CHEMICAL COMPOUNDS BACKGROUND OF THE INVENTION

The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS"), a disease characterized by the destruction of the immune system, particularly of CD4 ⁺ T-cells, with attendant susceptibility to opportunistic infections, and its precursor AIDS-related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.

A required step in HIV replication in human T-cells is the insertion by virally-encoded integrase of proviral DNA into the host cell genome. Integration is believed to be mediated by integrase in a process involving assembly of a stable nucleoprotein complex with viral DNA sequences, cleavage of two nucleotides from the 3' termini of the linear proviral DNA and covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The repair synthesis of the resultant gap may be accomplished by cellular enzymes.

There is continued need to find new therapeutic agents to treat human diseases. HIV integrase is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly HIV infections. Integrase inhibitors are disclosed in

WO2006/116724. The compounds of the present invention were designed to deliver active therapeutic agents.

SUMMARY OF THE INVENTION

The present invention features compounds that are prodrugs of HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC. The present invention features a compound of formula (I)

wherein:

R ¹ , R ² , and R ³ are independently selected from the group consisting of

(a) hydrogen

(b) C _1-6 alkyl;

(c) aryl;

(d) aralkyl;

(e) heterocyclyl;

(f) NR ⁴ R ⁵ wherein R ⁴ is hydrogen and R ⁵ is Ci _-6 alkyl;

(g) N(R ⁵ )C(O)OR ⁵ ;

(h) C(O)OR ⁶ wherein R ⁶ is hydrogen or aralkyl;

(i) C(O)R ⁷ wherein R ⁷ is alkoxy, heterocyclyl, or NR ⁸ R ⁹ wherein R ⁸ is hydrogen and R ⁹ is

XR ¹⁰ wherein X is alkylene and R ¹⁰ is alkoxy or heterocyclyl;

or when R ³ is hydrogen, R ¹ and R ² may together form a 5 or 6 membered heterocyle;

A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention features a compound of formula (I)

wherein:

R ¹ , R ² , and R ³ are independently selected from the group consisting of

(a) hydrogen

(b) C _1-6 alkyl;

(c) aryl;

(d) aralkyl;

(e) heterocyclyl;

(f) NR ⁴ R ⁵ wherein R ⁴ is hydrogen and R ⁵ is Ci _-6 alkyl;

(g) N(R ⁵ )C(O)OR ⁵ ; (h) C(O)OR ⁶ wherein R ⁶ is hydrogen or aralkyl;

(i) C(O)R ⁷ wherein R ⁷ is alkoxy, heterocyclyl, or NR ⁸ R ⁹ wherein R ⁸ is hydrogen and R ⁹ is

XR ¹⁰ wherein X is alkylene and R ¹⁰ is alkoxy or heterocyclyl;

or when R ³ is hydrogen, R ¹ and R ² may together form a 5 or 6 membered heterocyle;

A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

The term "alkyl", alone or in combination with any other term, refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.

The term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to twelve carbon atoms, unless otherwise defined. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, propylene, butylene, isobutylene and the like.

The term "alkoxy" refers to an alkyl ether radical, wherein the term "alkyl" is defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term "aryl" alone or in combination with any other term, refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-10 carbon atoms. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like. Unless otherwise indicated, the term "aryl" also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1-naphthyl, 2- naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 -phenanthridinyl, 2-phenanthridinyl, 3- phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.

The term "hete recycle," "heterocyclic," and "heterocyclyl" as used herein, refer to a 3- to 7- membered monocyclic heterocyclic ring or 8-to 11- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized, and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any carbon or heteroatom, provided that the attachment results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. "Heteroaromatics" or "heteroaryl" are included within the heterocycles as defined above and generally refers to a heterocycle in which the ring system is an aromatic monocyclic or polycyclic ring radical containing five to twenty carbon atoms, preferably five to ten carbon atoms, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, S and P. Preferred heteroaryl groups include 5-6 membered monocyclic heteroaryls and 8 - 10 membered bicyclic heteroaryls. Also included within the scope of the term "heterocycle, "heterocyclic" or

"heterocyclyl" is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. Unless otherwise indicated, the term "heterocycle, "heterocyclic" or "heterocyclyl" also included each possible positional isomer of a heterocyclic radical, such as in 1-indolinyl, 2-indolinyl, 3- indolinyl. Examples of heterocycles include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, oxadiazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl, dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.

The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) {N ⁺ -O ^" } and sulfur such as S(O) and S(O) ₂ , and the quaternized form of any basic nitrogen.

A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers of the present compounds are expressly included within the scope of the invention. Although the specific compounds exemplified herein may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.

Unless otherwise stated, structures depicted herein are also meant to include

compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are also within the scope of this invention.

It will be apparent to one skilled in the art that certain compounds of this invention may exist in alternative tautomeric forms. All such tautomeric forms of the present compounds are within the scope of the invention. Unless otherwise indicated, the representation of either tautomer is meant to include the other.

The term "pharmaceutically effective amount" refers to an amount effective in treating a virus infection, for example an HIV infection, in a patient either as monotherapy or in

combination with other agents. The term "treating" as used herein refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. The term "prophylactically effective amount" refers to an amount effective in preventing a virus infection, for example an HIV infection, or preventing the occurrence of symptoms of such an infection, in a patient. As used herein, the term "patient" refers to a mammal, including a human.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent.

The term "treatment" as used herein refers to the alleviation of symptoms of a particular disorder in a patient, or the improvement of an ascertainable measurement associated with a particular disorder, and may include the suppression of symptom recurrence in an

asymptomatic patient such as a patient in whom a viral infection has become latent. Treatment may include prophylaxis which refers to preventing a disease or condition or preventing the occurrence of symptoms of such a disease or condition, in a patient. As used herein, the term "patient" refers to a mammal, including a human.

As used herein, the term "subject" refers to a patient, animal or a biological sample. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

The present invention features a compound of formula (I) wherein wherein R ¹ , R ² , and R ³ are independently selected from the group consisting of hydrogen; C _1-6 alkyl; NR ⁴ R ⁵ wherein R ⁴ is hydrogen and R ⁵ is C _1-6 alkyl; or N(R ⁵ )C(O)OR ⁵ .

The present invention features a compound of formula (I) wherein R ¹ , R ² , and R ³ are independently selected from the group consisting of hydrogen; C _1-6 alkyl, and C(O)OR ⁶ wherein R ⁶ is hydrogen or aralkyl; or C(O)R ⁷ wherein R ⁷ is alkoxy, heterocyclyl, or NR ⁸ R ⁹ wherein R ⁸ is hydrogen and R ⁹ is XR ¹⁰ wherein X is alkylene and R ¹⁰ is alkoxy or heterocyclyl.

