroxy-6-r(S)-hvdroxy-(1-phenylcvcloDentvnmethvn-2.3 -dimethyl-3.4- dihydropyrazinoH ,2-c]pyrimidine-1 ,8-dione

and

(3S)-9-Hydroxy-6-r(R)-hydroxy-(1 -ph

dihydropyrazino[1 ,2-clpyrimidine-1 ,8-dione

Methyl 2-hydroxy-2-(1 -phenylcyclopentyl)ethanimidate hydrochloride (44 mg, 163 pmol), (S)- 1 ,6-dimethylpiperazin-2-one (31.4 mg, 245 Mmol) (see Example 13) and DIPEA (57 μΙ, 326 mol) were combined with THF (4 ml). AcOH (9 μΙ, 163 Mmol) was added. The mixture was stirred at room temperature for 3 d. The reaction mixture was cooled to -30 °C. 1 M LHMDS in THF (1.1 ml, 1.1 mmol) was added followed by diethyl oxalate (89 Ml, 652 Mmol). The reaction mixture was allowed to warm to room temperature and it was stirred for 3 h. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by reversed phase preparative HPLC to afford to the title compounds (Example 69: 8 mg, 13 %; Example 70: 7 mg, 1 1 %) as light yellow oils.

MS (ESI, m/z): 384.4 [M + H]+ (Example 69)

MS (ESI, m/z): 384.2 [M + H]+ (Example 70) Example 71 & Example 72

Example 71 :

(3SV6-KSH1-(3.5-Dimethylphenv0cvclopenM

dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

(The stereochemical configuration at the position of the benzylic alcohol may be reverted respectively)

and Example 72:

(3S)-6-r(R)-ri-(3,5-dimethylphenyl)cvclopentvn-hvdroxy-me thvn-9-hydroxy-2,3-dimethyl-3,4- dihydropyrazinoM ,2-c1pyrimidine-1 ,8-dione

(The stereochemical configuration at the position of the benzylic alcohol may be reverted respectively)

a) 2-n-(3,5-Dimethylphenyl)cyclopentyllacetonitrile

The title compound was prepared in analogy to 2-(1 -phenylcyclopentyl)acetonitrile (see Example 1 ) by using (3,5-dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) to give the title compound as a brown oil.

b) (3S)-6-r(S)-ri-(3,5-Dimethylphenyl)cvclopentvn-hvdroxy-methv n-9-hvdroxy-2.3-dimethyl- 3,4-dihydropyrazinon ,2-c1pyrimidine-1 ,8-dione

and

(3S)-6-r(RVri-(3.5-dimethylphenyl)cvclopentyll-hvdroxy-methy ll-9-hvdroxy-2,3-dimethyl-3.4- dihvdropvrazinofl ,2-clpyrimidine-1 ,8-dione

The two title compounds were prepared in analogy to Example 69 & Example 70 by using 2- [1 -(3,5-dimethylphenyl)cyclopentyl]acetonitrile in step b) to afford the two title compounds as off-white solids.

MS (ESI, m/z): 412.2 [M + H]+ (Example 71 )

MS (ESI, m/z): 412.4 [M + H]+ (Example 72) Example 73

(3S)-6-rri-(3-Bromo-5-ethyl-phenvncyclo^

dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

a) Methyl 2-fr(2S)-2-(tert-butoxycarbonylamino)propyllamino1acetate

To a solution of (S)-tert-butyl ( 1 -oxopropan-2-yl)carbamate (9.5 g, 54.8 mmol) in dichloromethane (350 ml) was added at 0 °C methyl 2-aminoacetate hydrochloride (1 1 g, 87.8 mmol) followed by Ν,Ν-diisopropylethylamine (11.5 ml, 65.8 mmol) and the resulting mixture was stirred at 0 °C for 30 min. Sodium triacetoxyborohydride (13.9 g, 65.8 mmol) was added in ten portions over a period of 1 h. The mixture was allowed to warm to room temperature and stirred at this temperature for 15 h. The mixture was cooled to 10 °C and quenched with sat. NaHC0 ₃ (200 ml). The aqueous layer was separated and extracted with DCM (3 x 200 ml). The combined organic layers were dried and evaporated. The residue was purified by flash chromatography (silica gel, 330 g, DCM/MeOH 60:1 to 30:1 ) to give the title compound (8.4 g, 62%) as light yellow oil with a purity of roughly 90%. This compound was used as such in the next step.

MS (ESI, m/z): 247.2 [M + H]+

b) tert-Butyl (3S)-3-methyl-5-oxo-piperazine-1-carboxylate

To a solution of methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)propyl]amino]acetate (9.61 g, 39 mmol) in dichloromethane (96 ml) was added slowly under temperature control (ice-bath cooling) at 22 °C 4M HCI in dioxane (48.8 ml, 195 mmol) and stirred at 22 °C for 3 h. The solvent was removed under reduced pressure and the resulting semisolid was dissolved in methanol (96 ml) and potassium carbonate (10.8 g, 78 mmol) was added. The resulting mixture was mechanically stirred at 22 °C for 3 h. The suspension was filtered through a membrane filter (RC 0.45), the solid was washed twice with methanol and the light brown filtrate was evaporated to give 9.75 g of a light brown foam.

To a solution of 9.27 g of the obtained foam in tetrahydrofuran (80 ml) was added at 22 °C a solution of di-tert-butyl dicarbonate (9.78 g, 10.4 ml, 44.8 mmol) in tetrahydrofuran (20 ml) followed by 1 M sodium hydroxide (37.7 ml, 37.7 mmol) and the mixture was stirred at 22 °C for 1 h. The mixture was quenched with water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were dried and evaporated. The residue was purified by flash chromatography (silica gel, 120 g, heptane/EtOAc 1 :1 then with 10% MeOH in DCM) to give the title compound (4.85 g, 61 % yield over two steps) as an off-white solid. MS (ESI, m/z): 159.1 [M + H - isobutene]+

c) tert-Butvl (3S)-4-ethvl-3-methvl-5-oxo-piperazine-1 -carboxylate

To a solution of tert-butyl (3S)-3-methyl-5-oxo-piperazine-1-carboxylate (1 g, 4.67 mmol) in DMF (13.3 ml) was added 55% NaH in mineral oil (224 mg, 5.1 mmol) at 0 °C. The mixture was warmed to room temperature and it was stirred for 2 h. lodoethane (450 μΙ, 5.6 mmol) was added drop-wise at 0 °C. The mixture was left stirring at room temperature for 2 h. The mixture was carefully quenched by the addition of H ₂ 0 (15 ml) while cooling in an ice bath. The mixture was diluted with brine (15 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml). The combined organic layers were dried and concentrated in vacuo. The residue was purified by flash chromatography (Si0 ₂ , 40 g Reveleris, 0% to 5% MeOH in DCM) to afford the title compound (990 mg, 88 %) as slightly yellow solid.

MS (ESI, m/z): 243.2 [M + H]+

d) (6S)-1 -Ethyl-6-methyl-piperazin-2-one

To a solution of tert-butyl (3S)-4-ethyl-3-methyl-5-oxo-piperazine-1 -carboxylate (290 mg, 1 .2 mmo!) in DCM (3 ml) was added at 22 °C 4M HCI in dioxane (3 mi, 12 mmol) and the mixture was stirred at 22 °C for 16 h. The solvent was concentrated in vacuo and a few drops of 25% NH ₄ OH (25% in H20) were added. The mixture was concentrated in vacuo and the residue was purified by chromatography (NH ₂ -modified silica gel, 20 g Telos, 5% MeOH in DCM) to afford the title compound (165 mg, 97%) as a yellow oil.

MS (ESI, m/z): 142.1 [M + H]+

e) (3S)-6-fri-(3-Bromo-5-ethyl-Dhenyl)cvclopentyl1methyll-2-eth yl-9-hvdroxy-3-methyl-^ dihvdropyrazino[1 ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 65 using (6S)-1-ethyi-6-methyi- piperazin-2-one instead of (6S)-1 ,6-dimethylpiperazin-2-one in step b) to give the title compound as an orange solid. MS (ESI, m/z): 488.3 [M + H]+

Example 74

2-[3-Ethyl-5-ri-[r(3S)-2-ethyl-9-hvdroxy-3-methyl-1.8-dioxo- 3,4-dihvdropyrazinof1 ,2- clpyrimidin-6-yllmethyllcvclopentvnphenyllacetonitrile

The title compound was prepared in analogy to Example 40 starting from (3S)-6-[[1 -(3-bromo- 5-ethyl-phenyl)cyclopentyl]methyl]-2-ethyl-9-hydroxy-3-methy i-3,4-dihydropyrazino[1 ,2- c]pyrimidine-1 ,8-dione to give the title compound as orange solid.

MS (ESI, m/z): 449.3 [M + H]+ Example 75

(3S)-6-rri-(3-Ethyl-2-methyl-phenvncvc[opentvnmethyl1-9-hvdr oxy-2.3-dimethyl^

dihydropyrazinoH ,2-c1pyrimidine-1 ,8-dione

a) 2-ri-(3-Ethyl-2-!Tiethv1-pheny1)cvclopentvnacetonitriie

To an ice cold solution of compound 3-Bromo-2-methylbenzaldehyde (5 g, 25 mmol) in MeOH (60 mL) was added NaBH ₄ (2.8 g, 75 mmol) portion wise and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with ice water and volatiles were removed under reduced pressure. The mixture was diluted with water and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound (4.8 g, 95%) as an off white solid.

b) (3-Bromo-2-methvi-phenyl)methyl methanesulfonate

To an ice cold solution of 2-[1 -(3-ethyl-2-methyl-phenyl)cyclopentyl]acetonitrile (4.8 g, 23.9 mmol) in DCM (50 mL) were added triethylamine (4.8 mL, 47.76 mmol) and methanesulphonyl chloride (2.8 mL, 35.8 mmol) sequentially and the reaction mixture was stirred at that temperature for 2 h. The reaction mixture was diluted with water and extracted with DCM (100 mL). The organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound 3 (6.0 g, crude) which was used as such in the next step.

c) 2-(3-Bromo-2-methyl-phenyl)acetonitrile

To a stirred solution of (3-bromo-2-methyl-phenyl)methyl methanesulfonate (6 g, 21 .5 mmol) in DMF (30 mL) was added KCN (1.68 g, 25.80 mmol) and the reaction mixture was stirred at room temperature for 16h. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirring continued for 30 min. The aqueous phase was extracted with DCM (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography (10% EtOAc in hexane) to get the title compound (3.8 g, 83% yield over two steps) as a viscous oil.

d) 1-(3-Bromo-2-methyl-phenyl)cvciopentanecarbonitriie

To an ice cooled suspension of NaH (1 g, 41.90 mmol) in DMSO (25 mL) was added a solution of 2-(3-bromo-2-methyl-phenyl)acetonitrile (4 g, 19 mmol) and 1 ,4 dibromobutane (2.73 mL, 22.85 mmol) in DMSO-diethyl ether (50 mL, 1 :1 ) and the reaction mixture was stirred for 16h at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by flash column (5% EtOAc in hexane) to get the title compound (3.8 g, 75%) as a colorless oil.

e) 1-(2-lv1ethyl-3-vinyl-phenyl)cvclopentanecarbonitrile

A stirred solution of 1 -(3-bromo-2-methyl-phenyi)cyclopentanecarbonitrile (3.8 g, 14.4 mmol), vinyl pinacol boronate (3.7 g, 21.6 mmol), Cs ₂ C0 ₃ (14.1 g, 43.2 mmol) in toluene (75 mL) was degassed with nitrogen for 10 min. To the reaction mixture were added Pd(dppf)CI ₂ (1 .2 g, 1.4 mmol) and dppf (1.2 g, 2.2 mmol) and the mixture was sequentially heated to 120°C for 24 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by flash column chromatography (5% EtOAc in hexane) to get the title compound (2 g, 65%) as a colorless oil.

f) 1 -(3-Ethyl-2-methyl-phenyl )cyciopentanecarbonitrile

To a solution of 1-(2-methyl-3-vinyl-phenyl)cyclopentanecarbonitrile (2 g, 9.5 mmol) in EtOAc (75 mL) was added 10% Pd/C (600 mg) and the reaction mixture was agitated under hydrogen (30 psi) atmosphere for 2 h in a Parr shaker. The reaction mixture was filtered through Celite, washed with EtOAc (50 mL) and the filtrate was concentrated to afford the title compound (2 g, 98%) as a colorless oil.

g) 2-[1-(3-Ethyl-2-methyl-phenyl)cvclopentyllacetonitrile

The title compound was obtained in analogy to 2-[1-(3-bromophenyi)cyciopentyi]acetonitriie (see Example 26, steps a-c) starting from 1-(3-ethyl-2-methyl-phenyl)cyclopentanecarbonitriie to afford the title compound as a colorless oil.

MS (ESI, m/z): 227.0 [M]+

h) (3S)-6-rri-(3-Ethyl-2-methyl-phenyl)cvclopentyl1methyl1-9-hv droxy-2,3-dimethyl-3,4- dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in anaolgy to Example 1 by using 2-[1 -(3-ethyl-2-methyl- phenyl)cyclopentyl]acetonitrile instead of 2-(1-phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as as a white solid.

MS (ESI, m/z): 410.3 [(M+H)+].

Example 76

(3S)-6-ff1 -(2-Chloro-3-ethyl-phenyl)cvclopentvnmethvn-9-hvdroxy-2,3-di methyl-3,4- dihydropyrazinoM ,2-clpyrimidine-1 ,8-dione

a) 1 -(2-Chloro-3-vinyl-phenyl)cvclopentanecarbonitrile

The title compound was prepared in analogy to 1 -(2-methyl-3-vinyl- phenyl)cyclopentanecarbonitrile (see Example 75, steps a-e) starting from 3-bromo-2- chlorobenzaldehyde to afford the title compound as a colorless oil. b) 1 -(2-Chloro-3-ethyl-phenyl)cyclopentanecarbonitrile

To a solution of 1-(2-ch!oro-3-vinyl-phenyl)cyclopentanecarbonitrile (1.0 g, 4.7 mmol) in EtOAc (50 mL) was added Pt0 ₂ (100 mg) and the reaction mixture was hydrogenated under an hydrogen (30 psi) atmosphere for 2 h. The reaction mixture was filtered washed with EtOAc and concentrated to afford the title compound (1.1 g, 99%) as a colorless oil.

c) (3S)-6-rri-i2-Chloro-3-ethv!-phenyl)cvciopentvi1methvn-9-hvd roxy-2,3-dimethyl-3,4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy Example 75 by using 1-(2-chloro-3-ethyl- phenyl)cyclopentanecarbonitrile instead of 1-(3-ethyl-2-methyl-phenyi)cyc!opentanecarbonitrile in step g) to give the title compound as a white solid. MS (ESI, m/z): 430.3 [(M+H)+]. Example 77

(3S)-6-fri-(5-Ethyl-2-methyl-phenyl)cvclopentyllmethvn-9-hvd roxy-2.3-dimethyl-3.4- dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

a) 2-Bromo-4-ethyl-1 -methyl-benzene

The title compound was prepared in analogy to 1-bromo-3-ethyl-2-fluoro-benzene (see Example 29, steps a-b) by starting from 3-bromo-4-methylbenzaldehyde instead of 3-bromo-2- fluorobenzaldehyde to give the title compound as a colorless liquid.

b) 5-Ethyl-2-methyl-benzaldehvde

To a solution of 2-bromo-4-ethyl-1 -methyl-benzene (2 g, 10.1 mmol ) and N,N,N',N",N"- pentamethyldiethylenetriamine (1.5 mL) in THF (10 mL) was added 1.6 M n-BuLi in hexane (12.5 ml, 20.10 mmol) drop-wise at -78 °C and the reaction mixture was stirred for 40 min at - 60 °C. The reaction mixture was cooled to -78°C and DMF (1.9 mL, 25.1 mmol) was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was treated with sat. NH ₄ CI and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to get the title compound (1.25, 84%) as a colorless oil which was used as such in next step.

c) 5-Ethyl-2-methyl-benzaldehyde

The title compound was prepared in analogy to 1 -(3-bromo-2-methyl- phenyl)cyclopentanecarbonitri!e (see Example 75, steps a-d) starting from 5-ethyl-2-methyl- benzaldehyde instead of 3-Bromo-2-methylbenzaldehyde to afford the title compound as a light brown oil.

d) 2-[1-(5-Ethyl-2-methyl-phenyl)cvclopentvnacetonitrile

The title compound was obtained in analogy to 2-[1 -(3-bromophenyl)cyclopentyl]acetonitrile (see Example 26, steps b-c) starting from 1 -(3-ethyl-2-methyl-phenyl)cyclopentanecarbonitrile to afford the title compound as a colorless viscous oil.

e) (3S)-6-rn -(5-Ethvl-2-methvl-phenvl)cvclopentvnmethvll-9-hvdroxy-2,3-d imethvl-3.4- dihydropyrazinofl ,2-clpvrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1 -(5-ethyl-2-methyl- phenyl)cyclopentyl]acetonitrile instead of 2-(1-phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white solid.

MS (ESI, m/z): 410.4 [( +H)+].

Example 78

(3S)-6-f[1 -(3-Chloro-4-ethyl-phenyl)cvclopentyl1methyl]-9-hvdroxy-2,3- dimethyl-3,4- dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

a) 4-Bromo-2-chloro-1 -ethyl-benzene

The title compound was prepared in analogy to 1-bromo-3-ethyl-2-fluoro-benzene (see Example 29, steps a-b) by starting from 2-chloro-4-bromobenzaldehyde to give the title compound as a colorless liquid.

b) (3S)-6-rn-(3-Chloro-4-ethyl-phenyl)cvclopentyllmethvn-9-hvdr oxy-2.3-dimethyl-3,4- dihvdropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 29 by using 4-bromo-2-chloro-1- ethyl-benzene instead of 1 -bromo-3-ethyl-2-fluoro-benzene in step c) to afford the title compound as a white powder.

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

Example 79

(3S)-6-ff1 -(4-Chloro-3-ethyl-phenyl)cvclopentyl1methyl1-9-hvdroxy-2.3- dimethyl^

dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (4-chloro-3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)- 1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a light yellow solid.

