HK40113325A - Compounds as inhibitors of the orthomyxovirus replication for treating influenza - Google Patents

Description

Compounds used as inhibitors of orthomyxovirus replication for the treatment of influenza

This application is a divisional application of Chinese Patent Application No. 201980015931.X, filed on February 26, 2019, entitled "10-(di(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione derivatives and related compounds as inhibitors of orthomyxovirus replication for the treatment of influenza".

Cross-references to related applications

This application claims priority to U.S. Provisional Application No. 62/636378, filed February 28, 2018, the contents of which are incorporated herein by reference.

Technical Field

This invention provides compounds and prodrugs that inhibit orthomyxovirus replication, which can thus be used to treat viral infections caused by orthomyxovirus. The invention also provides pharmaceutical compositions containing these compounds, and methods for treating or preventing viral infections caused by orthomyxovirus using these compounds.

Background Technology

Orthomyxoviruses possess a negative-sense single-stranded RNA genome and replicate in the nucleus of infected cells because they lack the mechanism to generate a cap structure to produce their own mRNA. Members of the Orthomyxoviridae family possess RNA-dependent RNA polymerases, which have endonuclease activity that cleaves the 5' end portion of cellular mRNA to create a cap; the RNA polymerase then uses the cleavage product as a primer for viral mRNA synthesis. This process is known as "cap-snatching." This endonuclease has been considered a promising target for developing effective antiviral drugs against orthomyxoviruses. ACS Med. Chem. Letters, 2014, vol. 5, 61-64. Inhibitors of this endonuclease have been disclosed in, for example, WO2015/038660, U.S. Patent No. 8,987,441, WO2010/147068, and U.S. Patent Application Nos. US2012/022251, US2013/0197219, US2014/256937 and US2015/0072982, in which the use of these inhibitors for the treatment of influenza infection in mammals has been reported.

The Orthomyxoviridae family includes influenza A, B, and C (all of which can infect humans), as well as several other genera of viruses that do not normally infect humans. Influenza A is the most virulent of these human pathogens, often causing large-scale severe outbreaks during a typical flu season. It is estimated that up to 40,000 people die from influenza annually in the United States, despite widespread vaccination reducing influenza incidence; therefore, there remains a significant need for effective antiviral treatments for influenza, especially influenza A. This invention provides compounds that inhibit the replication of orthomyxoviruses (including influenza A, B, and C viruses). Without being theoretically limited, these compounds are believed to achieve their antiviral effects by inhibiting the endonuclease function of viral polymerases. Because this endonuclease is highly conserved among influenza A viruses (ibid.), these compounds are particularly suitable for treating influenza A.

Summary of the Invention

In one aspect, the present invention provides compounds of formula (A):

As further described in this article.

In another aspect, the present invention provides compounds of formula (I):

Or its pharmaceutically acceptable salt, wherein:

^R1 is H, halogen, CN, COOR*, -CONR* ₂ or optionally a _C1 - _C6 alkyl group substituted with one or two groups selected from the following: –OR* and –NR* ₂ , _C1 - _C4 haloalkyl;

R* is independently H or optionally _C1 - _C6 alkyl substituted with –OR or –NR ₂ each time it appears;

^Z1 is N, and ^Z2 is C(R) ₂ ;

Or ^Z1 is CH, and ^Z2 is NR, O, S or _CH2 ;

^Z3 is _CH2 , Q, _{-CH2- CH2-} , -Q- _CH2- , _–CH2 -Q-, _-CH2 -Q- _CH2- , _-CH2 - _CH2 - _CH2- or _CX2 , where X is a halogen;

Q is selected from –NR-, O, S, SO and _SO2 ;

^R2 is selected from H, halogen, CN, _C1-4 alkyl, wherein the _C1-4 alkyl is optionally substituted by up to three independent groups selected from the following: halogen, CN, _C1-4 alkyl, -OR, _C1-4 haloalkoxy, _-NR2 and _C1-4 haloalkyl;

Each R ³ is a substituent optionally present on any carbon atom of the ring containing Z ² and Z ³ , and is independently selected from –OR, C _1-4 haloalkyl, C _1-4 haloalkoxy, oxo, CN, -NR ₂ , and C _1-4 alkyl optionally substituted by up to three groups independently selected from: halogen, CN, C _1-4 alkyl, -OR, C _1-4 haloalkoxy, -NR ₂ , and C _1-4 haloalkyl;

n is 0-2;