The present invention features a compound of formula (I) wherein R ¹ , R ² , and R ³ are C _{1- 6} alkyl.

The present invention features a compound of formula (I) wherein R ¹ , R ² , and R ³ are hydrogen.

The present invention features a compound of formula (I) wherein R ¹ is C(O)OR ⁶ and

R ² and R ³ are C _1-6 alkyl.

The present invention features a compound of formula (I) wherein R ¹ is C(O)R ⁷ and R ² and R ³ are C _1-6 alkyl. The present invention features a compound selected from the group consisting of:

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-g,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrTOlo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl 2,2- dimethylpropanoate;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ^-alpyrroloII'^'iS^limidazoII ,2-d]pyrazin-10-yl]oxy}methyl acetate;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl N-methyl-L- leucinate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-9,11-dioxo-2,3,4a,5,9,11,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrTOlo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl N- methylglycinate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl N-methyl-L- valinate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ^-alpyrroloir^'iS^limidazoII ,2-d]pyrazin-10-yl]oxy}methyl (2S)-

(methylamino)(phenyl)ethanoate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl L-prolinate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl N-methyl-L- alaninate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl N-methyl-L- phenylalaninate hydrochloride;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ^-alpyrroloII'^'iS^limidazoII ,2-d]pyrazin-10-yl]oxy}methyl acetate; 3-[({[(4aS, 13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-9, 11 -dioxo-

2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ^-alpyrroloII'^'iS^limidazoII ,2-d]pyrazin-10- yl]oxy}methyl)oxy]-2,2-dimethyl-3-oxopropanoic acid sodium salt; {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrτOlo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl 2,2-dimethyl- 3-(4-moφholinyl)-3-oxopropanoate;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrτolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl 2,2-dimethyl- 3-oxo-3-(1 -pyrrolidinyl)propanoate;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrTOlo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl 2,2-dimethyl- 3-{[2-(4-morpholinyl)ethyl]amino}-3-oxopropanoate;

{[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-9,11-dioxo-2,3,4a,5,9,11,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrτOlo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl 2,2-dimethyl- 3-{[2-(methyloxy)ethyl]amino}-3-oxopropanoate;

{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)- 3-methyl-5,7-dioxo-2,3,5,7,11 ,11a- hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-d]pyrazin-6-yl]oxy}methyl 2,2-dimethylpropanoate; and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.

Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW ₄ ⁺ (wherein W is Ci _-4 alkyl) and other amine salts. Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na ⁺ , NH ₄ ⁺ , and NW ₄ ⁺ (wherein W is a C _h alky! group). Preferred salts include sodium, calcium, potassium and hydrochloride. Other compounds of this invention may be prepared by one skilled in the art following the teachings of the specification coupled with knowledge in the art using reagents that are readily synthesized or commercially available.

Any reference to any of the above compounds also includes a reference to a

pharmaceutically acceptable salt thereof.

Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.

Compounds of the present invention are useful as prodrugs to deliver therapeutic compounds, for example, compounds disclosed in WO2006/116764, which were demonstrated to have HIV integrase inhibitory acitivity. One aspect of the instant invention relates to methods of treating or preventing viral infection, for example an HIV infection, in a biological sample comprising contacting the biological sample with compounds of formula (I) or pharmaceutically acceptable salts thereof. Another aspect of the instant invention relates to methods of treating or preventing viral infection, for example, an HIV infection, in a patient comprising administering to the patient a therapeutically effective amount of compounds of formula (I) or pharmaceutically acceptable salts thereof.

The compounds according to the invention are particularly suited to the treatment or prophylaxis of HIV infections and associated conditions. Reference herein to treatment may extend to prophylaxis as well as the treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia.

According to one embodiment of the invention, compounds of formula (I) or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition, which comprises a compound of formula (I) and pharmaceutically acceptable carrier, adjuvant or vehicle. In one embodiment, the composition comprises an amount of a compound of the present invention effective to treat or prevent viral infection, for example an HIV infection, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of a compound of the present innovation effective to inhibit viral replication or to treat or prevent a viral infection or disease or disorder, for example an HIV infection, and a

pharmaceutically acceptable carrier, adjuvant or vehicle, may be formulated for administration to a patient, for example, for oral administration. The present invention features compounds according to the invention for use in medical therapy, for example for the treatment or prophylaxis of a viral infection, for example an HIV infection and associated conditions. The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.

According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention. According to one aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection.

The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.

The compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.

The present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment or prophylaxis of any of the aforementioned diseases or conditions.

The compounds according to the invention and their pharmaceutically acceptable salts may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmaceutically active agent. The active ingredient(s) and

pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

Examples of other therapeutic agents include:

Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;

Non-nucleotide reverse transcriptase inhibitors (including an agent having anti- oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, and similar agents;

Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;

Entry inhibitors such as enfuvirtide T-20, T- 1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix and similar agents;

lntegrase inhibitors such as L-870,810, raltegravir and similar agents;

Budding inhibitors such as PA-344 and PA-457, and similar agents; and CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449 and similar agents.

The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least another therapeutic agent, such as those defined hereinbefore.

Compounds of the present invention may be administered with an agent known to inhibit or reduce the metabolism of compounds, for example ritonavir. Accordingly, the present invention features a method for the treatment or prophylaxis of a disease as hereinbefore described by administration of a compound of the present invention in combination with a metabolic inhibitor. Such combination may be administered simultaneously or sequentially.

In general a suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human) per day, advantageously in the range of 0.01 to 100 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound of formula (I); for salts or esters thereof, the weights would be increased proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub-doses

administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These sub-doses may be administered in unit dosage forms, for example, containing 1 to 1000 mg, 20 to 500 mg, 10 to 500 mg, or 1 to 400 mg of active ingredient per unit dosage form.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.

Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical

(including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

The present invention further includes a pharmaceutical composition as hereinbefore defined wherein a compound of the present invention or a pharmaceutically acceptable salt thereof and another therapeutic agent are presented separately from one another as a kit of parts.

Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1 ) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1 % to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Pharmaceutical compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray. Pharmaceutical compositions may contain in addition to the active ingredient such carriers as are known in the art to be appropriate.

Pharmaceutical compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.

Pharmaceutical compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Unit dosage pharmaceutical compositions include those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof.