MS (ESI, m/z): 430.3 [(M+H)+],

Examp!e 80

(3S)-6-rri-r3-(2-Fluoroethvnphenvl1cvclopentvllmethvn-9-hvdr oxv-2.3-dimethyl-3.4- dihydropyrazinoH ,2-clpyrimidine- ,8-dione

a) 2-[1-r3-(2-Benzyloxyethyl)phenvncyclopentyl1acetonitrile

The title compound was prepared in analogy to 2-[1 -(3-ethyl-2-fluoro- phenyl)cyclopentyl]acetonitrile (see Example 29) by using 1 -(2-benzyioxyethyi)-3-bromo- benzene (prepared according to Kiyoshi O. et al PCT patent application WO 2005100365) instead of 1-bromo-3-ethyi-2-fluoro-benzene in step c) to give the title compound as a pale yellow liquid.

b) 2-H -r3-(2-Hvdroxyethyl)phenyllcvclopentyllacetonit le

To a stirred solution of 2-[1-[3-(2-benzyloxyethyl)phenyl]cyclopentyl]acetonitrile (550 mg, 1.72 mmol) in ethanol (20 mL) was added Pd(OH) ₂ (0.1 1 g) and the resulting reaction mixture was stirred under an atmosphere of H ₂ for 16h. The reaction mixture was filtered through Celite and washed with ethanol (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (40% ethyl acetate in hexane) to get the title compound (0.32 g, 81 %) as a colorless oil.

MS (ESI, m/z): 230.2 [(M+H)+]. c) 2-Π -r3-(2-Fluoroethyl)phenvncvclopentyl1acetonitri[e

To an ice cold solution of 2-[1 -[3-(2-fluoroethyl)phenyl]cyclopentyl]acetonitrile (1.1 g, 4.8 mmol) in DCM (30 mL) was added DAST (1.0 g, 6.25 mmol) and the resulting reaction mixture was stirred at 25 °C for 16h. The reaction mixture was quenched with aq. sodium bicarbonate and the organic layer was separated. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to afford the title compound as a colorless oil.

MS (El, m/z): 231 [M+],

(3S)-6-ff1-r3-(2-Fluoroethyl)phenyllcvclopentyllmethyll-9 -hvdroxy-2,3-dimethyl-3.4- dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in anaolgy to Example 1 by using 2-[1-[3-(2- fluoroethyl)phenyl]cyclopentyl]acetonitrile instead of 2-(1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 - methylpiperazin-2-one in step h) to give the title compound as a white solid. MS (ESI, m/z): 414.3 [(M+H)+], Example 81

(3S)-6-rri-(3-Fluoro-5-methyl-phenvncvclopentyllmethvn-9-hvd roxy-2-isopropyl-3-meth dihydropyrazinoM ,2-clpyrimidine-1 ,8-dione

a) (6S)-1-lsopropyl-6-methyl-piperazin-2-one

The title compound was prepared in analogy to (6S)-1-ethyl-6-methyl-piperazin-2-one (see Example 73) by using 2-iodopropane instead of iodoethane in step c) to give the title compound as a yellow oil.

MS (ESI, m/z): 157.1 [(M+H)+].

b) (3S)-6-rri-(3-Fluoro-5-methyl-phenyl)cvclopentyllmethyll-9-h vdroxy-2-isopropyl-3-met^ 3,4-dihydropyrazino[1 ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3-fluoro-5- methylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1- isopropyl-6-methyl-piperazin-2-one instead of 6-ethyi-1-methylpiperazin-2-one in step h) to give the title compound as a white powder.

MS (ESI, m/z): 428.2 [(M+H)+j.

Example 82

(3S)-6-ff1-(3,5-Dimethylphenyl)cyclopentyl1methvn-9-hydroxy- 2-isopropyl-3-methyl-3,4- dihydropyrazino[1 ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylpenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)- 1-isopropyl-6-methyl-piperazin-2-one (see Example 81 , step a) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 424.3 [(M+H)+].

Example 83

(3S)-6-fri-(3,5-Dimethylphenyl)cvclop

dihydropyrazino[1 ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (4-chloro-3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1- isopropyl-6-methyl-piperazin-2-one (see Example 81 , step a) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as an off-white powder. MS (ESI, m/z): 458.2 [(M+H)+].

Example 84

(3S)-9-Hvdroxy-2-isopropyl-3-methyl-6-ff1-(m-tolyl)cvclopent vnmethvn-3,4- dihydropyrazinoM ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- methylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)- 1-isopropyl-6-methyl-piperazin-2-one (see Example 81 , step a) instead of 6-ethyl-1 - methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 410.2 [(M+H)+].

Example 85

(3S)-2-Ethyl-6-fri-(3-ethylphenvncvclopentyllmethvn-9-hvd roxy-3-methyl-3,4- dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1- ethyl-6-methyl-piperazin-2-one (see Example 73) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as an off-white solid. MS (ESI, m/z): 410.2 [(M+H)+].

Example 86

(3S)-6-rri -(3.5-Dimethylphenyl cvclopentyl1methyl1-2-ethyl-9-hvdroxy-3-met^

dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenyimagnesium bromide in step a) and (6S)-1-ethyl-6-methyi-piperazin-2-one (see Example 73) instead of 6-ethyl-1 -methylpiperazin- 2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 410,3 [(M+H)+].

Example 87

(3S)-6-ff1 -(3-Ethvlphenvl )cvclopentvllmethvll-9-hvdroxv-2.3-dimethvl-3.4-dihvdropyraz inof1 .2- clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenyimagnesium bromide in step a) and (6S)- 1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a light brown solid. MS (ESI, m/z): 396.3 [(M+H)+].

Example 88

(3S)-6-rri -(3-Ethylphenyl)cvclopentyllmethyl1-9-hvdroxy-2-(2-methoxyet hyl)-3-me

dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

a) (6S)-1 -(2-Methoxyethyl)-6-methyl-piperazin-2-one

The title compound was prepared in analogy to (6S)-1 -ethyl-6-methyl-piperazin-2-one (see Example 73) by using 1 -bromo-2-methoxyethane instead of iodoethane in step c) to give the title compound as a yellow oil.

MS (ESI, m/z); 173.1 [(M+H)+l, b) (3S)-6-fri-(3-Ethylphenvncvclopentvnmethvn-9-hvdroxy-2-(2-me thoxyethyl)-3-m dihydropyrazinofl ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1- (2-methoxyethyl)-6-methyl-piperazin-2-one instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the titie compound as a light yellow solid.

MS (ESI, m/z): 440.3 [(M+H)+].

Example 89

i3S)-6-rn-(3-Ethylphenyl)cvclopentyllmethvn-9-hvdroxy-3-m ethv!-2-(1-methylpyrazol-3-yl)-3,4- dihvdropyrazinofl ,2-clpyrimidine-1 ,8-dione

a) (6S)-6-Methyl-1 -( 1 -methylpyrazol-3-yl)piperazin-2-one

A suspension of tert-butyl (3S)-3-methyl-5-oxo-piperazine-1 -carboxylate (see Example 73, step b) (280 mg, 1.31 mmol) and 3-iodo-1-methyl-1 H-pyrazole (326 mg, 1.57 mmol) in dioxane (10 ml) was prepared and argon was bubbled for 10 minutes. K ₃ P0 ₄ (610 mg, 2.87 mmo!), copper (I) iodide (25 mg, 131 pmol) and N,N'-dimethylethylenediamine (28.1 μΙ, 261 pmol) were added. The mixture was heated to 120 °C for 20 h. The mixture was filtered, the soiids washed twice with ethyl acetate and the filtrate was evaporated. The residue was purified by flash chromatography (EtOAc in heptane 20% to 100%) to afford the title compound (287 mg, 75%) as a light yellow solid.

MS (ESI, m/z): 295.2 [(M+H)+].

b) (6S)-6-Methyl-1 -( 1 -methylpyrazol-3-yl)piperazin-2-one

To a solution of (6S)-6-methyl-1 -(1 -methylpyrazol-3-yl)piperazin-2-one (270 mg, 917 pmol) in dichloromethane (5.4 ml) was added at 4M HCI in dioxane (2.3 ml) and the resulting suspension was stirred at 22 °C for 5 h. The mixture was evaporated and to the residue was added 25% ammonium hydroxide (714 μΙ, 4,6 mmol) evaporated. The residue was suspended in dichloromethane and the solids were filtered off. The filtrate was evaporated and the residue was purified by flash chromatography (Si-NH _2> 5 g, MeOH in DCM 2%) to give the title compound (136 mg, 76%) as a yellow oil.

MS (ESI, m/z): 195.1 [(M+H)+]. (3S)-6-rri-(3-Ethylphenvncyclopentyl]m^

dihydropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenyimagnesium bromide in step a) and (6S)-6- methyl-1 -(1-methy!pyrazol-3-yl)piperazin-2-one instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a light yellow solid.

MS (ESI, m/z): 462.3 [(M+H)+j.

Example 90

2-f(3S)-6-rn-(3-Ethvlphenvl)cvclopentvllmethvll-9-hvdroxy -3-methyl-1 ,8-dioxo-3,4- dihydropyrazinofl ,2-c1pyrimidin-2-yll-N-methyl-acetamide

a) N-Methyl-2-f(2S)-2-methyl-6-oxo-piperazin-1 -yllacetamide

The title compound was prepared in analogy to (6S)-1 -ethyl-6-methyl-piperazin-2-one (see Example 73) by using 2-chloro-N-methylacetamide instead of iodoethane in step c) to give the title compound as a yellow oil.

MS (ESI, m/z): 186.1 [(M+H)+J.

b) 2-r(3S)-6-rf1-(3-Ethylphenyl)cvclopentyl1methvn-9-hvdroxy-3- methyl-1 ,8-dioxo-3.4- dihydropvrazino[1 ,2-c1pvrimidin-2-vn-N-methyl-acetamide

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyDmagnesium bromide instead of phenylmagnesium bromide in step a) and N- methyl-2-[(2S)-2-methyl-6-oxo-piperazin-1-yl]acetamide instead of 6-ethyl-1-methylpiperazin- 2-one in step h) to give the title compound as a white solid.

MS (ESI, m/z): 453.3 [(M+H)+].

Example 91

2-rf3S^rfW3-Ethylphenyl)cvclopentyl1methyl1-9-hvdroxy-3-meth yl-1.8 lioxo-3.^

dihvdropyrazinoi1 ,2-clpyrimidin-2-yll-N-phenyl-acetamide

a) 2-f(2S)-2-Methyl-6-oxo-piperazin-1 -yll-N-phenyl-acetamide

The title compound was prepared in analogy to (6S)-1-ethyl-6-methyl-piperazin-2-one (see Example 73) by using 2-chloro-N-phenylacetamide instead of iodoethane in step c) to give the title compound as a white solid. MS (ESI, m/z): 246.2 [(M-H)-].

b) 2-f(3S)-6-rf1-(3-Ethvlphenvl)cvclopentvllmethvll-9-hvdroxv-3 -methvl-1.8-dioxo-3,4- dihvdropvrazinori ,2-clpvhmidin-2-vll-N-phenyl-acetamide

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and 2-[(2S)- 2-methyl-6-oxo-piperazin-1 -yl]-N-phenyl-acetamide instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a yellow solid.

MS (ESI, m/z); 515.3 [(M+H)+].

Example 92

(3S)-9-Hvdroxy-2,3-dimethyl-6-rn-(5-methyl-3-thienyl)cvcl opentvnmethyll-3.4- dihvdropyrazinofl ,2-clpyrimidine-1 ,8-dione

a) (5-Methyl-3-thienyl)maqnesium bromide

To a suspension of magnesium turnings (1.4 g, 58 mmol) in THF (4 ml) was added at 22 °C 3 ml of a solution of 4-bromo-2-methylthiophene (10 g, 56.5 mmol) in THF (45 ml). A grain of iodine was added and the reacting mixture was slightly warmed up in a warm water bath until the reaction initiated as observed by an exothermal temperature increase. The remaining solution of 4-bromo-2-methylthiophene was added at such a speed in order to maintain a gentle reflux. After complete addition the mixture was refluxed for 1 h and cooled to room temperature. The solution obtained was used as such in the next step. b) (3S)-9-Hvdroxy-2,3-dimethyl-6-rri-(5-m^

dihydropyrazinoH ,2-clpyrimidine-l ,8-dione

The title compound was prepared in analogy to Example 1 by using (5-methyl-3- thienyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6S)-1 ,6- dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 388.2 [(M+H)+].

Example 93

(4R/S.12aSR)-7-Hvdroxy-4-methyl-10-f( 1 -phenylcvclopentvl)methyl1-3.4.12.12a-tetrahvdro-

2H-pyrimidof5,6lpyrazinof2,6-b1[1 ,3loxazine-6,8-dione

(rac) a) Ethyl 2-fbenzyloxycarbonyl(2-oxoethyl)amino1acetate

The title compound was prepared according to Hidemistu, N. et al, US patent application 2003/0045520 to afford the title compound as a light yellow oil.

b) Benzyl (4R S,9aS/R)-4-methyl-6-oxo-2,3,4,7,9,9a-hexahvdropyrazinof2,1-b 1i1 ,31oxazine-8- carboxylate

in a microwave-tube, ethyl 2-[benzyloxycarbonyl(2-oxoethyi)amino]acetate (330 mg, 1 .18 mmol) was diluted in DCM (8 ml), then (+/-)-3-aminobutan-1-ol (1 16 mg, 1.24 mmol) and acetic acid (39 μΙ, 673 prnol) were added to give a colorless solution. The reaction mixture was submitted to microwave heating for 1.5 h at 140 °C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 50% EtOAc in heptane) to give the title compound (183 mg, 51 %) as a colorless oil. The relative stereochemistry of the product was unambiguously assigned by NOESY NMR experiments.

MS (ESI, m/z): 305.2 [(M+H)+]. c (4R/S, 12aS/R)-7-Hvdroxy-4-methyl-104(1 -phenylcvclopentyl)methyl1-3.4, 12.12a-tetrahydro- 2H-pyrimido[5,6lpyrazinof2,6-b1H ,31oxazine-6,8-dione

To (4R/S, 12aS/R)-7-hydroxy-4-methyl-10-[(1 -phenylcyclopentyl)methyl]-3,4, 12, 12a- teirahydro-2H-pyrimido[5,6]pyrazino[2,6-b][1 ,3]oxazine-6,8-dione (216 mg, 710 μηιοΙ) in methanol (12 ml) was added 10% Pd/C (21.6 mg, 20.3 pmol). Then reaction mixture was stirred under an atmosphere of H ₂ for 100 min. The reaction mixture was filtered through glass fiber paper, washed with MeOH and the filtrate was evaporated. The residue was purified by flash chromatography (silica gel, 0% to 10% MeOH in DCM) to give the title compound (103 mg, 85 %) as a colorless oil.

MS (ESI, m/z): 171.1 [(M+H)+].

d) (4R/S, 12aSR)-7-Hvdroxy-4-methyl-10-f( 1 -phenylcvclopentyl)methyll-3,4, 12,12a-tetrahvdro- 2H-pyrimidoi5.61PYrazinoi2,6-blf1 ,31oxazine-6,8-dione

The title compound was prepared in analogy to Example 1 by using (4R/S, 12aS/R)-7-hydroxy- 4-methyl-10-[(1-phenylcyclopentyl)methyl]-3,4, 12,12a-tetrahydro-2H- pyrimido[5,6]pyrazino[2,6-b][1 ,3]oxazine-6,8-dione instead of 6-ethyl-1-methylpiperazin-2-one in step h) to give the title compound as a white solid.

MS (ESI, m/z): 410.3 [(M+H)+]. Example 94

(4R/S, 12aS/R)-10-ΓΠ -(3.5-Dimethylphenyl)cvclopentvnrnethyl1-7-hvdroxy-4-methyl- 3.4, 12, 12a- tetrahvdro-2H-pvrimidor5,6lDvrazinor2,6-biri ,31oxazine-6,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (4R/S, 12aS/R)-7-hydroxy-4-methyl-10-[( 1 -phenylcyclopentyl)methyl]-3,4, 12, 12a-tetrahydro- 2H-pyrimido[5,6]pyrazino[2,6-b][1 ,3]oxazine-6,8-dione (see Example 93) instead of 6-ethyl-1 - methylpiperazin-2-one in step h) to give the title compound as a white solid. MS (ESI, m/z): 438.3 [(M+H)+j.

Example 95 (4R, 12aS)-10-ΓΓ1 -(3.5-Dimethylphenvncvclopentvnmethvn-7-hvdroxy-4-methyl-3.4 .12.12a- tetrahvdro-2H-pyrimidof5,6lpyrazino[2,6-bli1 ,31oxazine-6,8-dione and Example 96

(4S, 2aR)-10-ΓΓ1 -( 3,5-Dimethylphenyl)cvclopentvnmethvn-7-hvdroxy-4-methyl-3.4. 12.12a- tetrahvdro-2H-pyrimidof5.6lpvrazinof2,6-blf1 ,3loxazine-6.8-dione

The enantiomers of (4R/S 2aS/R)-10-[[1-(3,5-dimethylphenyl)cyclopentyl]methyl]-7-hydr oxy- 4-methyl-3^ 2 2a-tetrahydro-2H-pyrimido[5,6]pyrazino[2 _i 6-b][1 ,3]oxazine-6,8-dione (32 mg) was separated in analogy to Example 2 and Example 3 to give the title compounds as white powders (3 mg for Example 95 and 4 mg for Example 96). The absolute configuration was tentatively assigned in analogy to Example 11 based on biological activity.

Example 95: MS (ESI, m/z): 483.3 [(M+Hf].

Example 96: MS (ESI, m/z): 483.3 [(M*H) ⁺ ].

Example 97

(3S)-6-[[1-(3-Bromophenyl)cvclohexyllmethyll-9-hvdroxy-2,3-d imethyl-3,4-dihvdropyrazino[1 ,2- c]pyrimidine-1 ,8-dione

a) 2-f1-(3-Bromophenyl)cyclohexynacetonitri!e

The title compound was prepared in analogy to 2-[1 -(3-bromophenyl)cyclopentyl]acetonitrile (see Example 26) by using 1 ,5-dibromopentane instead of 1 ,4-dibromobutane in step a) to give the title compound as light yellow oil.