Ar ¹ and Ar ² each independently represent a phenyl or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S as ring members, and each is independently substituted by up to three groups selected from the following: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkyne and CN;

Ar ¹ and Ar ² are optionally linked together by a bridge of the formula –C(R ^L ) ₂ -L- to form a tricyclic group, wherein Ar ¹ and Ar ² are each optionally substituted by up to three independent groups selected from the following: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkyne and CN;

R is independently H or _C1 - _C4 alkyl each time it appears, said _C1 - _C4 alkyl being optionally substituted by up to three groups independently selected from the following: halogen, OH, oxo, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 haloalkoxy and _C1-4 haloalkyl;

L is selected from S, S = O, _SO₂ , O, NR, C(R ^L ) _₂ , and _CF₂ ; and

And each ^RL is independently H or _C1-2 alkyl;

As further described in this article.

The present invention includes these compounds, pharmaceutically acceptable salts thereof, and compositions and combinations comprising these compounds (including pharmaceutically acceptable salts), and methods of using thereof, as further described herein.

Compounds of formula (A) are inhibitors of the function of influenza virus endonucleases (as shown in the data provided herein), which inhibit influenza virus replication. Therefore, these compounds can be used to treat or prevent orthomyxovirus infection in mammals susceptible to orthomyxovirus infection, and particularly for the treatment of influenza virus infection in humans. They can also be used to inhibit the replication of orthomyxoviruses, including influenza viruses, in cells.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (A), at least one pharmaceutically acceptable carrier or excipient mixed therewith, optionally comprising two or more pharmaceutically acceptable carriers or excipients. The compound may be used as a pharmaceutically acceptable salt.

On the other hand, the present invention provides a method for treating a subject infected with influenza A, B, or C virus, comprising administering to the subject requiring such treatment an effective amount of a compound of formula (A) or any subgenus or species thereof as described herein, or a pharmaceutical composition comprising this compound. The subject may be a mammal, preferably a human, although the compounds and methods of the present invention are applicable to treating other species exposed to influenza A, B, or C virus and other orthomyxoviruses. The present invention includes compounds of formula (A) and subgenus formula (I) as described herein, as well as all stereoisomers (including diastereomers and enantiomers), except for particularly indicated specific isomers, including their tautomers and isotopically enriched forms (including deuterium substitution), and pharmaceutically acceptable salts of these compounds. The compounds of the present invention also include polymorphs of compounds of formula (A) (or their sub-formulas) and their salts.

Detailed Implementation

Unless otherwise expressly provided, the following definitions shall apply:

As used herein, the terms “halogen” or “halogenated” refer to fluorine, bromine, chlorine or iodine, especially when combined with an alkyl group, generally referring to fluorine or chlorine, and when combined with an aryl or heteroaryl group, also including bromine or iodine.

Unless otherwise specified, the term “heteroatom” as used herein refers to a nitrogen (N), oxygen (O) or sulfur (S) atom.

As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 10 carbon atoms. Unless otherwise provided, alkyl refers to a hydrocarbon moiety having 1 to 6 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. Substituted alkyl groups are alkyl groups containing one or more substituents, such as one, two, or three (up to the number of hydrogen atoms present on the unsubstituted alkyl group). Unless otherwise specified, suitable alkyl substituents may be selected from halogens, CN, oxo, hydroxyl, _C1-4 alkoxy, substituted or unsubstituted _C3-6 cycloalkyl, substituted or unsubstituted phenyl, amino, ( _C1-4 alkyl)amino, di( _C1-4 alkyl)amino, _C1-4 alkylthio, _C1-4 alkylsulfonyl, -C( _{=O)-C1-4 alkyl, COOH, COO(C1-4 alkyl} ), -O(C=O)-C1-4 alkyl, –NHC(=O) _{C1-4 alkyl} , and –NHC(=O) _OC1-4 alkyl groups, wherein the substituents of the substituted cycloalkyl or phenyl groups are selected from up to three of the following groups: Me, Et, -OMe, -OEt, _CF3 , halogens, CN, OH, and _NH2 .