It should be understood that in addition to the ingredients particularly mentioned above the pharmaceutical compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.

The compounds of the present invention may be prepared according to methods disclosed in WO2006/116724, WO2010/011812, WO2010/011814, WO2010/011818, other methods known in the art, the following reactions schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.

Scheme 1

Scheme 2

Scheme 3

Scheme 4 The following examples are intended for illustratation only and are not intended to limit the scope of the invention in any way.

Example 1 : {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylmethyl 2,2-dimethylpropanoate.

Potassium carbonate (458 mg, 3.32 mmol) and 4aS,13af?)-Λ/-[(2,4- difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11 ,13,13a-octahydro-1 /-/-pyrido[1 ,2- a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt (0.5 g, 1.11 mmol) were suspended in water (8 ml_), tetrabutylammonium hydrogen sulphate (375 mg, 1.11 mmol) was added and the mixture was diluted with dichloromethane (8 mL) and stirred for 5 minutes to give a clear biphasic solution, lodomethyl 2,2-dimethylpropanoate (715 mg, 2.95 mmol) was added as a solution in dichloromethane (3 mL). The reaction was stirred at ambient temperature for 3 hours. The aqueous layer was extracted with dichloromethane, the organics were washed with saturated sodium bicarbonate solution, brine, dried over sodium sulphate and purified by silica- gel chromatography (0-12% methanol/ dichloromethane) to give a white solid impure with tetrabutylammonium iodide. This material was dissolved in a mixture of ethyl acetate and ether and the organics were washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to give a white solid. ¹ H NMR (CDCI ₃ ) δ 10.30 (m, 1 H), 8.37 (s, 1 H), 7.31 (m, 1 H), 6.81-6.73 (m, 2 H), 5.82 (m, 2 H), 4.59-4.56 (m, 2 H), 4.48 (m, 1 H), 4.25 (m, 1 H), 4.14 (m, 1 H), 3.83 (m, 1 H), 3.69 (m, 1 H), 3.10 (m, 1 H), 3.01 (m, 1 H), 2.79 (m, 1 H), 2.07- 1.86 (m, 3 H), 1.66 (m, 1 H), 1.14 (s, 9 H). ES ⁺ LCMS: 545 (M+1 ).

Example 2: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridori ,2-alPyrrolori',2':3,4limidazoπ ,2-dlPyrazin-10- ylloxylmethyl acetate.

The title compound was prepared in a manner similar to that described in example 1 from potassium carbonate (92 mg, 0.663 mmol), (4aS,13af?)-Λ/-[(2,4-difluorophenyl)methyl]-10- hydroxy-9,11-dioxo-2,3,4a,5,9,11 ,13,13a-octahydro-1H-pyrido[1 ,2- a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt (100 mg, 0.221 mmol), and tetrabutylammonium hydrogen sulphate (75 mg, 0.221 mmol), and bromomethyl acetate (715 mg, 2.95 mmol) as a white solid. ¹ H NMR (CDCI ₃ ) δ 10.26 (m, 1 H), 8.39 (s, 1 H), 7.29 (m, 1 H), 6.79-6.71 (m, 2 H), 5.79 (m, 2 H), 4.56-4.47 (m, 3 H), 4.26-4.16 (m, 2 H), 3.82 (m, 1 H), 3.68 (m, 1 H), 3.11-2.97 (m, 2 H), 2.78 (m, 1 H), 2.04-1.82 (m, 6 H), 1.63 (m, 1 H); ES ⁺ LCMS: 503 (M+1).

Example 3: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridori ,2-alPyrrolori',2':3,4limidazoπ ,2-dlPyrazin-10- ylloxylmethyl N-methyl-L-leucinate hydrochloride.

a) Chloromethyl N-fKI .I-dimethylethyOoxyJcarbonylJ-N-methyl-L-leucinate. N-{[(1 ,1- dimethylethyl)oxy]carbonyl}-N-methyl-L-leucine (1.49 g, 6.07 mmol) was dissolved in ethanol (21 mL) and water(9 ml_), cesium carbonate (1.98 g, 6.07 mmol) was added and this suspension was stirred 30 minutes, then concentrated under reduced pressure. The cesium salt was suspended in N,N-dimethylformamide (10 mL) and bromochloromethane (43 mL) was added and the reaction was stirred at ambient temperature for 12 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure and purified by silica-gel chromatography (0-100% ethyl acetate/hexanes) to give a colorless oil. The compound exists as rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 5.71-5.65 (m, 2 H), 4.89-4.55 (m, 1 H), 2.80-2.75 (m, 3 H), 1.80-1.48 (m, 3 H), 1.44-1.40 (m, 9 H), 0.94- 0.88 (m, 6 H). b) lodomethyl N-fKI .I-dimethylethyOoxyJcarbonylJ-N-methyl-L-leucinate. Chloromethyl N- {[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-leucinate (653 mg, 2.22 mmol) was dissolved in acetone (10 ml_), sodium iodide (666 mg, 4.45 mmol) was added and the mixture was heated at 45 C for 12 hours. The mixture was concentrated under reduced pressure and diluted with water and the aqueous layer was extracted with dichloromethane. The organics were washed with sodium thiosulfate solution, brine, dried over sodium sulphate and concentrated under reduced pressure to give a clear yellow oil. ¹ H NMR (CDCI ₃ ) δ 5.89 (br s, 2 H), 4.86-4.54 (m, 1 H), 2.79-2.75 (m, 3 H), 1.80-1.52 (m, 3 H), 1.51-1.42 (m, 9 H), 0.94-0.89 (m, 6 H). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-fKI .I-dimethylethyOoxyJcarbonylJ-N-methyl-L-leucinate. The title compound was prepared in a manner similar to that described in example 1 from (4aS,13af?)-Λ/-[(2,4- difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11 ,13,13a-octahydro-1 /-/-pyrido[1 ,2- a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt (300 mg, 0.663 mmol), potassium carbonate (275 mg, 1.99 mmol), tetrabutylammonium hydrogen sulphate (225 mg, 0.663 mmol), and iodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-leucinate (795 mg, 2.06 mmol) as a white solid after silica-gel chromatography. The compound exists as a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 10.26 (m, 1 H), 8.37 (m, 1 H), 7.33 (m, 1 H), 6.82-6.74 (m, 2 H), 5.92 (m, 1 H), 5.85-5.75 (m, 2 H), 4.86 (m, 1 H), 4.63-4.74 (m, 4 H), 4.24 (m, 1 H), 4.12 (m, 1 H), 3.86 (m, 1 H), 3.71 (m, 1 H), 3.14-3.01 (m, 2 H), 2.83-2.66 (m, 5 H), 2.08- 1.86 (m, 2 H), 1.74-1.66 (m, 2 H), 1.43-1.35 (m, 9 H), 0.94-0.87 (m, 6 H); ES ⁺ LCMS: 688 (M+1). d) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}m ethyl N-methyl-L-leucinate hydrochloride. Compound prepared as decribed in step c (373 mg, 0.542 mmol) was dissolved in dioxane (8 ml.) and cooled in an ice water bath. 4 N Hydrogen chloride in dioxane (6 ml.) was added and the ice bath was removed. Additional HCI in dioxane was added until the reaction was complete by LCMS. The mixture was concentrated under reduced pressure to give a white solid. ¹ H NMR (DMSO-Cf ₆ ) δ 10.16 (m, 1 H), 9.43 (br s, 1 H), 9.19 (br s , 1 H), 8.53 (s, 1 H), 7.38 (m, 1 H), 7.24 (m, 1 H), 7.03 (m, 1 H), 5.84 (m, 1 H), 5.69 (m, 1 H), 5.00-4.79 (m, 2 H), 4.49 (m, 2 H), 4.40-3.70 (m, 4 H), 3.30-3.00 (m, 2 H), 2.52 (m, 3 H), 1.99-1.54 (m, 6 H), 1.33 (m, 1 H), 0.88-0.79 (m, 6 H); ES ⁺ LCMS: 588 (M+1 ). Example 4: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo-