MS (ESI, m/z): 277.1 [(M+H)+].

b) (3S)-6-rf1 -(3-Bromophenyl)cvclohexyllmethyll-9-hvdroxy-2,3-dimethyl-3, 4- dihvdropyrazinon ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using 2-[1 -(3- bromophenyl)cyclohexyl]acetonitrile instead of 2-( 1 -phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin- 2-one in step h) to give the title compound as an off -white solid. MS (ESI, m/z): 461.3 [(M+H)+]. Example 98

(3S)-6-rri-(3-Ethylphenyl)cvclohexyllmethvn-9-hvdroxy-2,3-di methyl-3^-dih

clpyrimidine-1 ,8-dione

and

Example 99

(3S)-9-Hvdroxv-2,3-dimethv[-6-f(1-phenvlcvclohexvnmethvn-3^- dihvdropyrazinori ,2- clpyrimidine-1 ,8-dione

In a microwave tube(3S)-6-[[1-(3-bromophenyl)cyclohexyl]methyl]-9-hydroxy-2 ,3-dimethyl-3,4- dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (20 mg, 43 pmol) and Bis(triphenylphosphine)- palladium(ll) dichloride (10 mg, 14 pmol) were combined with THF (4 ml). 1 M Diethylzinc in hexane (217 pi, 217 pmol) was added. The reaction mixture was heated to 80 °C and stirred for 90 min. The reaction mixture was evaporated and the residue purified by preparative reversed phase HPLC to afford the to title compounds Example 98 (3 mg, 16%) as pink solid and Example 99 (2 mg, 13%) as off-white solid.

MS (ESI, m/z): 410.1 [(M+H)+] (Example 98)

MS (ESI, m/z): 382.2 [(M+H)+] (Example 99) Example 100

((3S)-9-Hvdroxy-2,3-dimethyl-6-fri-(m-tolyl)cvclohex

clpyrimidine-1 ,8-dione

The title compound was optained in analogy to Example 35 starting from (3S)-6-[[1-(3- faromophenyl}cyc!Qhexy1jmeihy!]-9-hydroxy

1 ,8-dione by using methylboronic acid instead of 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2- dioxaborolane to give the title compound as a pink solid.

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

Example 101

6-ff1-(3-Ethylphenyl)cvclohexyl1methvn-9-hvdroxy-2-isopropyl -3-methyl-3,4- dihvdropyrazinoH ,2-c]pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl 2-cyano-2- cyclohexylidene-acetate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a) and isopropylamine instead of methylamine in step f) to give the title compound as a white solid. MS (ESI, m/z): 438.3 [(M+H)+],

Example 102

(3S)-6-ff1 -(3.5-Dimethylphenyl)cvclohexynmethvn-9-hvdroxy-2.3-dim

dihvdropyrazinoH ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl 2-cyano- 2-cyclohexylidene-acetate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as a white solid.

MS (ESI, m/z): 410.1 [(M+H)+],

Example 103

(3S)-6-[[1 -(3,5-Dimethylphenyl)cyclohexyllmethvn-9-hvdroxy-2-isopropyl -3-methyl-3,4- dihydropyrazinoH ,2-c]pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl 2-cyano- 2-cyclohexylidene-acetate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 -isopropyl-6-methyl-piperazin-2-one (see Example 81 ) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 483.3 [(M+H)+J.

Example 104

(3S)-6-(2-Ethyl-2-phenyl-butyl)-9-hvdroxy-2,3-dimethyl-3,4-d ihvdropyrazino[1 ,2-c1pyrimidine- 1 ,8-dione

The title compound was prepared in analogy to Example 1 by using ethyl 2-cyano-3-ethyl- pent-2-enoate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a) and (6S)-1 ,6- dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 370.2 [(M+H)+], Example 105

(3S)-6-r2-(3,5-Dimethylphenyl)-2-ethyl-butyl1-9-hvdroxy-2.3- dimethyl-3^-di

clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl 2-cyano- 3-ethyi-pent-2-enoate instead of ethyl 2-cyano-2-cyclopentyiideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 398.3 [(M+H)+].

Example 106

(3S)-6-f2-(3.5-Dimethvlphenvl)-2-ethvl-butvl1-9-hydroxv-2-is opropvl-3-methvl-3.4- dihydropyrazinoM ,2-clpvrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl 2-cyano- 3-ethyl-pent-2-enoate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 -isopropyI-6-methyl-piperazin-2-one (see Example 81 ) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

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

Example 107

(3S)-6-f2-(3,5-Dimethylphenyl)-2-ethyl-pentyll-9-hvdroxy-2,3 -dimethyl-3,4-dihvdropyrazinori ,2- clpyhmidine-1 ,8-dione

a) (E/Z)-Ethyl 2-cvano-3-ethvlhex-2-enoate

To a solution of hexan-3-one (12.3 ml, 100 mmol) and ethyl 2-cyanoacetate (10.6 ml, 100 mmol) in toluene (90 ml) were added ammonium acetate (7.7 g, 100 mmol) and acetic acid (5.7 ml, 100 mmol) and the resulting mixture was stirred at 1 15 °C for 16h using a Dean- Stark trap in order to separate the water formed during the reaction. The mixture was quenched slowly with sat. NaHC0 ₃ (150 ml) (gas evolution) and partitioned between EtOAc (200 ml) and H ₂ 0 (50 ml). The aqueous layer was separated and extracted with EtOAc (200 ml). The combined organic layers were washed with brine (100 ml), dried with Na ₂ S0 ₄ , filtered and evaporated. The residue was filtered through a plug of silica gel eluting with 10 % EtOAc in heptane and the filtrate was evaporated to give the title compound (13.8 g, 71 %) as light yellow liquid. MS (ESI, m/z): 196.1 [(M+H)+],

b) (3S)-6-r2-(3,5-Dimethylphenyl)-2-ethyl-pentyll-9-hvdroxy-2,3 -dimethyl-3.4- dihydropyrazinon ,2-c|pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and (E/Z)-ethyl 2- cyano-3-ethylhex-2-enoate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as an white solid.

MS (ESI, m/z): 412.2 [(M+H)+],

Example 108

(3S)-6-f2-i3,5-Dimethylphenyl)-2-phenyl-butvn-9-hvdroxy-2 ,3-dimethyl-3,4- dihydropyrazinoH ,2-clpyrimidine-1 ,8-dione

a) (E/Z)-Ethyl 2-cyano-3-phenylpent-2-enoate

The title compound was prepared in analogy to (E/Z)-ethyl 2-cyano-3-ethylhex-2-enoate (see Example 107) by using propiophenone instead of hexan-3-one in step a) to give the title compound as a yellow oil.

MS (ESI. m/z): 230.1 [(M+H)+].

b (3S)-6-r2-(3.5-Dimethylphenvn-2-phenyl-butvn-9-hvdroxy-2,3-d imethyl-3,4- dihydropyrazinoM ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and (E/Z)-ethyl 2- cyano-3-phenyipent-2-enoate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as a light yellow solid.

MS (ESI, m/z): 446.3 [(M+H)+]. Example 109

(3S)-6-f2-(3.5-Dimethylphenvn-2-(methoxymethyl)butyl1-9-hvdr oxy-2,3-dim

dihydropyrazinoil ,2-c1pyrimidine-1 ,8-dione

a) (E/ZVEthyl 2-cvano-3-(methoxymethyl)pent-2-enoate

The title compound was prepared in analogy to (E/Z)-ethyl 2-cyano-3-ethylhex-2-enoate (see Example 107) by using 1 -methoxybutan-2-one instead of hexan-3-one in step a) to give the title compound as a yellow oil. MS (ESI, m/z): 198.1 [(M+H)+].

b) (3S)-6-f2-(3.5-Dimethvlphenvl)-2-(methoxvmethyl)butvl1-9-hvd roxv-2.3-dimethvl-3.4- dihvdropyrazinofl ,2-clpyrimidine-l ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and (E/Z)-ethyl 2- cyano-3-(methoxymethyl)pent-2-enoate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

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

Example 110

(3S)-6-r2-(3,5-Dimethvlphenvl)-2-(hvdroxvmethvl)butvll-9-hvd roxv-2.3-dimethvl- dihydropyrazino[1 ,2-clpyrimidine-1 ,8-dione

To a solution of (3S)-6-[2-(3,5-dimethylphenyl)-2-(methoxymethyl)butyl]-9-hyd roxy-2,3- dimethyl-3,4-dihydropyrazino[1 ,2-c]pyrimidine-1 ,8-dione (15 mg, 36.3 pmol, Eq: 1 ) in DCM (520 μΙ) was added at -40 °C a solution of sodium iodide (25 mg, 163 pmol) and 1 ,4,7, 10, 13- pentaoxacyclopentadecane (15-crown-5) (36 mg, 163 pmol) in DCM (260 μΙ) and the resulting mixture was stirred at -40 °C for 10 min. Then 1 M boron tribromide in DCM (109 μΙ, 109 μιτιοΙ) was added. After 2 h the mixture was allowed to warm to room temperature and the mixture was left stirring for 20 h. Chloroform (520 μΙ) was added and the mixture was warmed to 60 °C for 4 h. 1 M Boron tribromide in DCM (218 μΙ, 218 μιηοΙ) was added. After 20 h at 60 °C further 1 M boron tribromide in DCM (218 μΙ, 218 pmol) was added the mixture was stirred at 60 °C for h to give nearly complete conversion. The reaction was quenched with 1 M HCI and extracted with DCM (2 x 10 ml). The combined organic layers were dried and evaporated. The residue was purified reversed phase preparative HPLC to give the title compound (3 mg, 17%) as a light brown oil. MS (ESI, m/z): 400.2 [(M+H)+].

Example 111

(3S)-6-rri -(3,5-Dimethylphenyl)cv ^

dihydropyrazinofl ,2-c1pyrimidine-1 ,8-dione

a) Ethyl 2-cyano-2-cycloheptylidene-acetate

The title compound was prepared in analogy to (E/Z)-ethyl 2-cyano-3-ethylhex-2-enoate (see Example 107) by using cycloheptanone instead of hexan-3-one in step a) to give the title compound as a light yellow oil.

MS (ESI, m/z): 206.1 [(M-H)-].

b) (3S)-6-rri -(3.5-Dimethvlphenvl)cvcloheptvnmethvll-9-hvdroxv-2,3-dimeth yl-3.4- dihydropyrazinofl ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl 2-cyano- 2-cycloheptylidene-acetate instead of ethyl 2-cyano-2-cyclopentylideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1- methy!piperazin-2-one in step h) to give the title compound as an off-white solid.

IS (ESI, m/z): 424.3 [(M+H)+].

Example 112

(3S)-6-[ri-(3.5-Dimethvlphenvl)-2-methvl-cvclopentvllmethvll -9-hvdroxv-2.3-dimethyl-3.4- dihydropyrazinofl ,2-c]pyrimidine-1 ,8-dione

a) Ethyl (2E/Z)-2-cyano-2-(2-methylcyclopentylidene)acetate

The title compound was prepared in analogy to (E/Z)-ethyl 2-cyano-3-ethylhex-2-enoate (see Example 107) by using 2-methylcyclopentanone instead of hexan-3-one in step a) to give the title compound as a light yellow oil. MS (ESI, m/z): 194.1 [(M+H)+J.

b) (3S)-6-rri-(3.5-Dimethylphenyl)-2-methyl-cvclopentvnmethyll- 9-hvdroxy-2.3-dimethyl-3.4- dihvdropyrazinoH ,2-c1pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide and ethyl (2E/Z)-2- cyano-2-(2-methylcyclopentylidene)acetate instead of ethyl 2-cyano-2- cyclopentylideneacetate in step a), and by using (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as an off-white solid. MS (ESI, m/z): 410.2 [(M+H)+j.

Example 113

2-r(1 S/R,2R/S)-2-Benzyloxy-1 -(4-chlorophenv0cvclohexynacetonitrile

a) 2-f(1 S/R,2R/S)-1-(4-Chlorophenvl)-2-hydroxv-cvclohexvllacetonitri le

2-[1-(4-Chlorophenyl)-2-oxo-cyclohexyl]acetonitrile (800 mg, 3.23 mmol) (prepared according to Karlheinz, B. et al., PCT patent application WO 2009/087127) and NaBH ₄ (244 mg, 6.5 mmol) were combined with EtOH (50 ml) to give a white suspension. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was exctracted with diethyl ether and the combined organic phases were washed with brine, dried with Na ₂ S0 ₄ and concentrated in vacuo to give the title compound (610 mg, 76%) as a light yellow oil. The diastereomer was unambiguously assigned by NOESY NMR experiments.

MS (El, m/z): 249.1 [M+j. b) 2-[(1S/R,2R S)-2-Benzyloxy-1-(4-chlorophenyl)cvclohexynacetonitrile

2-[(1 S/R,2R S)-1 -(4-Chlorophenyl)-2-hydroxy-cyclohexyl]acetonitrile (500 mg, 2 mmol) was combined with DMF (10 ml) to give a colorless solution. This was cooled to 0 °C and 60% NaH in mineral oil (63 mg, 2.6 mmol) was added and the resulting mixture was stirred for 30 min before adding benzyl bromide (285 μΙ, 2.4 mmol) drop wise. The reaction mixture was stirred at room temperature for 1 h before heating the reacton mixture to 40 °C. Upon completion of the reaction the mixture was carefully diluted with H ₂ 0 (200 mL) and extracted with EtOAc (2 x 200 ml_).The combined organic layers were dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flash chromatography (0-20% AcOEt in heptane) to afford the title compound as a light yellow oil.

c) (3S)-6-[i2-Benzyloxy-1 -(4-chlorophenyl)cyclohexyllmethyl1-9-hvdroxy-2,3-dimethyi-3 ,4- dihydropyrazinon ,2-c]pyrimidine-1 ,8-dione

(1 : 1 mixture of diastereomers,

alkoxy and chlorophenyl are cis)

The title compound was prepared in analogy to Example 1 by using 2-[(1 S/R,2R/S)-2- benzyloxy-1 -(4-chlorophenyl)cyclohexyl]acetonitrile instead of 2-(1- phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a light brown solid.

MS (ESI, m/z): 522.2 [( +H)+J.

Example 114

(3R)-6-rn -(3-Ethylphenvncvclopentyl1methyl1-9-hvdroxy-3-methyl-2-i(1 RV2.2.2-trifluoro-1- methyl-ethvn-3,4-dihvdropyrazino[1 ,2-clpyrimidine-1 ,8-dione

a) tert-Butyl (3R)-3-methvl-5-oxo-4-f( 1 )-2,2.2-trifluoro-1-methvl-ethvllpiperazine-1 - carboxylate

The title compound was prepared in analogy to tert-Butyl 3-ethyl-4-methyl-5-oxo-piperazine-1- carboxylate (see Example 1 ) by using (R)-1 ,1 , 1 -trifluoropropan-2-amine instead of methylamine in step f) to give the title compound (single diastereomer) as a white solid. The configuration of the newly formed stereo center was tentatively assigned according to the biological activity of Example 1 14 in analogy to Example 11.

MS (El, m/z): 310.2 [M+],

b) (6R)-6-Methvl-1-r( 1 R)-2,2,2-trifluoro-1-methvl-ethvllpiperazin-2-one tert-Butyl (3R)-3-methyl-5-oxo-4-[(1 R)-2,2,2-trifluoro-1 -methyl-ethyl]piperazine-1 -carboxylate (1.1 g, 3.6 mmol) was dissolved in DCM (8 ml). 5M HCI in dioxane (9 ml) was added and the resulting mixture was at room temperature for 2 h. The reaction mixture was concentrated in vacuo, the residue was basified with 25% NH ₄ OH and concentrated in vacuo. The residue was filtered over a plug of NH ₂ -silica-gel eluting with 10% MeOH in DCM. MS (ESI, m/z): 21 1.1 [(M+H)+].

c) (3R)-6-rn-(3-Ethylphenyl)cvclopentyllmethyll-9-hvdroxy-3-met hyl-2-f(1 R)-2,2,2-trifluoro-1- methyi-ethyll-3,4-dihvdropyrazinof1 ,2-clpyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6R)-6- methy!-1-[(1 R)-2,2,2-trifluoro-1-methyl-ethyl]piperazin-2-one) instead of 6-ethyi-i- methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 478.2 [(M+H)+]. Example 115

(3R)-6-rM -(3,5-Dimethylphenyl)^

1 -methyl-ethvn-3,4-dihvdropyrazinori ,2-c]pyrimidine-1 ,8-dione

The title compound was prepared in analogy to Example 1 by using (3,5- dimethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and (6R)-6-methyl-1 [(1 R)-2,2,2-trifluoro-1 -methyl-ethyl]piperazin-2-one) (see Example 1 14) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as an off-white solid.

MS (ESI, m/z): 478.2 [(M+H)+].