As used herein, the term "alkylene" refers to a divalent alkyl group having 1-10 carbon atoms and two open valence states in combination with other features. Unless otherwise provided, an alkylene group refers to a moiety having 1-6 carbon atoms. Representative examples of alkylene groups include, but are not limited to: methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 2,2-dimethylbutylene, etc. Substituted alkylene groups are alkylene groups containing one or more, for example, one, two, or three substituents; unless otherwise specified, suitable substituents for alkylene groups are selected from the substituents listed above for alkyl groups.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen groups as defined herein. A haloalkyl group can be a monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl, including perhaloalkyl. A monohaloalkyl group may contain a chlorine or fluorine atom within the alkyl group. Chlorine and fluorine are common substituents on alkyl or cycloalkyl groups; fluorine, chlorine, and bromine are typically present on an aryl or heteroaryl group. Dihaloalkyl and polyhaloalkyl groups may have two or more identical halogen atoms or combinations of different halogen groups on the alkyl group. Polyhaloalkyl groups typically contain up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halogen groups. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. All-halogenated alkyl groups are alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl.

As used herein, the term "alkoxy" refers to an alkyl group (-O-), where the alkyl group is as defined above. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexoxy. Alkoxy groups typically have 1–6 carbon atoms, more commonly 1–4 carbon atoms.

"Substituted alkoxy" is an alkoxy group in which the alkyl moiety contains one or more, for example, one, two, or three substituents. Unless otherwise specified, suitable substituents are selected from the substituents listed above for alkyl groups, except that hydroxyl and amino groups are generally not present on the carbon atom directly bonded to the oxygen atom of the substituted "alkyl-O" group.

Similarly, the alkyl moiety in other groups, such as "alkylaminocarbonyl", "alkoxyalkyl", "alkoxycarbonyl", "alkoxy-carbonylalkyl", "alkylsulfonyl", "alkylsulfoxide", "alkylamino", and "haloalkyl", should have the same meaning as defined in the above definition of "alkyl". When used in this way, unless otherwise specified, alkyl groups are generally 1-4 carbon alkyl groups and are not substituted by other groups except for the indicated moiety. When these alkyl groups are substituted, the suitable substituents are those mentioned above for alkyl groups, unless otherwise specified.

As used herein, the term "haloalkoxy" refers to a haloalkyl group -O-, where the haloalkyl group is as defined above. Representative examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, etc. Typically, haloalkyl groups have 1-4 carbon atoms.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic, or spirocyclic hydrocarbon group having 3-12 carbon atoms. The cycloalkyl group may be unsaturated and may be fused with another ring, which may be saturated, unsaturated, or aromatic, provided that the cycloalkyl ring atom connected to the molecular formula of interest is not an aromatic ring carbon atom. Unless otherwise specified, cycloalkyl refers to a cyclic hydrocarbon group having 3-9 or 3-7 ring carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic ring having 3-7 ring atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, unless otherwise specified.

A substituted cycloalkyl group is a cycloalkyl group that has been substituted by one or two, or three or more substituents up to the number of hydrogen atoms on the unsubstituted group. Typically, a substituted cycloalkyl group will have 1-4 substituents unless otherwise specified. Unless otherwise specified, suitable substituents are independently selected from the following: halogen, hydroxyl, thiol, cyano, nitro, oxo, C1-C4-alkylimino, C1-C4-alkoxyimino, hydroxyimino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-thioalkyl, C2-C4-alkenyloxy, C2-C4-alkynyloxy, C1-C4-alkylcarbonyl, carboxyl, C1-C4-alkoxycarbonyl, amino, C1-C4-alkylamino. Di-C1-C4-alkylamino, C1-C4-alkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, C1-C4-alkylcarbonylamino, C1-C4-alkylcarbonyl(C1-C4-alkyl)amino, C1-C4-alkylsulfonyl, C1-C4-alkylaminosulfonyl, and C1-C4-alkylaminosulfonyl, wherein each of the aforementioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy) may, each time it appears, be further substituted with one or more groups independently selected from the list of “alkyl” substituents herein. Preferred substituents for cycloalkyl groups include C1-C4 alkyl groups, as well as the substituents listed above for suitable substituents of alkyl groups.

Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, and bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include adamantyl, etc.

Similarly, the cycloalkyl moiety of other groups, such as "cycloalkoxy," "cycloalkoxyalkyl," "cycloalkoxycarbonyl," "cycloalkoxy-carbonylalkyl," "cycloalkylsulfonyl," and "halogenated cycloalkyl," should have the same meaning as described in the above definition of cycloalkyl. When used in these terms, cycloalkyl is typically a monocyclic 3-7 carbon ring, unsubstituted or substituted with 1-2 groups. When optional substitution is used, the substituents are typically selected from C1-C4 alkyl groups and those suitable alkyl groups listed above.