2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylmethyl N-methylqlvcinate hydrochloride.

a) lodomethyl N-fKI .I-dimethylethylJoxyJcarbonylJ-N-methylglycinate. The title compound was prepared as a yellow oil in a manner similar to that described in example 3, steps a-b, from N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methylglycine. The compound exists as a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 5.91 (m, 2 H), 3.97 (s, 1 H), 3.89 (s, 1 H), 2.91 (m, 3 H), 1.43 (m, 9 H). b) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-

2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}m ethyl N-fKI .I-dimethylethyOoxyJcarbonylJ-N-methylglycinate. The title compound was prepared in a manner similar to that described in example 3, step c from

(4aS,13aR)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt, tetrabutylammonium hydrogen sulphate, and iodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N- methylglycinate as a white solid after purification by silica-gel chromatography. The compound exists as a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 10.22 (m, 1 H), 8.39 (m, 1 H), 7.28 (m, 1 H), 6.79-6.70 (m, 2 H), 5.90-5.78 (m, 2 H), 4.54-4.48 (m, 3 H), 4.23-4.14 (m, 2 H), 4.01- 3.79 (m, 3 H), 3.66 (m, 1 H), 3.07-2.96 (m, 2 H), 2.83-2.77 (m, 4 H), 2.03-1.82 (m, 3 H), 1.63 (m,1 H), 1.33 (m, 9 H); ES ⁺ LCMS: 632 (M+1 ). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-methylglycinate hydrochloride. The title compound was prepared as a white solid from {[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methylglycinate and 4 N hydrogen chloride in dioxane in a manner similar to that described in example 3, step d. ¹ H NMR (DMSO-c/ ₆ ) δ 10.21 (m, 1 H), 8.29 (br s, 2 H), 8.58 (s, 1 H), 7.40 (m, 1 H), 7.25 (m, 1 H), 7.08 (m, 1 H), 5.82 (m, 2 H), 5.10-4.92 (m, 2 H), 4,54 (m, 2 H), 4.50-4.05 (m, 3 H), 3.92 (br s, 2 H), 3.35-3.19 (m, 3 H), 2.58 (m, 3 H), 2.11-0.85 (m, 4 H); ES ⁺ LCMS: 532 (M+1 ).

Example 5: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylmethyl N-methyl-L-valinate hydrochloride.

a) lodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-valinate. The title compound was prepared as a clear yellow oil in a manner similar to that described in example 3, steps a-b, from N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-valine. The compound was a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 5.89 (m, 2 H), 4.43-4.07 (m, 1 H), 2.80 (m, 3 H), 2.19 (br s, 1 H), 1.44 (s, 9 H), 0.97 (m, 3 H), 0.86 (m, 3 H). b) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo^ 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}m ethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-valinate. The title compound was prepared in a manner similar to that described in example 3, step c from

(4aS,13aR)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt, tetrabutylammonium hydrogen sulphate, and iodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N- methyl-L-valinate as a white solid after purification by silica-gel chromatography. The compound was a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 10.25 (m, 1 H), 8.36 (s, 1 H), 7.31 (m, 1 H), 6.82-6.74 (m, 2 H), 5.98 (m, 1 H), 5.79 (m, 1 H), 4.59-4.38 (m, 3 H), 4.28-4.03 (m, 3 H) 3.85 (m, 1 H), 3.70 (m, 1 H), 3.15-3.00 (m, 2 H), 2.84-2.71 (m, 4 H), 2.23-1.84 (m, 4 H), 1.66 (m, 1 H), 1.36 (m, 9 H), 1.01-0.82 (m, 6 H); ES ⁺ LCMS: 674 (M+1). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}m ethyl N-methyl-L-valinate hydrochloride. The title compound was prepared as a white solid from {[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-valinate and 4 N hydrogen chloride in dioxane in a manner similar to that described in example 3, step d. ¹ H NMR (DMSO- Cf ₆ ) δ 10.18 (m, 1 H), 9.45 ( br s, 1 H), 9.08 (br s , 1 H), 8.57 (s, 1 H), 7.41 (m, 1 H), 7.25 (m, 1 H), 7.08 (m, 1 H), 5.95 (m, 1 H), 5.68 (m, 1 H), 5.05-4.95 (m, 2 H), 4.55-4.40 (m, 3 H), 4.21-4.05 (m, 2 H), 3.91 (m, 1 H), 3.27 (br s, 3 H), 2.57 (m, 3 H), 2.31 (m, 1 H), 2.14- 1.78 (m 4 H), 0.96 (m, 6 H); ES ⁺ LCMS: 574 (M+1 ).