Example 116

(3S)-6-f(5.7-Dimethvl-2.3.3a.4-tetrahvdro-1 H-cvclopentara1inden-8b-vl)methvn-9-hvdroxy-2,3- dimethvl-3,4-dihvdropyrazinof 1 ,2-clpvrimidine-1 ,8-dione

(1:1 mixture of cis diastereomers) a) 2-Allyl-4,6-dimethyl-indan-1-one

THF (33 ml) was cooled to -78 °C and 1 M LHMDS in THF (13.7 ml, 13.7 mmol) was added. After 10 min a solution of 4,6-dimethyl-2,3-dihydro-1 H-inden-1 -one (2 g, 12.5 mmol) (prepared according to Haadsma-Svensson, S. R. et al., PCT patent application WO 95/04713) in THF (20 ml) was added over 25 min and stirred for 1 h. Allyl bromide (1.19 ml, 13.7 mmol) was added slowly and the mixture was stirred for 1 h at -78°C. The reaction was allowed to warm to room temperature over 5 hours and was left at 4 °C for 3 days. The reaction was quenched with MeOH and sat. NH ₄ CI at 0 °C and stirred for 30 min. The mixture was extracted with EtOAc, the combined organic layers were washed with H ₂ 0, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 25% EtOAc in heptane) to give the title compound (507 mg, 20%) as a yellow liquid.

b) (2E/Z -2-(2-Allvl-4.6-dimethvl-indan-1 -vlidene)acetonitrile

Diethyl(cyanomethyl)phosphonate (642 μΙ, 4.1 mmol) was combined with THF (23 m!) to give and cooled to 0 °C. 1 M LHMDS in THF (4.08 ml, 4.08 mmol) was added dropwise and stirred for 45 min at 0 °C. The mixture was cooled to - 78 °C. A solution of 2-allyl-4,6-dimethyl-indan- 1 -one (545 mg, 2.7 mmol) in THF (4.5 ml) was added dropwise and the reaction mixture was stirred at -78 °C for 3 h. The reaction was warmed to -50 °C and stirred for 2 h. The reaction was warmed to 0 °C and stirred for 15 min and left at -20 °C for 3 days. The reaction mixture was stirred at 0 °C and allowed to warm to r.t. for 7 h. The reaction mixture was cooled to -50 °C then acetic acid (467 μΙ, 8.2 mmol) was added. The reaction mixture was extracted with DCM and the organic layers were washed with sat. NH ₄ CI, dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM) to give the title compound (522 mg, 91 %) as light yellow liquid. MS (ESI, m/z): 223.2 [(M+H)+]. c) (2E/Z)-2-r2-(3-Hvdroxypropyl)-4,6-dimethyl-indan-1-ylidene1a cetonitrile

(2E/Z)-2-(2-Allyl-4,6-dimethyl-indan-1 -yiidene)acetonitriie (355 mg, 1.6 mmol) was dissolved in THF (8 ml) under argon and the solution was to 0 °C. 0.5 M 9-BBN in THF (3.82 ml, 1.91 mmol, Eq: 1.2) was added and the reaction mixture was left warming up to room temperature in the ice bath. After 24 h, NaB0 ₄ (1 ,03 g, 6.7 mmo!) in. H ₂ 0 (15 m!) was added and the reaction mixture was left stirring vigorously for 4 h. The mixture was extracted with DCM, the combined organic phases were dried with MgS0 ₄ and evaporated. The residue was purified by flash chromatography eluting 0-90% EtOAc in heptane to afford the title compound (185 mg, 48%) as a yellow oil.

d) (2E/Z)-2-f2-(3-Bromopropvl)-4,6-dimethyl-indan-1 -vlidenelacetonitrile

(2E/Z)-2-[2-(3-Hydroxypropyl)-4,6-dimethyl-indan-1 -ylidene]acetonitrile (232 mg, 961 μητιοΙ) was dissolved in DCM (6 ml). The reaction mixture was cooled to 0°C and carbon tetra bromide (403 mg, 1 .2 mmol) was added followed by triphenylphosphine (315 mg, 1.2 mmol). The reaction mixture was allowed to warm to room temperature overnight. Si0 ₂ was added and the solvent was removed. The obtained powder was submitted to flash chromatography (silica gel, 0% to 30% EtOAc in heptane) to afford the title compound (252 mg, 86%) as light yellow oil. e) 2-r(3aS/R,8bF^S)-5J-Dimethyl-2.3,3a^-tetrahvdro-1 H-cvclopentara1inden-8b-yllacetonitri

(2E/Z)-2-[2-(3-Bromopropyl)-4,6-dimethyl-indan-1 -ylidene]acetonitrile (249 mg, 818 μιηοΙ), Bu ₃ SnH (339 μΙ, 1 .23 mmol) and AIBN (6.72 mg, 40.9 μιτιοΙ, Eq: 0.05) were combined with degassed benzene (41 ml). The reaction mixture was degassed and refluxed for 3.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 15% EtOAc in heptane) to afford the title compound (78 mg, 42%) as a colorless oil.

f) (3S)-6-f(5,7-Dimethyl-2,3.3a,4-tetrahvdro-1 H-cvclopentara1inden-8b-yl)methyl1-9-hvdroxy- 2,3-dimethvl-3,4-dihvdropvrazino[1 ,2-c1pyrimidine-1 ,8-dione

(1 :1 mixture of cis diastereomers)

The title compound was prepared in analogy to Example 1 by using 2-[(3aS/R,8bR/S)-5,7- dimethyl-2,3,3a,4-tetrahydro-1 H-cyclopenta[a]inden-8b-yl]acetonitrile instead of 2-(1- phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step h) to give the title compound as a white powder. MS (ESI, m/z): 408.3 [(M+H)+]. Example 117

(3S)-6-r(5J-Dimethyl-2.3.3a^-tetrahvdro-1 H-cvclopentafa1inden-8b-yl)methvn

dimethyl-3,4-dihvdropyrazinon ,2-c1pyrimidine-1 ,8-dione

(1 : 1 mixture of cis diastereomers)

The title compound was prepared in analogy to Example 1 16 by using tetralin-1-one instead of 4,6-dimethyl-2,3-dihydro-1 H-inden-1-one in step a) to afford the title compound as a white powder.

MS (ESI, m/z): 394.3 [(M+H)+j.

Example 118

(S)-9-Hvdroxv-2.3-dimethyl-6-(((6bS.9aR)-7.8.9.9a-tetrahvdro -6bH-cvclopentafblnaphthoi2.1 - dlfuran-6b-yl)methyl)-3,4-dihvdro-1 H-pyrazinoM ,2-clpyrimidine-l ,8(2H)-dione

(1 : 1 mixture of cis diastereomers) a) 2-[(2-Bromo-1 -naphthvQoxylcyclopentanone

2-Bromonaphthalen-1-ol (1.3 g, 6 mmol) and potassium carbonate (1.2 g, 8.9 mmol) were combined with acetone (30 ml) followed by the addition of 2-chlorocyclopentanone (1.2 ml, 1 1.9 mmol). The reaction mixture was refluxed for 3 h. The reaction mixture was extracted with EtOAc, the combined organic phases were washed with sat. Na ₂ C0 ₃ and brine, dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 30% EtOAc in heptane) to give the title compound (1.7 g, 94%) as a light grey oil.

b) (2E/Z)-2-[2-[(2-Bromo-1-naphthvl)oxvlcvclopentylidene1aceton itriie

Diethyl cyanomethylphosphonate (1.0 g, 5.6 mmol) was combined with THF (47 ml) and the mixture was cooled to 0 °C. 1 M LHMDS THF (5.6 ml, 5.6 mmol) was added drop wise and the mixture was stirred for 40 min at 0°C and then at -78 °C. A solution of 2-[(2-bromo-1 - naphthyl)oxy]cyclopentanone (1 .7 g, 5.6 mmol) in THF (9 ml) was added drop wise and the reaction mixture was stirred at -78 °C for 5.5 h. A solution was prepared in THF as above from diethyl cyanomethylphosphonate (1.01 g, 5.6 mmol) and 1 M LHMDS in THF (5.6 ml, 5.6 mmol) and was transferred via cannula to the reaction mixture at max. -65 °C internal temperature. The resulting mixture was stirred -78 °C for 1 h. The cooling bath was removed and the reaction mixture was allowed to warm to - 50°C. At that temperature acetic acid (641 μΙ, 1 1.2 mmol) was added. The reaction mixture was extracted with DCM, the combined organic layers were washed with sat. NH ₄ CI, dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM) to afford the title compound (1.8 g, 99%) as a colorless oil.

c) 2-((6bS/R.9aR/SV7.8.9.9a-Tetrahvdro-6bH-cvclopentafb1naphtho r2,1-d1furan-6b- yQacetonitrile

The title compound was prepared in analogy to 2-[(3aS/R,8bR/S)-5,7-dimethyl-2 _i 3 _i 3a _i 4 tetrahydro-1 H-cyclopenta[a]inden-8b-yl]acetonitrile (see Example 1 16) by using (2E/Z)-2-[2 [(2-bromo-1 -naphthyl)oxy]cyclopentylidene]acetonitrile instead of (2E/Z)-2-[2-(3-bromopropyl) 4,6-dimethyl-indan-1 -ylidene]acetonitrile in step e) to give the title compound as a pink oil.

(S)-9-Hvdroxy-2,3-dimethyl-6-(((6bS.9aR)-7.8.9.9a-tetrahv dro-6bH-cvclopentarblnaphthor2, 1 - dlfuran-6b-vl)methyl)-3,4-dihydro-1 H-pyrazinoM ,2-clpyhmidine-1 ,8(2H)-dione

(1 : 1 mixture of cis diastereomers)

The title compound was prepared in analogy to Example 1 by using 2-((6bS/R,9aR/S)- 7,8,9,9a-tetrahydro-6bH-cyclopenta[b]naphtho[2,1 -d]furan-6b-yl)acetonitrile instead of 2-(1- phenylcyclopentyl)acetonitrile in step c) and (6S)-1 ,6-dimethylpiperazin-2-one (see Example 13) instead of 6-ethyl-1 -methylpiperazin-2-one in step g) to give the title compound as an off- white powder. MS (ESI, m/z): 432.2 [(M+H)+]. Example 119

9-Hvdroxy-2,3-dlmethvi-6-r(1-phenylcvclopentyl)methvM-3,4 -dih

1 ,8-dione

a) 1-((t-Butyldimethylsilyl)oxy)-N-methylpropan-2-amine

TBS ' ^\ -^N^

H

To an ice-cooled solution of 1-((t-butyldimethylsilyl)oxy)propan-2-one (CAS 74685-00-0, 3 g, 16 mmol) in DCE (30 ml_) was added MeNH ₂ - HCI (2.15 g, 32 mmol) and AcOK (3.1 g,

32 mmol). The resulting mixture was stirred at 0 °C for 30 min, then NaBH(AcO) ₃ ( 6.7 g,

32 mmol) was added in portions. TLC monitored the reaction, after completion of the reaction, the mixture was quenched with water and extracted with DCM. The combined extracts were washed with brine, dried over sodium sulfate and concentrated to give a residue which was used to the next step directly without further purification. b) 5-(Benzyloxy)-6-hvdroxy-N-i 1-hvdroxypropan-2-yl)-N-methyl-2-((1- phenylcvclopentyl)methyl)pyrimidine-4-carboxamide

To a solution of 5-(benzyloxy)-6-hydroxy-2-((1-phenylcyclopentyl)methyl)pyrim idine-4- carboxylic acid (CAS 1616922-83-8 , prepared according to US 2014/0194431 , 450 mg, 1.08 mmol) in DCM (10 mL) was added HATU (1.24 g, 3.24 mmol) and DIPEA (414 mg, 3.24 mmol). The resulting mixture was stirred at 0 °C for 30 min, then a solution of 1 -((tert- butyldimethylsilyl)oxy)-N-methylpropan-2-amine (270 mg, 1.35 mmol) in DCM (1 mL) was added. Then, the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated and dissolved in THF/HCI (3 mL THF+0.9 mL HCI, 1 M) at 0 °C. The resulting mixture was stirred at room temperature for another 12 h, LCMS indicated that SM was consumed up and the mixture was purified by column chromatography eluting with DCM:MeOH = 20:1 to give the title product (350 mg, yield: 53%) as a light yellow solid.

MS (ESI, m/z): 476.2 [(M+H) ⁺ ]. c) 9-(Benzvioxy)-2,3-dimethvi-6-((1-phenylcvclopentyl)methyl)-3 ,4-dihvdro-1 H-pyrazinoH ,2- clpyrimidine-1 ,8(2H)-dione

To a solution of 5-(benzyloxy)-6-hydroxy-N-(1 -hydroxypropan-2-yl)-N-methyl-2-((1- phenylcyclopentyl)methyl)pyrimidine-4-carboxamide (50 mg, 0.105 mmol) in DCM (2 mL) was added Ph ₃ P (41 mg, 0.157 mmol) and DEAD (27 mg, 0.157 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC to give the title product (30 mg, yield: 59%) as a yellow solid.

MS (ESI, m/z): 458.2 [(M+H) ⁺ ]. d) 9-Hvdroxy-2,3-dimethyl-6-f(1 -phenylcvclopentyl)methvn-3,4→ ^■ dihydropyrazinon ,2- clpyrimidine-1 ,8-dione

A solution of 9-(benzyloxy)-2,3-dimethyl-6-((1 -phenylcyclopentyl)methyl)-3,4-dihydro-1 H- pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (80 mg, 0.16 mmol) in MeOH (5 mL) was

hydrogenated under 1atm H ₂ pressure for 12 h. After completion of the reaction, the mixture was filtered and concentrated to give the crude product, which was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title product as a light red solid (30 mg, yield: 46.8%).

MS (ESI, m/z); 368.1 [(M+H)*].

Example 120

7-Hvdroxy-10-((1 -phenylcvclopentyl)methyl)-3,4, 12,12a-tetrahvdro-1 H- pyrimidof1 ',6':4,5lpyrazinor2, 1-clf1 ,4loxazine-6,8-dione

a) Methyl 2-(1 -phenylcvclopentyl)acetimidate h drochloride

HCI (gas) was bubbled into a solution of 2-(1-phenylcyc!opentyl)acetonitrile (CAS 5407-84-1 , 1 g, 5.4 mmol) in anhydrous MeOH (20.0 mL) for 1 h under cooling with ice (0-5°C). Then the reaction was stirred at room temperature for 20 h. The solvent was evaporated and the residue was triturated with TBME (100 ml_) to give the title compound (1 g, 73%) as a pale white solid, which was used in the next step without further purification. H NMR (400 MHz, METHANOL-c/4) δ = 7.42 - 7.33 (m, 4 H), 7.31 - 7.24 (m, 1 H), 3.92 (s, 3 H), 2.95 (s, 2 H), 2.23 - 2.14 (m, 2 H), 2.13 - 2.03 (m, 2 H), 1.92 - 1.80 (m, 2 H), 1.78 - 1.66 (m, 2 H) ppm.

b) 8-(1-lmino-2-(1 -phenylcvclopentyl)ethyl)hexahvdropyrazinor2,1 -c1[1 ,4]oxazin-6(1 H)-one

Methyl 2-(1 -phenylcyclopentyl)acetimidate hydrochloride (86.6 mg, 0.342 mmol) was suspended in dry THF (8 ml). A solution of hexahydropyrazino[2, 1-c][1 ,4]oxazin-6(1 /- )-one (CAS 1154870-88-8, 80 mg, 0.513 mmol) and DIPEA (44.1 mg, 0.342 mmol) dissolved in dry THF (2 ml) were added in one portion to form a suspension. The mixture was stirred for 10 minutes. Acetic acid (20.5 mg, 0.342 mmol) was added and the mixture was stirred for 25 h at 20-25 °C while a precipitate was formed. The suspension was filtered and the filter cake was washed with anhydrous THF. The precipitate was collected to give the title compound (60 mg, 51 %) as a white solid.

MS (ESI, m/z): 342.1 [(M+Hf]. c) 7-Hvdroxy-10-(( 1 -phenylcvclopentyl)methyl)-3,4, 12,12a-tetrahvdro-1 H- pyrimidori ',6':4,51pyrazinof2,1-ciri,41oxazine-6 8-dione RW14-013F

To a suspension solution of 8-(1 -imino-2-(1-phenylcyclopentyl)ethyl)hexahydropyrazino[2,1 - c][1 ,4]oxazin-6(1 H)-one (30 mg, 0.088 mmol) in anhydrous THF (3 ml) was slowly added LiHMDS (1 M in THF, 0.528 mL, 0.528 mmol) over 5 min at 15 ~ 18 °C. The resulting brownish reaction solution was stirred for 10 min. Then a solution of diethyl oxalate (25.6 mg, 0.176 mmol) in THF (1 ml) was added over 30 min at 15 ~ 18 °C in portions to give a light orange suspension. The mixture was stirred 16 h at 15-18 °C. The mixture was quenched with 1 N HC!. aq and extracted with DCM (50 rnL*2). The combined organic layers were dried over a ₂ S0 ₄ , concentrated in vacuo to give the crude product which was purified by preparative HPLC (RP-18, MeCN/H ₂ 0 containig 0.225% HCOOH) to give the title compound (0.6 mg) as a light orange solid.

MS (ESI. m/z): 396.1 [(M+H) ⁺ ]. Example 121

(S)-9-Hvdroxy-3-(2-methoxyethyl)-2-methyl-6-((1-phenylcvclop entyl)methyl)-3,4-dihvdro-1 H- pvrazinofl ,2-c]pvrimidine-1 ,8(2H)-dione

a) (S)-Methyl 2-((t-butoxycarbonyl)amino)-4-methoxybutanoate

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-methoxybutanoic acid (CAS 104839-08- 9, 800 mg, 3.42 mmol) in acetone (10 mL) was added Mel (728 mg, 5.13 mmol) and K ₂ C0 ₃ (944 mg, 6.84 mmol). The resulting mixture was heated to 60 °C for 12 h. After completion of the reaction, the mixture was concentrated to afford a residue, the residue was diluted with DCM (100 mL) and the obtained organic layer was washed with brine (30 mL), dried with Na ₂ S0 ₄ and concentrated to give the crude product, the crude product was used to the next step directly (500 mg, crude). b) ( S)-4-Methoxy-2-(methylamino)butan-1 -ol

To a solution of LAH (230 mg, 6 mmol) in THF (5 mL) was added a solution of (S)-methyl 2-((f- butoxycarbonyl)amino)-4-methoxybutanoate (500 mg, 2 mmol) in THF (5 mL) dropwlse under 0 °C. The resulting mixture was heated to reflux for 12 h. After completion of the reaction, the mixture was diluted with ethyl acetate, then, carefully quenched with water (0.23 mL), 15% NaOH (0.23 mL) and water (0.7 mL). The mixture was allowed to warm to ambient

temperature, stirred for 30 min and filtered. The filtrate was concentrated to give the title product (250 mg, crude, used without further purification). c) (S)-9-Hvdroxy-3-(2-methoxyethyl)-2-methyl-6-((1 -phenvicvclopentyl)methyl)-3,4-dihvdro-1 H- pyrazinof 1 ,2-clpyhmidine-1 ,8(2H)-dione

The title product was prepared in analogy to Example 1 19, using

(S)-4-methoxy-2-(methylamino)butan-1-ol in step b) and obtained as a light red oil. MS (ESI, m/z): 412.1 [(M+H) ⁺ ]

Example 122

3,9-Dihydroxy-2-methyl-6-((1 -phenylcvclopentvnmethyl)-3.4-dihydro-1 H-pyrazinofl ,2- clpyrimidine-1 ,8(2H)-dione

a) 2-(Tosyloxy)ethyl 5-(benzyloxy)-6-hydroxy-2-((1 -phenylcyclopentyl)methyl)pyrimidine-4- carboxylate

To a solution of 5-(benzyloxy)-6-hydroxy-2-((1-phenylcyclopentyl)methyl)pyrim idine-4- carboxylic acid intermediate (CAS 1616922-83-8 , prepared according to US 20140194431 , 1.5 g, 3.71 mmol) and DIPEA (1.29 mL, 7.42 mmol) in anhydrous DCM (40 mL) was added HATU (1.7 g, 4.45 mmol). The mixture was stirred at 0 °C for 0.5 h, then 2-hydroxyethyl 4- methylbenzenesulfonate (882 mg, 4.08 mmol) was added and stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated under vacuum and purified by column chromatography on silica gel eluted PE/EA = 5/1 to 2/1 to provide the title compound (1.68 g, 75.3%) as a white solid.