As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-14 carbon atoms in the ring moiety. Typically, aryl groups are monocyclic, bicyclic, or tricyclic aryl groups having 6-14 carbon atoms, often 6-10 carbon atoms, such as phenyl or naphthyl. Additionally, as used herein, the term "aryl" refers to an aromatic substituent, which can be a monocyclic or polycyclic aromatic ring fused together. Non-limiting examples include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl, provided that the tetrahydronaphthyl is attached to the formula via a carbon atom on the tetrahydronaphthyl aromatic ring. Unless otherwise stated, the preferred aryl group is phenyl.

A substituted aryl group is an aryl group that is substituted by 1 to 5 (e.g., one, two, or three) substituents independently selected from the following: hydroxyl, thiol, cyano, nitro, _C1 - _C4 -alkyl, _C2 - _C4 -alkenyl, _C2 - _C4 -alkynyl, _C1 - _{C4 -} alkoxy, _{C1 - C4} -thioalkyl, C2- _C4 -alkenyloxy, _C2 -C4-alkynyloxy, halogen, _C1 - _C4 -alkylcarbonyl, carboxyl, _C1 - _C4 -alkoxycarbonyl, amino, _C1 - _C4 -alkylamino, di- _C1 - _C4 -alkylamino, _C1 - _C4 -alkylaminocarbonyl, di- _C1 - _C4 -alkylaminocarbonyl, _C1 - _C4 -alkylcarbonylamino, _C1 - _C4 -alkylcarbonyl( _C1 - _C4 -alkyl)amino, _C1 -C ₄ -alkylsulfonyl, aminosulfonyl, _C1 - _C4 -alkylaminosulfonyl, and _C1 - _C4 -alkylaminosulfonyl, wherein each of the aforementioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy) may be further substituted, each time it appears, by one or more groups independently selected from the list of suitable substituents for alkyl groups herein. Preferred substituents for the substituted aryl group are _C1-4 alkyl groups and groups listed above for suitable substituents for alkyl groups, except for divalent groups such as oxo groups.

Similarly, each aryl moiety of other groups such as "aryloxy", "aryloxyalkyl", "aryloxycarbonyl", and "aryloxy-carbonylalkyl" should have the same meaning as described in the above definition of "aryl".

As used herein, the term "heterocyclic group" refers to a heterocyclic group that is saturated or partially unsaturated, but not aromatic, and can be monocyclic or polycyclic (for polycyclic, especially bicyclic, tricyclic, or spirocyclic); and has 3-14, more commonly 4-10, and most preferably 5 or 6 ring atoms; one or more, preferably 1-4, especially 1 or 2 of these ring atoms are heteroatoms independently selected from O, S, and N (the remaining ring atoms are therefore carbon). Even if it is described as, for example, a C5-6 atomic ring, the heterocycle contains at least one heteroatom as a ring atom, while the other ring atoms are carbon and have the stated number of ring atoms, i.e., 5-6 in this example. Preferably, the heterocyclic group has 1 or 2 heteroatoms as ring atoms, and preferably the heteroatoms are not directly connected to each other. The bonded ring (i.e., the ring connected to the formula of interest) preferably has 4-12, especially 5-7 ring atoms, unless otherwise stated. The heterocyclic group may be fused with an aromatic ring, provided that the atoms of the heterocyclic group connected to the formula of interest are not aromatic. Heterocyclic groups can be bonded to heteroatoms (typically nitrogen) or carbon atoms of interest via the heterocyclic group. Heterocyclic groups can include fused or bridging rings, as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazoline, pyrrolidone, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiopentane, 1,3-dioxane, 1,3-dithiane, oxathiohexane, thiomorpholine, etc.

The substituted heterocyclic group is a heterocyclic group that is independently substituted by 1 to 5 (e.g., one, two, or three) substituents selected from the substituents described above for cycloalkyl groups.

Similarly, each heterocyclic moiety of other groups, such as “heterocyclic oxy,” “heterocyclic alkyl,” and “heterocyclic carbonyl,” should have the same meaning as described in the above definition of “heterocyclic group.”

As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1-8 heteroatoms as ring members and the remaining ring atoms being carbon; the heteroatoms are selected from N, O, and S. Typically, heteroaryls are 5-10 membered ring systems, especially 5-6 membered monocyclic or 8-10 membered bicyclic groups. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrroleyl, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, 1- or 2-tetrazolyl, 2-, 3- or 4-pyridinyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4- or 5-pyrimidinyl.