Example 6: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridori ,2-alPyrrolori',2':3,4limidazoπ ,2-dlPyrazin-10- ylloxylmethyl (2S)-(methylamino)(phenyl)ethanoate hydrochloride.

a) lodomethyl (2S)-[{[(1 ,1-dimethylethyl)oxy]carbonyl} (methyl)amino](phenyl) ethanoate. The title compound was prepared as a clear yellow oil in a manner similar to that described in example 3, steps a-b, from (2S)-[{[(1 ,1-dimethylethyl)oxy]carbonyl}( methyl)amino](phenyl) ethanoic acid. The compound was a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 7.37- 7.22 (m, 5 H), 6.21-5.60 (m, 2 H), 4.20 (m, 1 H), 2.64 (m, 3 H), 1.46 (m, 9 H). b) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl (2S)-[{[(1 ,1-dimethylethyl)oxy]carbonyl} (methyl)amino](phenyl)ethanoate. The title compound was prepared in a manner similar to that described in example 3, step c from

(4aS,13aR)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt, tetrabutylammonium hydrogen sulphate, and iodomethyl (2S)-[{[(1 ,1-dimethylethyl)oxy]carbonyl} (methyl)amino](phenyl) ethanoate as a white foam after purification by silica-gel

chromatography. The compound existed as a mixture of rotamer by NMR. ¹ H NMR (CDCI ₃ ) δ 10.26 (m, 1 H), 8.38 (s, 1 H), 7.32-7.21 (m, 6 H), 6.78-6.69 (m, 2 H), 6.20-4.39 (m, 3 H), 4.56- 4.15 (m, 5 H), 3.81 (m, 1 H), 3.65 (m, 1 H), 3.05 (m, 1 H), 2.95 (m, 1 H), 2.79-2.60 (m, 4 H), 2.01-1.80 (m, 3 H), 1.61 (m, 1 H), 1.37 (m, 9 H); ES ⁺ LCMS: 708 (M+1 ). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl (2S)-(methylamino)(phenyl)ethanoate hydrochloride. The title compound was prepared as a white solid from {[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl) - 9, 11-dioxo-2,3,4a,5,9, 11 , 13, 13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2- d]pyrazin-10-yl]oxy}methyl (2S)-[{[(1 ,1-dimethylethyl)oxy]carbonyl}

(methyl)amino](phenyl)ethanoate and 4 N hydrogen chloride in dioxane in a manner similar to that described in example 3, step d. ¹ H NMR (DMSO-Cf ₆ ) δ 10.17 (m, 1 H), 9.95 (m, 1 H), 9.77 (m, 1 H), 8.56 (s, 1 H), 7.49-7.29 (m, 6 H), 7.26 (m, 1 H), 7.08 (m, 1 H), 5.96 (m, 1 H), 5.93 (m, 1 H), 5.25 (m, 1 H), 5.05-4.94 (m, 2 H), 4.53 (m, 2 H), 4.41 (m, 1 H), 4.18 (m, 2 H), 3.25 (br s, 3 H), 2.56 (m, 2 H), 2.08-1.83 (m, 4 H); ES ⁺ LCMS: 608 (M+1 ).

Example 7: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridori ,2-alPyrrolori',2':3,4limidazoπ ,2-dlPyrazin-10- ylloxylmethyl L-prolinate hydrochloride.

a) 1-(1 ,1-Dimethylethyl) 2-(iodomethyl) (2S)-1 ,2-pyrrolidinedicarboxylate. The title compound was prepared as a clear yellow oil in a manner similar to that described in example 3, steps a-b, from 1-{[(1 ,1-dimethylethyl)oxy]carbonyl}-L-proline. ¹ H NMR (CDCI ₃ ) δ 6.05-5.79 (m, 2 H), 4.25 (m, 1 H), 3.55-3.34 (m, 2 H), 2.15 (m, 1 H), 1.96-1.85 (m, 2 H), 1.41 (m, 9 H). b) 2-({[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbon yl)-9,11-dioxo-

2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}m ethyl) 1-(1 ,1-dimethylethyl) (2S)-1 ,2-pyrrolidinedicarboxylate. The title compound was prepared in a manner similar to that described in example 3, step c from

(4aS,13aR)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt, tetrabutylammonium hydrogen sulphate, and 1-(1 ,1-dimethylethyl) 2-(iodomethyl) (2S)-1 ,2- pyrrolidinedicarboxylate as a yellow oil after purification by silica-gel chromatography.The compound existed as a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 10.25 (m, 1 H), 8.35 (m, 1 H), 7.33 (m, 1 H), 6.78 (m, 2 H), 5.88 (m, 2 H), 4.59-4.53 (m, 3 H), 4.31-4.11 (m, 3 H), 4.09-3.69 (m, 3 H), 3.47-2.80 (m, 7 H), 2.26-1.30 (m, 14 H); ES ⁺ LCMS: 658 (M+1). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl L-prolinate hydrochloride. The title compound was prepared as a white solid from -({PaS.ISaRJ-δ-^^Λ-DifluorophenyOmethylJaminoJcarbonyO-θ. i i-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl) 1-(1 ,1-dimethylethyl) (2S)-1 ,2-pyrrolidinedicarboxylate and 4 N hydrogen chloride in dioxane in a manner similar to that described in example 3, step d. ¹ H NMR (DMSO-c/ ₆ ) δ 10.40-10.16 (m, 2 H), 8.94 (br s, 1 H), 8.58 (s, 1 H), 7.41 (m, 1 H), 7.25 (m, 1 H), 7.07 (m, 1 H), 5.81 (m, 2 H), 5.06-4.94 (m, 2 H), 4.60-4.19 (m, 6 H), 3.30-3.13 (m, 5 H), 2.25-1.82 (m, 8 H); ES ⁺ LCMS: 558 (M+1 ).

Example 8: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylm ethyl N-methyl-L-alaninate hydrochloride.

a) lodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-alaninate. The title compound was prepared as a amber oil in a manner similar to that described in example 3, steps a-b, from N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-alanine. ¹ H NMR (CDCI ₃ ) δ 5.90 (m, 2 H), 4.78-4.41 (m, 1 H), 2.83 (m, 3 H), 1.44-1.35 (m, 12 H). b) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-alaninate. The title compound was prepared in a manner similar to that described in example 3, step c from