MS (ESI, m/z): 603.2 [(M+Hf] b) 9-(Benzvloxv)-6-(( ^' 1 -phenvlcvclopentvl)methvl)-3.4-dihydropvrimido[6, 1-clf1.4loxazine-1 ,8- dione

To a solution of 2-(tosyloxy)ethyl 5-(benzyloxy)-6-hydroxy-2-((1-phenylcyclopentyl)methyl) pyrimidine-4-carboxylate (1.68 g, 2.79 mmol) in anhydrous DMF (75 mL) was added Cs ₂ C0 ₃ (1.37 g, 4.19 mmol). The mixture was stirred for 18 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EA. The organic extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude product, which was purified by column chromatography on silica gel eluted DCM/EA = 10/1 to 5/1 to provide the title product (798 mg, 66.5%) as a white solid.

MS (ESI, m/z): 431 .1 [(M+H) ⁺ ] c) 5-(Benzyloxy)-3-(2-hvdroxyethyl)-N-methyl-6-oxo-2-((1-phenyl cvclopentyl)methyl)-3,6- d i h yd ropyri mid ine-4-ca rboxam ide

A mixture of 9-(benzyloxy)-6-((1-phenylcyclopentyl)methyl)-3,4-dihydropyr imido[6,1 - c][1 ,4]oxazine-1 ,8-dione (370 mg, 0.86 mmol) in 27-32% CH ₃ NH ₂ in ethanol (30 mL) was stirred at 27-31 °C for 1 h. The solvent was removed under reduced pressure to give the crude product, which was triturated with PE/EA = 5/1 to give the title product (340 mg, 85.8%) as a white solid.

MS (ESI, m/z): 462.2 [(M+H) ⁺ ] d) 9-(Benzyloxy)-3-hvdroxy-2-methyl-6-((1-pheny[cvclopentyl)met hylV3,4-dihvdro-1 H- pyrazinoH ,2-c1pyrimidine-1 ,8(2/-/)-dione

To a solution of 5-(benzyloxy)-3-(2-hydroxyethyl)-A/-methyl-6-oxo-2-((1- phenylcyclopentyl)methyl)-3,6-dihydropyrimidine-4-carboxamid e (340 mg, 0.303 mmol) in anhydrous DCM (60 mL) was added Dess-Martin reagent (1.25 g, 2.95 mmol). The mixture was stirred at 25-32 °C for 3 h and most white precipitate was formed in reaction mixture. The mixture was diluted with DCM (150 mL) and washed with 2 N NaOH aq. (20 mL), the water layer was extracted with DCM (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and filtered, concentrated in vacuum to give a crude product. The crude product was purified by column chromatography on silica gei eiuted PE/EA from 5/1 to 2/1 to give the title product (15 mg, white solid).

MS (ESI, m/z): 460.2 [(M+H) ⁺ ] e) 3,9-Dihvdroxy-2-methyl-6-((1-phenylcvciopentyl)methyl)-3,4-d ihydro-1 H-pyrazino[1 ,2- clpyrimidine-1 ,8(2/-/)-dione

To a solution of 9-(benzyloxy)-3-hydroxy-2-methyl-6-((1-phenylcyclopentyl)met hyl)-3,4- dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione 14 (50 mg, 0.11 mmol) in MeOH (5 mL) and DCM (5 mL) was added Pd/C (10 mg). The mixture was stirred for 4 h at 23-28 °C under H ₂ (1 atm). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude product. The crude product was purified by prep-TLC (DCM/MeOH = 10/1 ) and reversed phase chromatography (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title compound (2.5 mg, 6.7%) as a pale white solid. MS (ESI, m/z): 370.1 [(M+H) ⁺ ]

Example 123

9-Hvdroxy-3-methoxy-2-methyl-6-((1-phenylcvclopentyl)methyl) -3,4-dih

clpyrimidine-1 ,8(2rt)-dione

a) 9-(Benzyloxy)-3-methoxy-2-methyl-6-((1 -phenylcvclopentyl)methyl)-3,4-dihydro-1 H- pyrazinofl ,2-clpyrimidine-l ,8(2H)-dione

To a stirred solution of 9-(benzyloxy)-3-hydroxy-2-methyl-6-((1-phenylcyclopentyl)met hyl)-3,4- dihydro-1 /-/-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione 14 (55 mg, 0.12 mmol) in MeOH (15 mL) was added TsOH H ₂ 0 (91.2 mg, 0.48 mmol), and the mixture was stirred for 120 h at 20-25 °C. The solvent was removed in vacuo and the residue was purified by prep-TLC (DCM/MeOH = 10/1 ) to give the desired product (45 mg, 79.3%) as a white solid.

MS (ESI, m/z): 474.1 [(M+H) ^* ] b) 9-Hvdroxv-3-methoxv-2-methvl-6-((1-phenylcyclopentvl)methyl) -3,4-dihydro-1 /-/- pyrazinofl ,2-clpyrimidine-1 ,8(2H)-dione

A mixture of 9-(benzyloxy)-3-methoxy-2-methyl-6-((1 -phenylcyclopentyl)methyl)-3,4-dihydro- 1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione 16 (45 mg, 0.095 mmol) and 10% Pd/C (wet) (20 mg) in MeOH (15 ml_) was stirred at 6-18 °C for 2.0 h under H ₂ . The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0,225% HCOOH) to give the title product (1 1 mg, 30.5%) as a pale white solid.

MS (ESI, m/z): 384.0 [(M+Hf]

Example 124

9-Hvdroxy-3-(methoxymethyl)-2-methyl-6-((1-phenylcvclopentvi )methvi)-3,4-dihvdro-1 H- pvrazinofl ,2-c]pyrimidine-1 ,8(2/-/)-dione

The title compound was prepared in analogy to Example 121 using 2-amino-3- methoxypropanoate hydrochloride in step b) and obtained as a white solid.

MS (ESI, m/z): 398.0 [(M+H) ⁺ ] Example 125

(fl)-9-Hydroxy-3-(2-methoxyethyl)-2-me

pyrazinofl ,2-c1pyrimidine-1 ,8(2/-/)-dione

a) 9-(Benzyloxy)-3-(2-methoxyethyl)-2-methyl-6-((1 -phenylcvclopentyl)methyl)-3,4-dihvdro-1 H- pyrazinon ,2-c1pvrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 119 using 4-methoxy-2- (methylamino)butan-l -ol (CAS 1341671 -97-3) in step b), without the deprotection step d) and obtained as a white solid.

MS (ESI, m/z): 502.2 [(M+H) ⁺ ] b) (R)-9-Hvdroxy-3-(2-methoxyethyl^

1 /-7-pyrazinof ,2-clpyrimidine-1 ,8(2H)-dione

The enantiomers of the product in step a) were separated by SFC (column: AS-10 urn, AS (250 mm ^* 30 mm, 10 urn particle), conditions: 30% EtOH, 0.1% NH ₃ -H ₂ 0, 100 bar 70% C0 ₂ , 35 °C, flow rate: 60 mL/min, wavelength: 220 nm). The separated products were then deprotected in analogy to Example 119, step d). Assignment of absolute configuration was done by comparison to Example 121. The product was obtained as a pale-red oil.

MS (ESI, m/z): 412.1 [(M+H) ^' ]

Example 126

(S)-6-((1-(3-Ethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-met hyl-3-phenyl-3,4-dihvdro-1 H- pyrazinofl ,2-c1pyrimidine-1 ,8(2H)-dione

Ph

a) 2-(1 -(3-Bromophenyl)cyclopentyl)acetonitrile

Potassium feri-butoxide (88.7 g, 792 mmol) was suspended in THF (600 ml) and cooled to -75 °C. TOSMIC (77 g, 396 mmol) dissolved in THF (600 ml) was added drop wise over 10 min. The resulting dark brown solution was stirred for 20 min at -75 °C. 1-(3-

Bromophenyl)cyclopentanecarbaldehyde (CAS 1267906-1 1 -5, 50 g, 198 mmol) dissolved in THF (300 ml) was added over 15 min. The mixture was stirred for 90 min at -75 °C. Methanol (400 mi) was added drop wise. The cooling bath was removed and allowed the mixture was warmed to 5 X and then heated for 90 min under reflux. The reaction mixture was washed with water and extracted with ethyl acetate, the organic layer was washed with brine, dried with Na ₂ SQ ₄ and filtered. The obtained filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (PE/EA = 3/1 ) to give the title compound (36 g, 69%) as a yellow oil. b) 2-(1-(3-Bromophenyl)cyclopentyl)acetimidamide hydrochloride

To a stirred suspension of NH ₄ CI (18.9 g, 351 mmol) in dry toluene ( 50 mL) was added trimethyl aluminum (2 M in toluene, 176 mL, 351 mmol) at 5 °C. Then, the mixture was warmed to 25 °C and stirred for 2 h. A solution of 2-(1 -(3-bromophenyl)cyclopentyl) acetonitrile (31 g, 117 mmol) in toluene (150 mL) was added to the above reaction mixture and stirred for 14 h at 80 °C. After completion of the reaction, it was quenched with suspension of silica gel (35 g) in DCM (50 mL), reaction mixture was stirred for half an hour at 25 °C and filtered through sintered funnel. The cake was washed with methanol. The combined filtrate was concentrated under reduced pressure to obtain the title compound that was used without further purification in the next step. c) 2-((1 -(3-Bromophenyl)cvclopentyl)methyl)-5,6H ^■ d i h yd roxyp yri m id i ne-4-ca rboxylate

To a stirred solution of 2-(1-(3-bromophenyl)cyclopentyl)acetimidamide hydrochloride (10 g, 31 mmol) and 4-tert-butyl 1 -methyl 2-(benzyloxy)-3-hydroxyfumarate (13.6 g, 44 mmol) in methanol (50 ml_) was added sodium methoxide (7 g, 93 mmol) at 0 °C, then the reaction mixture was allowed to warm to 25 °C and stirred for 16 h. The reaction was quenched with 1 N HCI and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound that was used without further purification in the next step. d) 2-(f H3-Bromophenyl)cyOlopentv' methy^ acid

To a stirred solution rerr-butyl-2-((1 -(3-bromophenyl)cyclopentyl)methyl)-5 _> 6- dihydroxypyrimidine-4-carboxylate (10 g, 22 mmol) in THF-water (2: 1 , 150 mL) was added LiOH (5.2 g, 220 mmol), then the mixture was stirred at 80 °C for 18 h. The mixture was concentrated almost to dryness, water was added and extracted with ethyl acetate to remove non acidic impurities. The aqueous layer was acidified with (1 N) HCI to a pH around 5 to 6 and then extracted with DCM. The organic layer was dried with Na ₂ S0 ₄ and concentrated to obtain the title compound (4.5 g, crude) as a yellow solid.

MS (ESI, m/z): 393.1 [(M+Hf] e) (S)-Methyl 2-amino-2-phenylacetate hydrochloride

Ph

O To a suspension of (S)-2-amino-2-phenylacetic acid (10 g, 66.15 mmol) in anhydrous MeOH (150 mL) was slowly added SOCI ₂ (7.22 mL, 99.22 mmol) at 0 °C. Then the mixture was stirred for 18 h at 60-70 °C. The solvent was removed in vacuo to give the title compound (13 g) as a white solid, which was used to the next step without further purification. f) (S)-Methyl 2-((tert-butoxycarbonyl)amino)-2-phenylacetate

Ph

To a solution of (S)-methyl 2-amino-2-phenylacetate hydrochloride (13 g, 66.2 mmol) in MeOH (300 mL) was slowly added TEA (36.8 mL, 264.8 mmol) and Boc ₂ 0 ( 8 g, 82.8 mmol) at 0 °C. Then the mixture was stirred for 2 h at 8-18 °C. The solvent was removed in vacuo and the residue was dissolved with EA (500 mL), the organic layer was washed with 10% aq. citric acid (100 mL), brine (100 mL), and dried over Na ₂ S0 ₄ . After filtration, the filtrate was concentrated in vacuo to give the crude product, which was triturated with PE/EA = 50/1 to give the title compound (15.5 g) as a white solid, which was used in the next step without further purification. g) (S)-9-(Benzyloxy)-6-((1 -(3-bromophenyl)cvclopentyl)methyl)-2-methyl-3-phenyl-3,4-di hydro-

1 H-pvrazinof1 ,2-c]pyrimidine-1 ,8(2H)-dione

Ph

The title compound was obtained in analogy to Example 121 using (S)-methyl 2-((tert- butoxycarbonyl)amino)-2-phenylacetate in step b) and 2-((1 -(3- bromophenyl)cyclopentyl)methyl)-5,6-dihydroxypyrimidine-4-ca rboxylic acid in step c) without final cleavage of the OBn group. The title compound was obtained as a light yellow solid. MS (ESI, m/z): 598.2 [(M+Hf] h) (S)-2,9-Dimethyl-3-phenyl-6-((1 -(3^

pyrazinon ,2-clpyrimidine-1 ,8(2H)-dione

A mixture of (S)-9-(benzyloxy)-6-((1-(3-bromophenyl)cyclopentyl)methyl)-2 -methyl-3-phenyl- 3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (165 mg, 0.276 mmol), 4,4,5,5- tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (106 mg, 0.69 mmol), Pd(PPh ₃ ) ₄ (31.9 mg,

0.0276 mmol) and Na ₂ C0 ₃ (73 mg, 0.69 mmol) in THF/H20 (5.0 mL/0.5 mL) was stirred for 12 h at 70-80 °C. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EA (2 x 75 mL). The organic extracts were combined and washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the crude product, which was purified by prep-TLC (PE/EA = 1/8) to obtain the title compound (1 10 mg, 73.3 %) as a yellow solid.

MS (ESI, m/z): 546.2 [(M+H) ⁺ ] i) (S)-9-(Benzyloxy)-6-((1-(3-ethylphenvDcvciopentyl)methvi)-2- methyl-3-phenyl-3,4-dihvdro-

1 H-pyrazino[1 ,2-clpvrimidine-1 ,8(2/-/)-dione

Ph

A mixture of (S)-2,9-dimethyl-3-phenyl-6-((1-(3-vinylphenyl)cyclopentyl)m ethyl)-3,4-dihydro- 1 H-pyrazino[1 ,2-c]pyrimidine-1.8(2H)-dione (1 0 mg, 0.202 mmol) and 10% Pd/C (wet) (25 mg) in ethyl acetate (15 mL) was stirred at 20-25 °C for 3.5 h under H ₂ . The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (1 10 mg, 99.6%) as a light yellow oil, which was used in the next step without further purification. MS (ESI, m/z): 548,2 [(M+H) ⁺ ] i) (S)-6-((1-(3-Ethylphenyl)cvclope^

pyrazinofl ,2-c1pyrimidine-1 ,8(2H)-dione

To a stirred solution of (S)-9-(benzyloxy)-6-((1-(3-ethy!phenyl)cyclopenty!)methy!)-2 -methy!^ phenyl-3,4-dihydro-1 /-/-pyrazino[1 _J 2-c]pyrimidine-1 ,8(2/- )-dione (110 mg, 0.201 mmol) in MeOH (6 mL) was added cone. aq. HCI (6 mL) at 0 °C and the mixture was stirred for 20 h at 8-17 °C. After completion of the reaction, the solvent was concentrated and ice (-20 g) was added, the mixture was extracted with 10% methanol in DCM (50 mL x 2), the organic layer was dried and concentrated. The crude product was purified by prep-HPLC (RP-18,

MeCN/H ₂ 0 containing 0.225% HCOOH) to give the titie compound (22.8 mg, 24.7%) as a red solid. MS (ESI, m/z): 458.1 [(M+Hf] Example 127

(S)-9-(Benzyloxy)-2-methyl-3-phenyl-6-((1-(m-tolyl)cvclopent yl)methylV3,4-dihydro-1 H- pyrazinofl ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was obtained in analogy to Example 126 using 2,4,6-trimethyl-1 ,3,5,2,4,6- trioxatriborinane in step h) without the following hydrogenation step and obtained as a pale white solid.

MS (ESI, m/z): 444.1 [(M+H) ⁺ ] Example 128

(S)-6-((1 -(3-Ethylphenvncvclopentyl)methyl)-9-hvdroxy-3-(2-methoxyeth vn-2-meth dihydro-1 H-pyrazino[1 ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 126 from (S)-2-((tert- butoxycarbonyl)amino)-4-methoxybutanoic acid and obtained as a colorless oil. MS (ESI, m/z): 440.2 [(M+H) ⁺ ]

Example 129

(S)-9-Hvdroxy-2,3-dimethyl-6-((1 -(3-vinylphenyl)cyclopentyl)methyl)-3,4-dihydro-1 H- pyrazinoH ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 126 from (S)-methyl 2-((tert- butoxycarbonyl)amino)propanoate without the hydrogenation step i) and obtained as a pale red solid. MS (ESI, m/z): 394.1 [(M+H) ⁺ ] Example 130

(/?)-6-((1 -(3-Ethylphenyl)cyclopenM

dihydro-1 H-pyrazino[1 ,2-c|pvrimidine-1 ,8(2H)-dione

5 The title compound was prepared in analogy to Example 126 from (S)-2-amino-3- methoxypropanoic acid and obtained as a white solid.

MS (ESI, m/z): 426.1 [(M+H) ⁺ ] I rr»._.~._ i _

l u [..Ααι ι ιμΐίί u i

( )-3-(Ethoxvmethyl)-6-((1-(3-ethylphenyl)cvclopentyl)methyl)- 9-hydroxv-2-methyl-3,4- dihydro-1 /-/-pyrazinofl ,2-c†pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 126 from (S)-2-amino-3-5 ethoxypropanoic acid and obtained as a white solid.

MS (ESI, m/z): 440.2 [(M+Hf] Example 132

(S)-6-((1 -(3-Ethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-methyl-3-phe neth^

pyrazinoH ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 126 from (S)-2-amino-3- methylbutanoic acid and obtained as a reddish solid.

MS (ESI, m/z): 424.1 [(M+H) ⁺ ] Example 133

(S)-6-((1-(3-Ethylphenyl)cvclopentyl)methvn-9-hvdroxy-3-isob utyl-2-methyl-3.4-dihvdro-1 H- pyrazinofl ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 126 from (S)-4-methyl-2- (methylamino)pentanoic acid and obtained as a reddish solid.

MS (ESI, m/z): 438.1 [(M+H) ⁺ ] Example 134

pyrazinoM ,2-clpyrimidine-1 ,8(2 -/)-dione

The title compound was prepared in analogy to Example 126 from (S)-2-(methylamino)-3- phenylpropanoic acid and obtained as a reddish solid.

MS (ESI, m/z): 472.1 [(M+H) ⁺ ] Example 135

(SV6-((1 -(3-Ethv!phenvncvclopentyl)methylV9-hvdroxy-2-methyl-3-phene thyl-3,4-dihvdro-1 '- pyrazinof ,2-clpyrimidine-1 ,8(2/-/)-dione

The title compound was prepared in analogy to Example 126 from (S)-2-amino-4- phenylbutanoic acid and obtained as a reddish solid.

MS (ESI, m/z): 486.2 [(M+H) ⁺ ] Example 136

(S)-6-((1 -(3-Ethylphenyl)cvclopentyl)m

pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione

a) (5)-1-((tert-Butyldimethylsilyl)oxy)propan-2-amine

To an ice-cooled solution of (S)-2-aminopropan-1 -ol (1.3 g, 17.3 mmol) in DCM (20 ml.) was DIPEA (2.8 g, 21.6 mmol) and TBSCI (2.6 g, 17.3 mmol). Then the mixture was stirred for 12 h at 5-15 °C. The mixture was washed with water (50 mL) and brine (20 m!_). The organic phase was separated and dried over sodium sulfate and concentrated to give 2.2 g of the crude title compound which was used without further purification in the next step. b) (S)-1-((terf-Butyld!methylsily!)oxy)-A/-!Sopropy!propan-2-am ine

To an ice-cooled solution of (S)-1-((tert-butyldimethylsilyl)oxy)propan-2-amine (1.0 g,

5.3 mmol) in DCE (30 mL) was added acetone (0.61 g, 10.6 mmol) at 0 °C, the resulting mixture was stirred for 30 min at 0 °C. Then NaBH(OAc) ₃ (2.2 g, 10.6 mmol) was added. The reaction mixture was stirred at 5-15 °C for 15 h. The mixture was quenched with MeOH (50 mL) and then filtered. The filtrate was concentrated and the residue was re-dissolved in DCM (50 mL), which was neutralized with saturated aq NaHC0 ₃ and the organic was separated. The organic phase was dried over sodium sulfate and concentrated to give 1 .1 g of the title compound which was used in the next step without further purification. c) Ethyl 2-cvano-2-(1-(3-ethylphenyl)cvclopentyl)acetate

To a suspension of CuCN (20.8 g, 230.4 mmol) in dry THF (120 mL) was added 1 M (3- ethylphenyl)magnesium bromide (CAS 50777-51-0) in THF (432 mL, 432 mmol) while stirring vigorously at 0 °C. Then the ice bath was removed, and the mixture was warmed to 20 °C and stirred for 1 h. The mixture was then cooled to 0 °C and a solution of 2-cyano-2- cyciopentylideneacetate (CAS 5407-83-0, 28.0 g, 160 mmol) in dry THF (120 mL) was added. The ice bath was removed and the reaction was warmed to 20 °C and stirred for 12 h. The mixture was quenched by the addition of Na ₂ C0 ₃ :H ₂ 0 (1 :1 , 1200 mL) and extracted with

EtOAc (1200-3 mL). The combined organic phases was dried with Na ₂ S0 ₄ and evaporated to give the crude product which was purified by silica gel column chromatography (PE/EA = 30/1 ) to give the title compound (30 g, 68%) as a yellow oil. d) 2-(1 -(3-Ethylphenyl)cvclopentyl)acetonitrile

To a stirred solution of ethyl 2-cyano-2-(1 -(3-ethylphenyl)cyclopentyl)acetate (20 g, 70 mmol) in DMSO (200 mL) was added NaCI (1.46 g, 25 mmol) and H ₂ 0 (3.01 g, 167.3 mmol), then the reaction mixture was heated to 160 °C and stirred for 12 h. The mixture was diluted with H ₂ 0 (400 mL) and extracted with ethyl acetate (three times 600 mL). The combined organic layers were washed with H ₂ 0 (400 mL) and with brine (400 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to give a brown oil, which was purified by silica gel column chromatography (PE/EA = 30/1 ) to give the title compound (10 g, 66%) as a yellow oil. e) 5-(Benzyloxy)-2-((1-(3-ethylphenv0cvclopentyl)methv^

acid

The title compound was obtained in analogy to Example 126, steps b)-d) from 2-(1 -(3- ethylphenyl)cyclopentyl)acetonitrile and obtained as a white powder.

MS (ESI, m/z); 433.1 [(M+H) ⁺ ] f) (S)-5-(Benzyloxy)-N-(1-((tert-butyldimethylsilyl)oxy)propan- 2-yl)-2-((1-(3- ethylphenyl)cyclopentyl)methyl)-6-hydroxy-N-isopropylpyrlmid ine-4-carboxamide

To a solution of 5-(benzyloxy)-2-((1-(3-ethylphenyl)cyclopentyl)methyl)-6-hyd roxypyrimidine-4- carboxylic acid (200 mg, 0.46 mmol) in DMF (5 mL) was added HATU (349.6 mg, 0.92 mmol) and DIPEA (1 18.7 mg, 0.92 mmol). The resulting mixture was stirred at 0 °C for 30 min and then a solution of (S)-1 -((tert-butyldimethylsilyl)oxy)-A/-isopropylpropan-2-amine (212 mg, 0.92 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 5-15 °C for 2 h. The mixture was quenched with water (10 mL) and extract with ethyl acetate (20 mL*2). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with PE/EA = 5/1 to 1/1 to give 180.0 mg of the desired product as a white solid.

MS (ESI, m/z): 646.2 [(M+H) ⁺ ] g) (S)-5-(Benzyloxy)-2-((1-(3-ethylphenyl)cvclopentyl)methyl)-A /-(1-hvdroxypropan isopropyl-6-oxo-3,6-dihvdropyrimidine-4-carboxamide

To a solution of (S)-5-(benzyloxy)-A/-(1-((tert-butyldimethylsilyl)oxy)propan -2-yl)-2-((1 -(3- ethylphenyl)cyclopentyl)methyl)-6-hydroxy-A/-isopropylpyrimi dine-4-carboxamide (180 mg, 0.28 mmol) in THF (2 ml_) was added aq. HCI (0.42 ml_, 0.42 mmol, 1 M). The reaction mixture was stirred at 5-15 °C for 15 h. The mixture was concentrated to dryness to give the title compound as a yellow solid which was used in the next step without further purification. h) (S)-9-(Benzvioxy)-6-((1-(3-ethylphenyl)cvclopentyl)methyl)-2 -isopropyl-3-methyl-3,4- dihvdro-1 H-pyrazinoM ,2-clpyrimidine-1 ,8(2H)-dione

To an ice-cooled solution of (S)-5-(benzyloxy)-2-((1-(3-ethylphenyl)cyclopentyl)methyl)-N -(1 hydroxypropan-2-yl)-A/-isopropyl-6-oxo-3,6-dihydropyrimidine -4-carboxamide (140 mg, 0.26 mmol) in DCM (5 mL) was added triphenylphosphine ( 36 mg, 0.72 mmol) and DEAD (90 mg, 0.52 mmol). The resulting mixture was stirred at 5-15 °C for 4 h. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with PE/EA 1/2 to DCM/MeOH = 20/1 to give 80 mg of the title compound as a yellow oil. MS (ESI, m/z): 514.3 [(M+H) ⁺ ] i) (S)-6-(n-(3-Ethylphenyl)cvc[opentyl)methyl)-9-hvd

pyrazinoH ,2-clpyrimidine-1 ,8(2H)-dione

To an ice-cooled solution of (S)-9-(benzy!oxy)-6-((1-(3-eihyiphen

isopropyl-3-methy|-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (80 mg,

0.16 mmol) in MeOH (2.5 mL) was added cone. aq. HCI (2.5 mL). Then the mixture was stirred for 15 h at 5-15 °C. The mixture was concentrated. The residue was purified by prep- HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give 18.5 mg of the title compound as a white solid.

MS (ESI, m/z): 424.1 [(M+H) ⁺ ]

Example 137

(S)-Methyl 2-(6-((1-i3-ethylphenyl)cvclopentyl)methylV9-hvdroxy-2-methy l-1 ,8-dioxo-2, 3,4,8- tetrahydro-1 H-pyrazino[1 ,2-c]pyrimidin-3- acetate

a) (S)-tert-Butyl 3-(benzylamino)-4-hvdroxybutanoate

To a solution of (S)-ferf-butyl 3-amino-4-hydroxybutanoate (CAS 440321-02-8, 800 mg. 4.6 mmol) in MeOH (5 mL) was added benzaldehyde (484 mg, 4.6 mmol). After being stirred for 2 h, NaBH ₃ CN (579 mg, 9.2 mmol) was added. The resulting mixture was stirred at 5-15 °C for 4 h and the mixture was purified by reversed phase chromatography to give 830 mg of the title compound as a colorless oil. MS (ESI, m/z): 266.2 [(M+H) ⁺ ] b) (S)-ferf-Butyl 4-hydroxy-3-(methylamino)butanoate

Pd(OH) ₂ (60 mg) was added to a solution of (S)-terf-butyl 3-(benzyl(methyl)amino)-4- hydroxybutanoate (610 mg. 2.2 mmol) in MeOH (20 ml_). The resulting mixture was hydrogenated at 5-15 °C under 45 psi for 15 h. The catalyst was removed by filtration and the filtrate was concentrated to give 300 mg of the title compound as a colorless oil. c) (SHerf-Butyi 2-(9-(benzyloxy)-6-((1-(3-ethylphenyl)cvclopentyl)methyl)-2- methyl-1.8-dioxo-

2,3,4,8-tetrahvdro-1 H-pyrazinofl ,2-c]pyrimidin-3-vl)acetate

The title compound was prepared in analogy to Example 136 without the deprotection steps from (S)-rerf-butyl 4-hydroxy-3-(methylamino)butanoate and was obtained as a colorless solid.

MS (ESI, m/z): 586.3 [(M+H) ⁺ ] d) (S)-Methyl 2-(6-((1 -(3-ethylphenyl)cyclopentyl)methyl)-9-hydroxy-2-methyl-1 ₁ 8-dioxo- 2,3,4,8-tetrahvdro-1 H-pyrazinoM ,2-clpyrimidin-3-yl)acetate

To an ice-cooled solution of (S)-tert-butyl 2-(9-(benzyloxy)-6-((1 -(3- ethylphenyl)cyclopentyl)methyl)-2-methyl-1 , 8-d ioxo-2 , 3 , 4, 8-tetrahyd ro- 1 H-pyrazino[1 ,2- c]pyrimidin-3-yl)acetate (60 mg, 0.12 mmol) in MeOH (1 mL) was added cone, aq HCI (1 mL). Then the mixture was stirred for 15 h at 5-15 °C. The mixture was concentrated, and the residue was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title product (27 mg) as a white solid.

MS (ESI, m/z): 454.2 [(M+H) ⁺ ]

Example 138 and Example 139

(S)-6-((1 -(3-Ethylphenyl)cvclopentyl)methyl)-9-hydroxy-3-(3-methoxypr opyl)-2-methyl-3,4- dihvdro-1 H-pyrazino[1 ,2-clpyrimidine-1 ,8( ^' 2 -/)-dione

( )-6-((1 -(3-Ethylphenyl)cvclopentyl)methyl)-9-hvdroxy-3-(3-methoxypr opyl)-2-methyl-3,4- dihydro-1 /-/-pyrazinoM ,2-clpyrimidine-l ,8(2H)-dione

a) 2-Bromo-5-methoxypentanoate

To a solution of methyl 5-methoxypentanoate (CAS 52546-36-8, 2.0 g, 13.7 mmol) in THF (30 mL) at -78 °C was added TMSCI (2.2 g, 20.5 mmol) and then LDA (8.6 mL, 17.1 mmol). The mixture was stirred at -78 °C for 1 h upon which time a solution of NBS (4.85 g,

27.4 mmol) in THF (20 mL) was added. The mixture was stirred for 30 min at -78 °C. The mixture was diluted with EA (50 mL) and a saturated solution of NH ₄ CI (50 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with PE and filtered. The filtrate was concentrated to give 3.0 g of the title compound as a yellow oil, used directly in next step. b) Methyl 2-(benzyl(methyl)amino)-5-methoxypentanoate

To a solution of methyl 2-bromo-5-methoxypentanoate (3.0 g. 13.3 mmol) in MeCN (50 mL) was added N-methyl-1 -phenylmethanamine (2.4 g, 20.0 mmol) and potassium carbonate (5.5 g, 40 mmol). The resulting mixture was stirred at 5- 5 °C for 15 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with PE/EA from 30/1 to 20:1 to give 2.5 g of the title compound as a yellow oil. e) 2-(Benzyl(methyl)amino)-5-methoxypentan-1 -ol

To an ice-cooled solution of LAH (358 mg, 9.4 mmol) in THF (20 mL) was a solution of methyl 2-(benzyl(methyl)amino)-5-methoxypentanoate (2.5 g, 9.4 mmol) in THF (20 mL). Then the mixture was stirred for 2 h at 0 °C. The mixture was diluted with EA (100 mL) under 0 °C. The mixture was quenched with 0.35 mL water, followed by addition of 0.35 mL 15% NaOH and

1.1 mL water. After being stirred for 30 min, anhydrous sodium sulfate was added. The resulting suspension was filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography eluting with PE/EA from 10/1 to 1/1 to give

2.2 g of the title compound as a colorless oil. f) 5-Methoxy-2-(methylamino)pentan-1 -ol

To a solution of 2-(benzyl(methyl)amino)-5-methoxypentan-1 -ol (2.2 g, 9.3 mmol) in MeOH (50 mL) was added Pd(OH) ₂ /C (220 mg). The resulting mixture was hydrogenated at 50 psi for 12 h. The catalyst was removed by filtration, the filtrate was concentrated to give 1 .4 g of the title compound as a colorless oil. g) (S)-9-(Benzyloxy)-6-((1-(3-ethylphenyl)c^^

3,4-dihydro-1f/-pyrazino[1 ,2-c1pyrimi ine-1 ,8(2H)-dione

(ft)-9-(Benzyloxy)-6-((1-(3-ethylphenylte^

dihydro-1 H-pyrazinofl ,2-clpyrimidine-1 ,8(2H)-dione

The title compounds were prepared in analogy to Example 136 without the deprotection steps from 5-methoxy-2-(methylamino)pentan-1-ol. Enantiomers were separated by SFC (column: AD-10 um, AD (250 mm ^* 30 mm, 10 μιτι particle), conditions: 30% MeOH, 0.1 % NH ₃ .H ₂ 0, 100 bar 70% C0 ₂ , 35 °C, flow rate: 60 mUmin, wavelength: 220 nm). The title compounds were obtained as light yellow solids.

MS (ESI, m/z): 544.3 [(M+Hf] h) (S)-6-((1-(3-Ethylphenyl)cvclopentvnmethyl)-9-hvdroxy-3-(3-m ethoxypropyl)-2-methyl-3,4- dihydro-1 H-pyrazinoM ,2-clpvrimidine-1.S^ffi-dione

(R)-6-((1 -(3-Ethylphenyl)cvclopent

dihvdro-1 /-/-pyrazinof 1 ,2-c1pyrimidine-1 ,8(2H)-dione

The title compounds were obtained in analogy to the final deprotection step of Example 136 from (S)-6-((1 -(3-Ethylphenyl)cyclopentyl)methyl)-9-hydroxy-3-(3-methoxypr opyl)-2-methyl- 3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione and (R)-6-((1-(3- Ethylphenyl)cyclopentyl)methyl)-9-hydroxy-3-(3-methoxypropyl )-2-methyl-3,4-dihydro-1 H- pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione as white solids.

MS (ESI, m/z): 454.1 [(M+H) ⁺ ] Example 140 and Example 141

(S)-5-(Benzvloxv)-2-((1-(3-bromophenvl)cvclopentvl)methvl)-6 -hvdroxv-A/-(2-hydroxv-1 - phenylethvl)-A/-methvlpyrimidine-4-carboxamide and (R)-5-(benzyloxy)-2-((1-(3- bromophenvl)cvclopentvl)methvl)-6-hvdroxv-A/-(2-hvdroxv-1 -phenvlethvl)-A/-methylpvrimidine- 4-carboxamide and

The title compounds were prepared in analogy to Example 122 from 5-(benzyloxy)-2-((1 -(3- ethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carbox ylic acid. The benzyl protected intermediate (in analogy to step Example 122 d) was separated into the corresponding enantiomers via SFC (column: OD-10 urn, OD (250 mm*30 mm, 10 urn particle), conditions: 40% MeOH, 0.1 % NH ₃ .H ₂ 0, 100 bar 60% C0 ₂ , 35 °C, flow rate: 70 mL/min, wavelength: 220 nm). The title compounds were obtained as light red solids.