(4aS,13aR)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt, tetrabutylammonium hydrogen sulphate, and iodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N- methyl-L-alaninate as a white solid after purification by silica-gel chromatography. ¹ H NMR (CDCI ₃ ) δ 10.28 (m, 1 H), 8.36 (s, 1 H), 7.33 (m, 1 H), 6.82-6.74 (m, 2 H), 5.84 (m, 2 H), 4.84 (m, 1 H), 4.60-4.50 (m, 3 H), 4.26 (m, 1 H), 4.11 (m, 1 H), 3.90-3.69 (m, 3 H), 3.14-3.00 (m, 2 H), 2.81-2.71 (m 3 H), 2.08-1.87 (m, 3 H), 1.66 (m, 1 H), 1.54-1.34 (m, 12 H); ES ⁺ LCMS: 646 (M+1). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-methyl-L-alaninate hydrochloride. The title compound was prepared as a white solid from {[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-alaninate and 4 N hydrogen chloride in dioxane in a manner similar to that described in example 3, step d. ¹ H NMR (DMSO- Cf ₆ ) δ 10.19 (m, 1 H), 9.64 (br s, 1 H), 9.28 (m, 1 H), 8.56 (s, 1 H), 7.41 (m, 1 H), 7.23 (m, 1 H), 7.07 (m, 1 H), 5.80 (m, 2 H), 5.14-4.97 (m, 2 H), 4.54-4.47 (m, 3 H), 4.23-4.03 (m, 3 H), 3.32 (br s, 3 H), 2.55-2.49 (m, 3 H), 2.10-2.49 (m, 4 H),1.43 (m, 3 H); ES ⁺ LCMS: 546 (M+1 ). Example 9: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo-

2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylmethyl N-methyl-L-phenylalaninate hydrochloride.

a) lodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-phenylalaninate. The title compound was prepared as a amber oil in a manner similar to that described in example 3, steps a-b, from N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-phenylalanine. The compound was a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 7.27-7.13 (m, 5 H), 5.92 (m, 2 H), 4.84- 4.53 (m, 1 H), 3.25 (m, 1 H), 2.99 (m, 1 H), 2.68 (m, 3 H), 1.33 (m, 9 H). b) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo-

2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-phenylalaninate. The title compound was prepared in a manner similar to that described in example 3, step c from (4aS,13aR)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11- dioxo-2,3,4a,5,9,11 ,13,13a- octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1 ',2':3,4]imidazo[1 ,2-d]pyrazine-8-carboxamide sodium salt, tetrabutylammonium hydrogen sulphate, and iodomethyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N- methyl-L-phenylalaninate as a white solid after purification by silica-gel chromatography. The compound was a mixture of rotamers by NMR. ¹ H NMR (CDCI ₃ ) δ 10.26 (m, 1 H), 8.28 (m, 1 H), 7.36-7.11 (m, 6 H), 6.81-6.73 (m, 2H), 6.00 (m, 1 H), 5.86 (m, 1 H), 4.97 (m, 1 H), 4.72 (m, 1 H), 4.59 (m, 2 H), 4.50 (m, 1 H), 4.25 (m, 1 H), 4.13 (m, 1 H), 3.84 (m, 1 H), 3.71 (m, 1 H), 3.34 (m, 1 H), 3.15-2.96 (m, 3 H), 2.81 (m, 1 H), 2.67 (m, 2 H), 2.08-1.86 (m, 3 H), 1.85 (m, 1 H), 1.23 (m, 9 H); ES ⁺ LCMS: 722 (M+1). c) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-methyl-L-phenylalaninate hydrochloride. . The title compound was prepared as a white solid from {[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-methyl-L-phenylalaninate and 4 N hydrogen chloride in dioxane in a manner similar to that described in example 3, step d. ¹ H NMR (DMSO-c/e) δ 10.18 (m, 1 H), 9.85 (br s, 1 H), 9.15 (br s, 1 H), 8.57 (s, 1 H), 7.40 (m, 1 H), 7.29-7.22 (m, 6 H), 7.06 (m, 1 H), 5.90 (m, 1 H), 5.58 (m, 1 H), 5.05-4.92 (m, 3 H), 4.54-4.10 (m, 6 H), 3.28-3.17 (m, 5 H), 2.57 (m, 2 H), 2.07-1.82 (m, 4 H); ES ⁺ LCMS: 622 (M+1 ).

Example 10: {[(4aS, 13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl)-9, 11 -dioxo- 2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylmethyl acetate.

a) Bis(phenylmethyl) dimethylpropanedioate. N,N-disopropylethylamine (37 mL, 212 mmol), and DMAP (0.962 g, 7.87 mmol) were added to a solution of dimethylpropanedioic acid (8 g, 60.6 mmol) in dichloromethane(80 mL). Benzylbromide (18 mL, 151 mmol) was added and the reaction was stirred at ambient temperature for 72 hours. The mixture was diluted with water, the aqeous layer was extracted with dichloromethane.and the combined organics were washed with 1 N HCI, sodium bicarbonate solution, dried over sodium sulphate and

concentrated under reduced pressure to give a clear amber oil. ¹ H NMR (CDCI ₃ ) δ 7.30-7.21 (m, 10 H), 5.09 (s, 4 H), 1.46 (s, 6 H). b) 2,2-Dimethyl-3-oxo-3-[(phenylmethyl)oxy]propanoic acid. Combined bis(phenylmethyl) dimethylpropanedioate, potassium hydroxide, and benzyl alcohol and stirred at ambient temperature for 3 days. The aqueous layer was washed with ether, acidified to pH 2 with 4 N HCI, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduce pressure to give a clear yellow oil impure with benzyl alcohol. ¹ H NMR (CDCI ₃ ) δ 7.34-7.23 (m, 5 H), 5.15 (s, 2 H), 1.46 (s, 6 H). c) Chloromethyl phenylmethyl dimethylpropanedioate. 2,2-Dimethyl-3-oxo-3- [(phenylmethyl)oxy]propanoic acid (1 g, 4.50 mmol) was dissolved in ethanol (14 mL) and water (6 mL) and cesium carbonate (1.47 g, 4.50 mmol) was added and the reaction was stirred overnight at ambient temperature and concentrated under reduced pressure.

This cesium salt was dissolved in N,N-dimethylformamide (8mL) and

bromochloromethane 32 mL) was added slowly and the reaction was stirred at ambient temperature overnight. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure and purified by silica-gel

chromatography (10-100% ethyl acetate/hexanes) to give a clear oil. ¹ H NMR (CDCI ₃ ) δ 7.33- 7.23 (m, 5 H), 5.63 (s, 2 H), 5.15 (s, 2 H), 1.46 (s, 6 H). d) lodomethyl phenylmethyl dimethylpropanedioate. Sodium iodide (1.11 g, 7.38 mmol)was added to a solution of chloromethyl phenylmethyl dimethylpropanedioate (666 mg, 2.46 mmol) in acetone (10 mL) and the mixture was heated at 40 C overnight. The reaction was concentrated under reduced pressure and diluted with water. The aqueous layer was extracted with dichloromethane, and the combined organics were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to give a colorless oil. ¹ H NMR (CDCI ₃ ) δ 7.35-7.23 (m, 5 H), 5.84 (s, 2 H), 5.14 (s, 2 H), 1.45 (s, 6 H). e) {[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl acetate. The title compound was prepared in a manner similar to that described in example 3, step c from (4aS,13af?)-Λ/-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11 -dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1/-/-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazine-8- carboxamide sodium salt (317 mg, 0.700 mmol), tetrabutylammonium hydrogen sulphate (238 mg, 0.700 mmol), and iodomethyl phenylmethyl dimethylpropanedioate (761 mg, 2.10 mmol) as a yellow solid after purification by silica-gel chromatography. ¹ H NMR (CDCI ₃ ) δ 10.27 (m, 1 H), 8.36 (s, 1 H), 7.34-7.20 (m, 6 H), 6.80-6.72 (m, 2 H), 5.85 (m, 1 H), 5.75 (m, 1 H), 5.06 (s, 2 H), 4.56 (m, 2 H), 4.41 (m, 1 H), 4.21-4.09 (m, 2 H), 3.81-3.59 (m, 2 H), 3.11-2.97 (m, 2 H), 2.77 (m, 1 H), 2.06-2.82 (m, 3 H), 1.65 (m, 1 H), 1.40 (s, 6 H); ES ⁺ LCMS: 665 (M+1 ).

Example 11 : 3-r({r(4aS,13aR)-8-({r(2,4-difluorophenyl)methyllamino)carbo nyl)-9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridori ,2-alPyrrolori',2':3,4limidazoπ ,2-dlPyrazin-10- ylloxy)methyl)oxyl-2,2-dimethyl-3-oxopropanoic acid sodium salt.

a) 3-[({[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbo nyl)-9,11-dioxo-

2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl)oxy]-2,2-dimethyl-3-oxopropanoic acid. {[(4aS,13aR)-8-({[(2,4- DifluorophenyOmethylJaminoJcarbonyO-Θ.H-dioxo^.S^a.S.Θ.H .IS.ISa-octahydro-I H- pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl acetate (73 mg, 0.110 mmol) and palladium on carbon (10 wt%, 30 mg) were suspended in methanol (4 ml.) and acetic acid (1 mL) and purged with a balloon of hydrogen. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give a tan solid. ¹ H NMR (DMSO-CZ ₆ ) δ 10.32 (m, 1 H), 8.55 (s, 1 H), 7.39 (m, 1 H), 7.21 (m, 1 H), 7.06 (m, 1 H), 5.72 (s, 2 H), 4.63-4.49 (m, 4 H), 4.03 (m, 1 H), 3.90 (m, 1 H), 3.62 (m, 1 H), 3.50 (br s, 1 H), 3.04-2.80 (m, 3 H), 1.95-1.60 (m, 4 H), 1.26-1.19 (m, 6 H); ES ⁺ LCMS: 575 (M+1 ). b) 3-[({[(4aS,13aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbo nyl)-9,11-dioxo-

2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl)oxy]-2,2-dimethyl-3-oxopropanoic acid sodium salt. 3-[({[(4aS,13aR)-8-({[(2,4- DifluorophenyOmethyllaminoJcarbonyO-Θ.H-dioxo^.S^a.S.Θ.H .IS.ISa-octahydro-I H- pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}nnethyl)oxy]-2,2-dinnethyl-3- oxopropanoic acid (61 mg, 0.106 mmol) was dissolved in dioxane (3 mL) ,1 N NaOH (0.1 ml_, 0.100 mmol) was added, the mixture was stirred 15 minutes at ambient temperature, and concentrated under reduced pressure to give the title compound as a tan solid. ¹ H NMR (DMSO-Ci ₆ ) δ 10.38 (m, 1 H), 8.51 (s, 1 H), 7.38 (m 1 H), 7.22 (m, 1 H), 7.06 (m 1 H), 5.67 (m 1 H), 5.53 (m, 1 H), 4.69-4.52 (m, 4 H), 4.01 (m, 1 H), 3.86 (m, 1 H), 3.61 (m, 1 H), 2.99 (m, 1 H), 2.91-2.88 (m, 2 H), 1.90 (m, 2 H), 1.67 (m, 2 H), 1.05 (m, 6 H); ES ⁺ LCMS: 575 (M+1 , carboxylic acid).

Example 12: {r(4aS,13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylmethyl 2,2-dimethyl-3-(4-morpholinyl)-3-oxopropanoate.

HATU (318 mg, 0.835 mmol) was added to a mixture of 3-[({[(4aS,13aR)-8-({[(2,4- difluorophenyOmethylJaminoJcarbonyO-Θ.H-dioxo^.S^a.S.Θ.H .IS.ISa-octahydro-I H- pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10-yl]oxy}methyl)oxy]-2,2-dimethyl-3- oxopropanoic acid (320 mg, 0.557 mmol), N,N-diisopropylethylamine (0.15 ml_, 0.835 mmol), and morpholine (0.07 ml_, 0.835 mmol) in N,N-dimethylformamide (3 mL) at 0 C. The reaction was allowed to stir at ambient temperature for 12 hours, additional N,N-diisopropylethylamine (0.15 mL, 0.835 mmol),, morpholine (0.07 mL, 0.835 mmol), and HATU (318 mg, 0.835 mmol) were added at ambient temperature. The reaction was stirred for 1 hour, then poured over cold brine, the aqueous layer was extracted with ethyl acetate, the organics were washed with brine. The aqeous layer was back-extracted with ethyl acetate, and the combined organics were dried over sodium sulphate and purified by silica-gel chromatography (0-12% methanol/

dichloromethane) to give a white solid. ¹ H NMR (CDCI ₃ ) δ 10.47 (m, 1 H), 8.37 (s, 1 H), 7.33 (m, 1 H), 6.78 (m, 2 H), 5.94 (m, 1 H), 5.81 (m, 1 H), 4.60-4.50 (m, 3 H), 4.27-4.11 (m, 3 H),

3.83 (m, 1 H), 3.70 (m, 1 H), 3.59-3.40 (m, 6 H), 3.15-3.01 (m 2 H), 2.80 (m, 1 H), 2.07-1.87 (m, 3 H), 1.67 (m, 1 H), 1.53-1.40 (m, 7 H); ES ⁺ LCMS: 644 (M+1 ).