MS (ESI, m/z): 398.2 [(M+H) ⁺ ]

Example 142

(S)-9-Hvdroxy-2,3-dimethyl-6-((1-(3-(prop-1 -en-2-yl)phenyl)cvclopentyl)methyl)-3,4-dihvdro- 1 H-pyrazinof 1 ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 129 using prop-1-en-2-ylboronic acid and obtained as an off-white solid.

MS (ESI, m/z): 408.2 [(M+H) ⁺ ] Example 143

(S)-9-Hvdroxv-6-((1-(3-isopropvlphenvl)cvclopentvl)methvl)-2 ,3-dimethvl-3,4-dihydro- ·//-/- pyrazino[ ,2-clpyhmidine-1 ,8(2 -/)-dione

a) (S)-9-(Benzyloxy)-2,3-dimethyl-6-((1 -(3-(prop-1-en-2-vnphenyl)cvclopentyl)methyl)-3 dihydro-1 H-pyrazinoF1 ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 142 without deprotection of the OBn group and was obtained as a yellow solid.

MS (ESI ⁺ ) [(M+H) ⁺ ]: 498.2. b) (SVg-fBenzyloxyVe-fd-O-isopropylphenvDcvclopentvDmethvD^^-di methyl-S^-dihvdro- 1 H-pyrazinof1 .2-clpyrimidine-1 ,8(2H)-dione

To a solution of (S)-9-(benzyloxy)-2,3-dimethyl-6-((1 -(3-(prop-1-en-2- yl)phenyl)cyclopentyl)methyl)-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (60 mg, 0.012 mmol) in ethyl acetate (5 ml_) was added Pd/C (3 mg). Then the mixture was

hydrogenated for 15 h at 5-15 °C under 1 atm. The catalyst was removed by filtration and the filtrate was concentrated to give 60 mg of the title compound as a colorless solid.

MS (ESI, m/z): 500.3 [(M+Hf] c) (S)-9-Hydroxy-6-((1 -(3-isopropylphenyl)cvclopentyl)methyl)-2,3-dirnethyl-3,4-cl ihvdro-1 H- pyrazinori ,2-clpyrimidine-1 ,8(2H)-dione

To an ice-cooled solution of (S)-9-(benzyloxy)-6-((1 -(3-isopropylphenyl)cyclopentyl)methyl)- 2,3-dimethyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (60 mg, 0.12 mmo!) in MeOH (1 mL) was added cone, aq HCI (1 mL). Then the mixture was stirred for 15 h at 5-15 °C. The mixture was concentrated, and the residue was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give 24.2 mg of the title compound as a white solid.

MS (ESI, m/z): 410.1 [(M+H) ⁺ ]

Example 144 and Example 145 (S)-6-((R)-1-(1-(3-Ethylphenyl)cvclopentyl)-2-hvdroxyethyl)- 9-hvdroxy-2,3-dimethyl-3,4- dihydro-1 H-pyrazinoM .2-clpvrimidine-1 ,8(2H)-dione,

(S)-6-((S)-1 -(1 -(3-ethvlphenvl)cvclopentvl)-2-hvdroxvethyl)-9-hydroxv-2,3-d imethyl-3.4- dihydro-1 H-pyrazinoH ,2-c1pyrimidine-1 ,8(2H)-dione

a) (S)-9-(Benzvloxv)-6-((1 -(3-ethvlphenvl)cvclopentvl)methvn-2.3-dimethvl-3.4-dihvdro- 1 /-/- pyrazino[1 ,2-clpyrimidine-1 ,8(2H)-dione

A mixture of (S)-9-(benzyloxy)-2 -dimethyl-6-((1-(3-vinylphenyl)cyclopentyl)methyl)-3,4- dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (intermediate from Example 129, 310 mg, 0.642 mmol) and 10% Pd/C (wet) (50 mg) in ethyl acetate (15 mL) was stirred at 15-18 °C for 4 h under H ₂ . The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (295 mg) as a light yellow oil, which was used in the next step without further purification.

MS (ESI, m/z); 486.2 [(M+H) ⁺ ] b) (3S)-9-(Benzvloxv)-6-(1 -(1-(3-ethvlphenvl)cvclopentvlV2-hvdroxvethvi)-2,3-dimethyl- 3.4- dihvdro-1 H-pyrazinoH ,2-clpyrimidine-1 ,8(2H)-dione

To a suspension solution of (S)-9-(benzyloxy)-6-((1 -(3-ethylphenyl)cyclopentyl)methyl)-2,3- dimethyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2/-/)-dione (315 mg, 0.65 mmol) in anhydrous THF (15 ml) was slowly added LiHMDS 1 M in THF (1 .95 mL, 1.95 mmol) over 5 min at -65 °C. The resulting brownish red reaction suspension was stirred for 10 min. Then paraformaldehyde (58.5 mg, 1.95 mmol) was added at -65 °C. The reaction mixture was allowed to warm to ambient temperature. During warming up, formation of a light brownish solution appeared. The mixture was stirred 3 h at 15-18 °C. The reaction mixture was quenched with 1 N aq. HCI and extracted with ethyl acetate, the organic layer was washed with water (15 mL), brine (15 mL) and dried over Na ₂ S0 ₄ . The organic layer was filtered and concentrated in vacuo to give the crude product, which was purified by prep-TLC (DCM/MeOH = 15/1 ) to give the title product (150 mg, 45%) as a mixture of diastereomers in the form of a yellow solid.

MS (ESI, m/z): 516.2 [(M+H) ^* ] c) fS 6-((RV1 -f 1-(3-Ethylphenyl)cvclopentylV2-hvdroxyethyl 9-hvdroxy-2.3 limethyl-3.4- dihydro-1 H-pyrazinoM ,2-clpyrimidine-1 ,8(2H)-dione,

A mixture of (3S)-9-(benzyioxy)-6-(1-(1 -(3-ethyiphenyi)cyciopentyl)-2-hydroxyethyl)-2,3- dimethyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (150 mg, 0.29 mmol) and 10% Pd/C (wet) (50 mg) in MeOH (15 mL) was stirred at 15-18 °C for 2 h under H ₂ . The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated with prep-HPLC (RP-18, MeCN/H ₂ Q containing 0.225% HCOOH) to give the title product as a light red solid.

MS (ESI, m/z): 426.3 [(M+H) ⁺ ] d) (S)-6-((S)-1-(1-(3-Ethylphenyl)cvclopentyl)-2-hvdroxyethyl)- 9-hvdroxy-2,3-dimethyl-3,4- dihydro-1 H-pyrazinof1 ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was obtained in analogy to step c) and obtained as a white solid.

MS (ESI, m/z): 426.2 [(M+H) ⁺ ]

Example 146

(S)-2-(9-(Benzyloxy)-6-((1 -(3,5-dimethylphenyl)cvclopen^

tetrahydro-1 H-pyrazino[1 ,2-clpyrimidin-3-yl)acetonitrile

a) 5-(Benzvloxy)-2-((1 -(3,5-dimethvlphenvl)cvclopentyl)methvl)-6-hydroxvpvrirriidi ne-4- carboxylic acid

The title compound was obtained in analogy to txampie 138 steps c-e using the Grignard reagent prepared from 1-bromo-3,5-dimethylbenzene as a yellow solid.

MS (ESI, m/z): 433.2 [(M+H) ⁺ ] b) 2-(9-(Benzyloxy)-6-((1-(3,5-dimethylphenyl)cyclopentyl)methy l)-2-methyl-1 ,8-dioxo-2,3,4,8- tetrahydro-1 H-pyrazinoM ,2-clpyrimidin-3- l acetate

The title compound was prepared in analogy to Example 137 step a-c using 5-(benzyloxy)-2- ((1 -{3,5-dimethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine -4-carboxylic acid in step c as a colorless solid. MS (ESI, m/z): 586.3 [(M+Hf]

tetrahydro-1 H-pyrazinoM ,2-clpyrimidin-3-yl)acetic acid

To an ice-cooled solution of (S)-tert-butyl 2-(9-(benzyloxy)-6-((1 -(3,5- dimethylphenyl)cyclopentyl)methyl)-2-methyl-1 ,8-dioxo-2,3,4,8-tetrahydro-1 H-pyrazino[1 ,2- c]pyrimidin-3-yl)acetate (420 mg, 0.72 mmol) in THF (5 ml_) was added cone, aq HCI (5 ml_). Then, the mixture was stirred for 15 h at 5-15 °C. The mixture was concentrated to give a residue. The product was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title compound (180 mg, 57%) as a white solid.

MS (ESI, m/z): 440.2 [(M+H) ⁺ ]

d) (S)-2-(6-(n-(3.5-Dimethvlphenvl)cvclopentvl)methvl)-9-hvdrox v-2-methyl-1.8-dioxo-2, 3,4,8- tetrahydro-1 H-pyrazino[1 ,2-clpyrimidin-3-yl)acetamide

To a solution of (S)-2-(6-((1-(3,5-dimethylphenyl)cyclopentyl)methyl)-9-hydro xy-2-methyl-1 ,8- dioxo-2,3,4,8-tetrahydro-1 /-/-pyrazino[1 ,2-c]pyrimidin-3-yl)acetic acid (90 mg, 0.2 mmol) in DMF (2 mL) was added HATU (152 mg, 0.4 mmol) and DIPEA (51.6 mg, 0.4 mmol), followed by addition of NH ₄ CI (53.5 mg, 1.0 mmol) at 10-25 °C. The resulting mixture was stirred at 10- 25 °C for 15 h. The mixture was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title compound (70 mg, 78%) as a white solid.

MS (ESI, m/z): 439.2 [(M+H) ⁺ ] e (S)-2-(9-(Benzyloxy)-6-((1-(3,5-dimethylphenyl)cvclopentyl)m ethyl)-2-methyl-1 ,8-dioxo- 2,3,4,8-tetrahvdro-1 H-pyrazino[1 ,2-c1 rimidin-3-yl)acetonitrile

To a solution of (S)-2-(6-((1 -(3,5-dimethylpheny!)cyclopenty!)methy!)-9-hydroxy-2-methyl- ,8- dioxo-2,3,4,8-tetrahydro-1 /-/-pyrazino[1 ,2-c]pyrimidin-3-yl)acetamide (45 mg, 0.1 mmol) in THF (2 mL) was added Burgess reagent (49 mg, 0.2 mmol). The resulting mixture was stirred at 15-30 °C for 2 h. The mixture was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title compound (20.6 mg, 47.9) as a white solid. MS (ESI, m/z): 421.2 [(M+H) ⁺ ]

Example 147

(S)-2-(6-((1 -(3-Ethvlphenvl)cvclopentvl)methyl)-9-hvdroxv-2-methvl-1 ,8-dioxo-2.3.4.8- tetrahvdro-1 H-pyrazinof1 ,2-c1pyrimidin-3-yl)acetic acid

To a solution of (S)-methyl 2-(6-((1 -(3-ethylphenyl)cyclopentyl)methyl)-9-hydroxy-2-methyl- l ^-dioxo^.S^.S-tetrahydro-I H-pyrazinotl ^-clpyrimidin-S-y acetate (Example 137, 17 mg, 0.04 mmol) in MeOH/H ₂ 0 (2 ml_) was added LiOH ( 5 mg, 0.1 mmol). The resulting mixture was stirred at room temperature for 12 h. The mixture was acidified by 1 HCI to pH = 2. The mixture was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give product the title compound (5 mg, 4 mg was delivered) as a white solid.

MS (ESI, m/z): 440.3 [(M+H) ⁺ ] Example 148 and Example 149

(S)-6-((1 -(3,5-Dimethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-methyl- 3-(((SHetrahvdrofuran-

2-vl)methvl)-3,4-dihydro-1 H-pyrazino[1 ,2-c1pyrimidine-1 ,8(2H)-dione

(S)-6-((1 -(3,5-Dimethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-methyl- 3-(((R)-tetrahvdrofuran- 2-yl)methvl)-3,4-dihydro-1 H-pyrazinoH ,2-c1pvrimidine-1 ,8(2H)-dione

The title compounds were prepared in analogy to Example 126 using (2S)-2-amino-3- (tetrahydrofuran-2-yl)propanoic acid (CAS 904789-76-0) and 5-(benzyloxy)-2-((1 -(3,5- dimethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-car boxylic acid. The OBn protected intermediate mixture of diastereomers was separated with prep. TLC on silica gel (PE/EA 1/4).

Example 148: Light red solid. MS (ESI, m/z): 466.3 [(M+H)+]

Example 149: Red solid. MS (ESI, m/z): 466.3 [(M+H)+] Example 150 and Example 151

(S)-6-f(1-f3-Ethylphenyl)cvclope^

yl)methyl)-3,4-dihvdro-1 H-pyrazinoM ,2-clpyrimidine-l ,8(2H)-dione

(S)-6-((1-(3-Ethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2- methyl-3-(((R)-tetrahvdrofuran-2- v0methyl)-3,4-dihvdro-1 H-pyrazinoH ,2-clpyrimidine-1 ,8(2H)-dione

The title compounds were prepared in analogy to Example 148 and Example 151 using 5- (benzyloxy)-2-((1-(3-ethylphenyl)cyclopentyl)methyl)-6-hydro xypyrimidine-4-carboxylic acid.

Example 150: Red solid. MS (ESI, m/z): 466.3 [(M+H)+]

Example 151 : Light red solid. MS (ESI, m/z): 466.3 [(M+H)+]

Example 152

(f?V6-((1-(3,5-Dimethylphenyl)cvclopentvnmethyn-9-hvdroxy -2-methyl-3-(phenoxymethylV3,4- dihydro-1 H-pyrazinon ,2-clpyrimidine-1 ,8(2H)-dione

_^ OPh

a) (R)-tert-Butyl (1 -hvdroxy-3-phenoxypropan-2-yl)carbamate

A mixture of (S)-fert-butyl 2,2-dimethyl-4-(phenoxymethyl)oxazolidine-3-carboxylate (CAS 1025753-10-9, 4.0 g, 13.0 mmol) and PPTs (936 mg, 5.2 mmol) in MeOH (100 mL) was heated to 70 °C and stirred for 15 h. TLC showed that no starting material remained. After cooling to ambient temperature, TEA (1.3 g, 13.0 mmol) and (Boc) ₂ 0 (2.8 g, 13 mmol) were added respectively and the resulting mixture was stirred at 10-15 °C for 5 h. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with PE/EA = 4/1 to give 3.5 g the desired product as a colorless oil. b) (R)-6-((1 -(3,5-Dimethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-methyl- 3-(phenoxymethyl)- 3,4-dihydro-1 /-/-pyrazinofl ,2-c]pyrimidine-1 ,8(2H)-dione

The title compounds were prepared in analogy to Example 121 using (R)-tert-butyl ( -hydroxy- 3-phenoxypropan-2-yl)carbamate in step b) and 5-(benzyloxy)-2-((1-(3,5- dimethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-car boxylic acid in step c). The compounds were obtained as white solids.

MS (ESI, m/z): 488.2 [(M+Hf]

Example 153

(R)-6-((1 -(3-Ethylphenyl)cyclopentyl)me

3,4-dihvdro-1 H-pyrazinoH ,2-c1pyrimidine-1 ,8(2H)-dione

a) (R)-9-(Benzyloxy)-6-(( 1 -(3-ethylphenyl)cvclopentyl)methyl)-2-methyl-3-

((methvlsulfonyi)methvl)-3,4-dihvdro-1 H-pvrazino[1 ,2-c|pvrimidine-1 ,8(2H)-dione

To a stirred solution of (R)-9-(benzyloxy)-6-((1-(3-ethylphenyl)cyclopentyl)methyl)-2 -methyl-3- ((methylthio)methyl)-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (Example 154 step b, 140 mg, 0.263 mmol) in DCM (4 mL) was added a suspension of m-CPBA (85%, 96 mg, 0.47 mmol) in DCM (2 mL) over a period of 10 min at 0 °C. An additional 1.5 mL of DCM was used to complete the transfer of oxidant. The reaction was stirred for 2 h at 0 °C. The mixture was diluted with DCM (50 mL) and sodium hydrogen carbonate (20 mL of a saturated aqueous solution). The organic layer was separated and the organic fraction was washed successively with sodium hydrogen carbonate (20 mL of a saturated aqueous solution) and brine (30 mL), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The product was purified by prep-TLC on silica gel (PE/EA = 1/6) to provide the title compound (60 mg) as a white solid. MS (ESI, m/z): 564.3 [(M+H) ⁺ ]. b) (R)^- H3-Ethylphenyl)cvclopentvnmethvn-9-hvdroxy-2-methyl-3-ffmeth ylsulfonyl)methyl)-

3,4-dihvdro-1 H-pyrazinon ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 154 step b) from (R)-9-(benzyloxy)-6- ((1 -(3-ethylphenyl)cyclopentyl)methyl)-2-methyl-3-((methylsulfo nyl)methyl)-3,4-dihydro-1 H- pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione and was obtained as a light red solid.

MS (ESI, m/z): 474.3 [(M+H)l.

Example 154

(R)-6-((1 -(3-Ethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-methyl-3-((m ethylthio)methvn-3.4- dihydro-1 H-pyrazinof1 ,2-clpyrimidine-1 ,8(2H)-dione s

a) (R)-9-(Benzvloxv)-6-((1-(3-ethvlphenyl)cvclopentvl)methvlV2- methvl-3-((methylthio)methvl)- 3,4-dihydro-1 H-pyrazinon ,2-clpvrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 126, steps e-g using ((R)-2-amino-3- (methylthio)propanoic acid (CAS 1 187-84-4) and 5-(benzyloxy)-2-((1 -(3- ethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carbox ylic acid and obtained as a yellow solid.

MS (ESI, m/z): 532.3 [(M+H) ⁺ ] b) (R -6-((1-(3-Ethylphenyl)cvclopenM

dihydro-1 H-pyrazinoF1 ,2-clpyrimidine-1 ,8(2H)-dione

To a solution of (R)-9-(benzyloxy)-6-((1 -(3-ethylphenyl)cyclopentyl)methyl)-2-methyl-3- ((methylthio)methyl)-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (50 mg,

0.0941 mmol) in MeOH (4 ml_) was added cone. HCI (4 mL) at 0 °. Then, the mixture was stirred for 17 h at 15-18 °C. The solvent was removed in vacuo to give the crude product, which was purified by prep-HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title compound as a light red solid.

MS (ESI, m/z): 442.3 [(M+H) ⁺ ] Example 155

(3R)-6-((1-(3-Ethylphenvncvclopentyl)methyl)-9-hvdroxy-2- methyl-3-((methylsulfinyl)methyl)- 3,4-dihydro-1 H-pyrazinofl ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 153 but using 0.6 equivalents of m- CPBA in step a) and obtained as a red solid.

MS (ESI, m/z): 458.3 [(M+H) ⁺ ]

Example 156

(R)-6-((1-(3,5-Dimethylphenyl)cvclopentyl)methvn-9-hvdroxy-2 -methyl-3- ((methylsulfonyl)methyl)-3,4-dihvdro-1 H- yrazinof1 ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 153 using 5-(benzyIoxy)-2-((1 -(3,5- dimethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-car boxylic acid and obtained as a white solid.

MS (ESI. m/z): 474.3 [(M+H) ⁺ ]

Example 157

(R)-6-((1 -(3.5-Dimethvlphenvl)cvclopentvl)methvl)-9-hvdroxv-2-methvl- 3-((methvlthio)methvl)- 3,4-dihvdro-1 H-pyrazinof 1 ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 154 using 5-(benzyloxy)-2-((1 -(3,5- dimethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-car boxylic acid and obtained as a light red solid.

MS (ESI, m/z): 442.3 [(M+H) ⁺ ] Example 158

(3R)-6-((1-(3,5-Dimethylphenyl)cvclopentyl)methyl)-9-hvdroxy -2-methyl-3- ((methylsulfinyi )methyl)-3,4-dihvdro-1 H-pyrazinof 1 ,2-c1pyrimidine-1 ,8(2H )-dione

The title compound was prepared in analogy to Example 155 using 5-(benzyloxy)-2-((1 -(3,5- dimethylphenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-car boxylic acid and obtained as a light red solid.

MS (ESI, m/z): 458.3 [(M+H) ⁺ ]

Example 159

(S)-6-((1 -(3-Ethylphenvl)cvclopentvl)methvl)-9-hvdroxv-2-methvl-3-(2- (methvlsulfonvl)ethyl)- 3,4-dihvdro-1 H-pyrazino[1 ,2-clpyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 153 from (S)-2-((tert- butoxycarbonyl)amino)-4-(methylthio)butanoic acid (CAS 54399-73-4) which was converted in the first step to the methyl ester in analogy to Example 121 step a) and obtained as a pale white solid.

MS (ESI, m/z): 488.2 [(M+H) ⁺ ] Example 160

(S)-6-((1 -(3-Ethylphenvncvclopentvhmethvn-9-hvdroxy-2-methyl-3-(2-(me th

dihydro-1 H-pyrazinoH ,2-clpyrimidine-1 ,8(2/- )-dione

The title compound was prepared in analogy to Example 154 from (S)-2-((tert- butoxycarbonyl)amino)-4-{methylthio)butanoic acid (CAS 54399-73-4) which was converted in the first step to the methyl ester in analogy to Example 121 step a). It was obtained as a light red solid. MS (ESI, m/z): 456.3 [(M+H) ⁺ ] Example 161

(S)-6-((1 -(3,5-Dimethylphenyl)cvciopentyl)methvn-9-hvdroxy-2-methyl-3 -(2- (methylsulfonyl)ethyl)-3,4-dihvdro-1 /-/-pyrazinofl ,2-clpyrimidine-1 ,8(2/-/)-dione

The title compound was prepared in analogy to Example 156 from (S)-2-((tert- butoxycarbonyl)amino)-4-(methylthio)butanoic acid (CAS 54399-73-4) which was converted in the first step to the methyl ester in analogy to Example 121 step a). It was obtained as a light red solid.

MS (ESI, m/z): 488.3 [(M+H) ⁺ ] Example 162

(S)-6-((1 -(3.5-Dimethylphenyl cvclopentvnmethyl)-9-hvdroxy-2-methyl-3-(2-(meth

3,4-dihvdro-1 H-pyrazinoH ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 157 from (S)-2-((tert- butoxycarbonyl)amino)-4-(methylthio)butanoic acid (CAS 54399-73-4) which was converted in the first step to the methyl ester in analogy to Example 121 step a). It was obtained as a light red solid. MS (ESI, m/z): 456.3 [(M+H)+]

Example 163

(3S)-6-(( 1 -(3.5-Dimethvlphenvl)cvclopentyl)methvl)-9-hvdroxv-2-methvl- 3-(2- (methylsulfinyl)ethyl)-3,4-dihydro-1 /-/-pyrazinoM ,2-c1pyrimidine-1 ,8(2H)-dione

The title compound was prepared in analogy to Example 158 from (S)-2-((tert- butoxycarbonyl)amino)-4-(methylthio)butanoic acid (CAS 54399-73-4) which was converted in the first step to the methyl ester in analogy to Example 121 step a). It was obtained as a light red solid.

MS (ESI, m/z): 472.3 [(M+H)+] Example 164

(fi)-6-((1 -(3,5-Dimethylphenyl)cyclop

dihydro-1 H-pyrazino[ ,2-c1pyrimidine-1 8(2/-/)-dione

a) 2-(Benzyl(methyl)amino)-3-((terf-butyldiphenylsilyl)oxy)prop anoate

To a solution of (S)-methyl 2-(benzylamino)-3-((fe/f-butyldiphenylsilyl)oxy)propanoate (CAS 1419222-17-5, 9.2 g. 20.5 mmol) in MeOH (100 ml_) was added HCHO aq (10 mL) at 10-20 °C. After being stirred for 2 h, NaBH ₃ CN (1.3 g, 20.5 mmol) was added. The resulting mixture was stirred at 10-20 °C for 15 h. The mixture was concentrated and the obtained residue was purified by silica gel chromatography eluting with PE/EA = 15/1 to give the title product (6.5 g, 68.5%) as a colorless oil. b) (f?)-2-(Benzyl(methyl)amino)-3-((tert-butyldiphenylsilyl)oxy )propan-1 -ol

To an ice-cooled solution of (S)-methyl 2-(benzyl(methyl)amino)-3-((tert- butyldiphenylsilyl)oxy)propanoate (6.5 g. 14.1 mmol) in THF/EtOH (100 mL, 9:1 ) was added LiCI (3.8 g, 91.6 mmol) and NaBH ₄ (2.9 g, 77.5 mmol) at 10-20 °C. The resulting mixture was stirred at 10-20 °C for 15 h. The reaction mixture was cooled to 0 °C and quenched with 10% citric acid aq. to pH = 7. The mixture was extracted with ethyl acetate (50 mL ^* 2), the combined organic phases were washed with brine, dried over sodium sulfate and

concentrated. The residue was purified by silica gel chromatography eluting with PE/EA from 20/1 to 3/1 to give the title product (3 g, 47.6%) as a colorless oil. c) (/ ^: ?)-3-((te -Butyldiphenylsilyl)oxy)-2-(methylamino)propan-1-ol

"N H

^C ⁾ ,L O H

TBDPS ^ \^

To a solution of (f?)-2-(benzyl(methyl)amino)-3-((tert-butyldiphenylsilyl)oxy )propan-1 -ol (3.0 g. 6.9 mmol) in MeOH/DCM (60 mL) was added Pd(OH) ₂ /C (300 mg). The resulting mixture was hydrogenated under the pressure of 50 psi at 10-25 °C for 15 h. The catalyst was removed by filtration. The filtrate was concentrated and the obtained residue was purified by silica gel chromatography eluting with PE/EA = 3/1 to DCM/MeOH = 10/1 to give the title product (1.5 g, 63%) as a white solid. d) (R)-9-(Benzvloxv)-3-(((tert-butvldiphenvlsilvl)oxv)methyl)-6 -(( 1 -(3,5- dimethylphenyl)cvclopentyl)methyl)-2-methyl-3,4-dihvdro-1 H-pvrazinof1 ,2-c1pyrimidine-

1 ,8(2H)-dione

PS

The title compound was prepared in analogy to Example 1 19, steps a) and b) without HCI treatment in step b) from (R)-3-((ferf-butyldiphenylsilyl)oxy)-2-(methylamino)propan-1 -ol and 5-(benzyloxy)-2-((1-(3,5-dimethylphenyl)cyclopentyl)methyl)- 6-hydroxypyrimidine-4-carboxylic acid and obtained as a yellow solid. MS (ESI, m/z): 740.3 [(M+H)+] e) (R)-9-(Benzyloxy)-6-((1-(3,5-dimeth^

methyl-3,4-dihydro-1 H-pyrazino[1 ,2-clpyrimidine-1 ,8(2H)-dione

To a stirred solution of (R)-9-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6 -((1 -(3,5- dimethylphenyl)cyclopentyl)methyl)-2-methyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrir^

1 ,8(2H)-dione (180 mg, 0.24 mmol) in THF (5 mL) was added TBAF (180 mg, 0.74 mmol) at 0

°C. The resulting mixture was warmed to at 15-30 °C and stirred for 15 h. The reaction mixture was purified by flash column (RP-18, MeCN/H ₂ 0 containig 0.225% HCOOH) to give the title product (120 mg, 98.4%) as a white solid.

MS (ESI, m/z): 502.2 [(M+H)+] f) (R)-6-((1 -(3,5-Dimethylphenvi)cyciopentyl)methyl)-9-hydroxy-3-(hydrox ymethvi )-2-methvi- 3.4-dihydro-1 H-pyrazinof ,2-clpyrimidine-l ,8(2H)-dione

To an ice-cooled solution of ( )-9-(benzyloxy)-6-((1-(3,5-dimethylphenyl)cyclopentyl)methyl )- 3-(hydroxymethyl)-2-methyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (100 mg, 0.16 mmol) in THF (2 mL) was added cone. aq. HCI (2 mL) at 10-25 °C. The resulting mixture was stirred at 10-25 °C for 12 h. The mixture was purified by reversed phase chromatography (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title product (41 mg, 49.9%) as a white solid.

MS (ESI, m/z): 412.2 [(M+H)+] Example 165

(ffl-6-gi-(3,5-Dimethylphenvncvclo^

tetrahydro-1 /-/-pyrazino[1 ,2-clpyrimidine-3-carboxylic acid

To a solution of (R)-6-((1-(3,5-dimethylphenyl)cyclopentyl)methyl)-9-hydroxy- 3-

(hydroxymethyl)-2-methyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (46 mg, 0.1 1 mmol) and TEMPO (5.27 mg, 0.033 mmoi) in DCM/H ₂ 0 (3 mi_) was added Phl(OAc) ₂ (70.6 mg, 0.048 mmol) at 15-30 °C. The resulting mixture was stirred at 15-30 °C for 1 h. The organic phase was separated, washed with 1 N HCl (1 ml_) and concentrated. The residue was purified by prep-HPLC (RP-18, eCN/H ₂ 0 containing 0.225% HCOOH) to give the title product (30 mg, 63%, 4.6 mg) as an off white solid.

MS (ESI, m/z): 426.1 [(M+H)+] Example 166

(S)-2-(6-((1 -(3.5-Dimethvlphenvl)cvclopentvl)methyl)-9-hvdroxv-2-methvl- 1.8-dioxo-2.3.4,8- tetrah dro-1 H-pyrazino[1 ,2-c1pyhmidin-3-yl)acetamide

The title compound was obtained as intermediate in Example 146 step d) and obtained as a white solid.

MS (ESI, m/z): 439.2 [(M+Hf] Example 167

(S)-2-(6-(( 1 -(3,5-Dimethylphenyl)cvclopentyl)methylV9-hvdroxy-2-methyi-1 ,8-dioxo-2,3,4,8- tetrahvdro-1 H-pyrazinori ,2-clpyrimidin-3-yl)-A/-methylacetamide

The title compound was obtained in analogy to Example 1 6 step d) using MeNH ₂ instead of NH ₄ CI. It was a white solid.

MS (ESI, m/z): 453.2 [(M+H) ⁺ ]

Example 168

(S)-2-(6-((1 -(3.5-Dimethylphenyl)cvclopentyl)methyl)-9-hvdroxy-2-methyl- 1 ,8-dioxo-2.3.4,8- tetrahydro-1 -/-pyrazinori ,2-clpyrimidin-3-yl)-/\/,A/-dimethylacetamide.

The title compound was obtained as a white solid in analogy to Example 146 step d) using Me ₂ NH instead of NH ₄ CI.

MS (ESI , m/z): 467.2 [(M+Hf]

Example 169

(3S)-6-(n-(3,5-Dimethylphenyl)cvclopentyl)(hvdroxy)methyl)-9 -hvdroxy-2,3-dimeth

dihydro-1 H-pyrazinof 1 ,2-clpyrimidine-1 ,8(2H)-dione

a) (S)-9-(Benzyloxy)-6-((1-(3,5-dimethylphenyl)cvclopentyl)meth yl)-2,3-dimethyl-3

1 H-pyrazinoM ,2-c1pyrimidine-1 ,8(2/- )-dione

The title compound was obtained from 5-(benzyioxy)-2-((1 -(3,5- dimethylphenyi)cyclopentyl)methyl)-6-hydroxypyrimidine-4-car boxylic acid and (S)-2- (methylamino)propan-l-ol (CAS 40916-73-2) in analogy to Example 1 19, steps a) and b) without the HCI treatment in step b. It was obtained as a yellow solid.

MS (ESI, m/z): 486.2 [(M+H) ⁺ ] b) (3S)-9-(Benzyloxy)-6-(chloro(1 -(3,5-dimethylphenvncvclopentvnmethyl)-2.3-dimethyl-3,4- dihydro-1 H-pyrazino[1 ,2-c1pyrimidine-1 ,8(2H)-dione

To a solution of (S)-9-(benzyloxy)-6-((1 -(3,5-dimethylphenyl)cyclopentyl)methyl)-2,3-dimethyl- 3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (250 mg, 0.51 mmol) in CHCI ₃ (10 mL) was added 1 ,3,5-trichloro-1 ,3,5-triazinane-2,4,6-trione (95 mg, 0.41 mmol, in three portions) at 16 °C. The reaction mixture was heated to 75 °C and stirred for 2 h. The reaction mixture was concentrated and purified by preparative HPLC (RP-18, eCN/H ₂ 0 containing 0.225% HCOOH) to give the title product (35 mg, 13%) as a yellow oil.

MS (ESI, m/z): 520.2 [(M+Hf] c) (3S)-6-(Chloro(1-(3,5-dimethylphenyl)cvcioper)tyl )methyl)-9-hvdroxy-2,3-dim

dihvdro-1 H-pyrazinoH ,2-clpyrimidine-1 ,8(2H)-dione

To a suspension of (3S)-9-(benzyloxy)-6-(chloro(1 -(3,5-dimethylphenyl)cyclopentyl)methyl)- 2,3-dimethyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (55 mg, 0.10 mmol) in MeOH (5 mL) was added cone, aq HCI (5 mL) drop wise and the mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated in vacuo to give 35 mg of the title compound as a brown solid.

MS (ESI, m/z): 430.1 [(M+Hf] d) (1-(3.5-Dimethylphenyl)cvclopentyl)((S)-9-hvdroxy-2,3-dimeth yl-1 ,8-dioxo-2,3,4,8- tetrahydro-1 H-pyrazinofl ,2-clpvrimidin-6-yl)methyl acetate

To a suspension of (3S)-6-(chloro(1 -(3,5-dimethylphenyl)cyclopentyl)methyl)-9-hydroxy-2,3- dimethyl-3,4-dihydro-1 H-pyrazino[1 ,2-c]pyrimidine-1 ,8(2H)-dione (43 mg, 0.1 mmol) in DMF (5 mL) was added NaOAc (66 mg, 0.8 mmol) and Nal (60 mg, 0.4 mmol) at 26 °C and the mixture was stirred at 26 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL*3). The organic layer was dried with Na ₂ S0 ₄ and concentrated in vacuo to give 30 mg of the title compound which was used in the next step without further purification. e) (3S)-6-((1 -(3.5-Dimethvlphenvl)cvclopentvl)(hvdroxv)m^

dihvdro-1 /-/-pyrazinofl ,2-clpyrimidine-1 ,8(2H)-dione

To a suspension of (1-(3,5-dimethylphenyl)cyclopentyi)((S)-9-hydroxy-2,3-dimeth yl-1 ,8-dioxo- 2,3 ,4,8-tetrahydro-l H-pyrazino[1 ,2-c]pyrimidin-6-yl)methyl acetate (30 mg, 0.07 mmol) in MeOH (2 ml_) was added aq. NaOH (0.4 mL 0.35 mmol, 1 M) drop wise at 0 °C. The mixture was warmed to 26 °C and stirred for 1 h. 1 M aq HCI (10 mL) was added and extracted with ethyl acetate (10 mL*3), the organic layer was washed with brine (10 ml_*3), dried with Na ₂ S0 ₄ and concentrated in vacuo to obtain the crude product which was purified by preparative HPLC (RP-18, MeCN/H ₂ 0 containing 0.225% HCOOH) to give the title compound (3.6 mg, 13%) as a red solid.

MS (ESI, m/z): 412.3 [(M+Hf] Example 170

1-rf1 -(3-Ethylphenyl)cvclopentvnmethvn-4-hydroxy-8,9,9a,10-tetrah vdro-7H- Pvrroloi3,41pvrazinoi3,5-blpvrimidine-3,5-dione

The title compound was prepared in analogy to Example 1 by using (3- ethylphenyl)magnesium bromide instead of phenylmagnesium bromide in step a) and hexahydro-pyrrolo[1 ,2-a]pyrazin-4-one instead of 6-ethyl-1-methyl-piperazin-2-one in step h) to give the title compound as a white powder.

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