Example 13: U(4aS, 13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl)-9, 11 -dioxo- 2.3.4a.5.9.11.13.13a-octahvdro-1 H-Dyridori .2-alDyrrolori'.2':3.4limidazon .2-dlDyrazin-10- ylloxylm ethyl 2,2-dimethyl-3-oxo-3-(1-pyrrolidinyl)propanoate.

The title compound was prepared In a manner similar to that described in example 12 from 3-[({[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbo nyl)-9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl)oxy]-2,2-dimethyl-3-oxopropanoic acid (300 mg, 0.522 mmol), N, N- diisopropylethylamine (0.14 mL, 0.783 mmol), pyrrolidine (0.07 mL, 0.783 mmol) and HATU (298 mg, 0.783 mmol) as a white solid after purification by silica-gel chromatography. ¹ H NMR (CDCI ₃ ) δ 10.28 (m, 1 H), 8.38 (s, 1 H), 7.33 (m, 1 H), 6.78 (m, 2 H), 5.92 (m, 1 H), 5.83 (m, 1 H), 4.60-4.57 (m, 2 H), 4.29-4.15 (m, 2 H), 3.90-3.70 (m, 3 H),3.41-3.03 (m, 5 H), 2.85 (m, 1 H), 2.10-1.91 (m, 3 H), 1.78-1.72 (m, 3 H), 1.53-1.46 (m, 3 H), 1.38 (s, 6 H); ES ⁺ LCMS: 628 (M+1 ). Example 14: (r(4aS,13aR)-8-((r(2,4-Difluorophenyl)methyllamino)carbonyl) -9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridon ,2-alpyrrolori',2':3,4limidazori ,2-dlpyrazin-10- ylloxylm ethyl 2,2-dimethyl-3-{r2-(4-morpholinyl)ethyllamino)-3-oxopropanoa te.

The title compound was prepared in a manner similar to that described in example 12 from 3-[({[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbo nyl)-9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl)oxy]-2,2-dimethyl-3-oxopropanoic acid (320 mg, 0.557 mmol), N, N- diisopropylethylamine (0.15 ml_, 0.835 mmol), [2-(4-morpholinyl)ethyl]amine (0.11 mL, 0.835 mmol) and HATU (318 mg, 0.835 mmol) as a white solid. ¹ H NMR (DMSO-Cf ₆ ) δ 10.27 (m, 1 H), 9.56 (br s, 1 H), 8.58 (s, 1 H), 7.95 (br s, 1 H), 7.39 (m, 1 H), 7.24 (m, 1 H), 7.06 (m, 1 H), 5.71 (m 2 H), 4.67-4.53 (m, 4 H), 4.06-3.89 (m 4 H), 3.67-2.82 (m, 13 H), 1.96-1.61 (m 4 H), 1.27 (m, 6 H); ES ⁺ LCMS: 687 (M+1 ).

Example 15: {[(4aS, 13aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl)-9, 11 -dioxo- 2,3,4a,5,9,11 ,13,13a-octahvdro-1 H-pyridori ,2-alPyrrolori',2':3,4limidazoπ ,2-dlPyrazin-10- ylloxylmethyl 2,2-dimethyl-3-{r2-(methyloxy)ethyllamino)-3-oxopropanoate.

The title compound was prepared in a manner similar to that described in example 12 from 3-[({[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbo nyl)-9,11-dioxo- 2,3,4a,5,9,11 ,13,13a-octahydro-1 H-pyrido[1 ,2-a]pyrrolo[1',2':3,4]imidazo[1 ,2-d]pyrazin-10- yl]oxy}methyl)oxy]-2,2-dimethyl-3-oxopropanoic acid (320 mg, 0.557 mmol), N, N- diisopropylethylamine (0.15 ml_, 0.835 mmol), [2-(methyloxy)ethyl]amine (0.07 ml_, 0.835 mmol) and HATU (318 mg, 0.835 mmol) as a white solid after purification by silica-gel chromatography. ¹ H NMR (CDCI ₃ ) δ 10.20 (m, 1 H), 8.39 (s, 1 H), 7.33 (m, 1 H), 6.78 (m, 2 H), 5.93 (m, 1 H),5.79 (m, 1 H), 4.60-4.50 (m, 3 H), 4.26 (m, 1 H), 4.16 (m, 1 H), 3.88 (m, 1 H), 3.72 (m 1 H), 3.41-3.38 (m, 4 H), 3.25 (s, 3 H), 3.15-3.04 (m, 2 H)2.82 (m, 1 H), 2.09-1.89 (m, 3 H), 1.67 (m,1 H), 1.42 (m, 6 H); ES ⁺ LCMS: 632 (M+1 ).

Example 16: {[(3S,11aR)-8-({r(2,4-Difluorophenyl)methyllamino)carbonyl)- 3-methyl-5,7-dioxo- 2,3,5,7,11 ,11a-hexahvdrori ,3loxazolor3,2-alpyridoπ ,2-dlpyrazin-6-ylloxy)methyl 2,2- dimethylpropanoate.

Potassium carbonate (112 mg, 0.807 mmol) and 1b (115 mg, 0.269 mmol) were suspended in water(8 ml_), tetrabutylammonium hydrogen sulphate (91 mg, 0.269 mmol) was added and the mixture was diluted with dichloromethane (8 ml.) and stirred for 5 minutes to give a clear biphasic solution, lodomethyl 2,2-dimethylpropanoate (130 mg, 0.538 mmol) was added as a solution in dichloromethane (3 ml_). The reaction was stirred at ambient temperature for 4 hours, additional iodomethyl 2,2-dimethylpropanoate and tetrabutylammonium hydrogen sulphate were added and the reaction was stirred until complete by lcms. The aqueous layer was extracted with dichloromethane, the organics were washed with saturated sodium bicarbonate solution, brine, dried over sodium sulphate and purified by silica-gel

chromatography (0-12% methanol/ dichloromethane) to give a white solid. This material was redissolved in dichloromethane and water was added. The organic layer was removed under reduced pressure and the white precipitate was collected by vacuum filtration and washed with water to give the title compound as a white solid. ¹ H NMR (CDCI ₃ ) δ 10.24 (m, 1 H), 8.42 (s, 1 H), 7.26 (m, 1 H), 6.74 (m, 2 H), 5.82 (br s, 2 H), 5.26 (m, 1 H), 4.54-4.29 (m, 5 H), 3.85 (m, 1 H), 3.62 (m, 1 H), 1.34 (m, 3 H), 1.12 (s, 9 H); ES ⁺ LCMS: 520 (M+1 ).