The term "heteroaryl" also refers to a group in which a heteroaryl ring is fused with one or more aryl, cycloalkyl, or heterocyclic groups. Non-limiting examples include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.

A substituted heteroaryl group is a heteroaryl group containing one or more substituents, typically one or two substituents, which are selected from the substituents suitable for aryl groups mentioned above.

Similarly, each heteroaryl moiety of other groups, such as “heteroaryloxy,” “heteroaryloxyalkyl,” and “heteroaryloxycarbonyl,” should have the same meaning as described in the above definition of “heteroaryl.”

This document describes various embodiments of the invention. It should be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the invention. The embodiments listed below are representative aspects of the invention:

In one embodiment, the present invention provides a compound of formula (A):

Or its pharmaceutically acceptable salt, wherein:

Y is a group in the following formula

The dashed lines represent the bonds connecting Y to the three-ring core of equation (A);

G is H or a group selected from: R 0 , –C(O)R 0 , –C(O)-OR 0 , –C( RG ) 2 -OC(O)R 0 , –C( RG ) 2 -OC(O)-OR 0 , –C(O)-N(R 0 ) 2  and –C( RG ) 2 -OC(O)N(R 0 ) 2 , wherein each R 0  is independently H or a group selected from: C 1 -C 6  alkyl, phenyl, pyridyl, C 3 -C 7  cycloalkyl, and 3-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members; and each R 0  that is not H is optionally substituted by one or two groups selected from: halogen, CN, -OH, amino, C 1-4  alkyl, phenyl, C 1-4  alkoxy, C 1-4  haloalkyl, C1-4 1-4 haloalkoxy groups, and 3-6 membered heterocycles containing one or two heteroatoms selected from N, O and S as ring members, and optionally substituted by one or two groups selected from: halogen, CN, -OH, oxo, amino, C1-4 alkyl, phenyl, C1-4 alkoxy, C1-4 haloalkyl and C1-4 haloalkoxy groups;

Furthermore, each ^RG is independently selected from H and _C1-4 alkyl groups;

^R1 is H, halogen, CN, COOR*, -CONR* ₂ or optionally a _C1 - _C6 alkyl group substituted with one or two groups selected from the following: –OR* and –NR* ₂ , _C1 - _C4 haloalkyl;

R* is independently H or optionally _C1 - _C6 alkyl substituted with –OR or –NR ₂ each time it appears;

^Z1 is N, and ^Z2 is C(R) ₂ ;

Or ^Z1 is CH, and ^Z2 is NR, O, S or _CH2 ;

^Z3 is _CH2 , Q, _{-CH2- CH2-} , -Q- _CH2- , _–CH2 -Q-, _-CH2 -Q- _CH2- , _-CH2 - _CH2 - _CH2- or _CX2 , where X is a halogen, such as F;

Q is selected from –NR-, O, S, SO and _SO2 ;

^R2 is selected from H, halogen, CN, _C1-4 alkyl, wherein the _C1-4 alkyl is optionally substituted by up to three independent groups selected from the following: halogen, CN, _C1-4 alkyl, -OR, _C1-4 haloalkoxy, _-NR2 and _C1-4 haloalkyl;

Each R ³ is a substituent optionally present on any carbon atom of the ring containing Z ² and Z ³ , and is independently selected from halogen, –OR, C _1-4 haloalkyl, C _1-4 haloalkoxy, oxo, CN, -NR ₂ , and C _1-4 alkyl optionally substituted by up to three groups independently selected from: halogen, CN, C _1-4 alkyl, -OR, C _1-4 haloalkoxy, -NR ₂ , and C _1-4 haloalkyl;

n is 0-2;

Ar ¹ and Ar ² each independently represent a phenyl or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S as ring members, and each is independently substituted by up to three groups selected from the following: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkyne and CN;

Ar ¹ and Ar ² are optionally linked together by a bridge of the formula –C(R ^L ) ₂ -L- to form a tricyclic group, wherein Ar ¹ and Ar ² are each optionally substituted by up to three independent groups selected from the following: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkyne and CN;

R is independently H or _C1 - _C4 alkyl each time it appears, said _C1 - _C4 alkyl being optionally substituted by up to three groups independently selected from the following: halogen, OH, oxo, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 haloalkoxy and _C1-4 haloalkyl;

L is selected from S, S = O, _SO₂ , O, NR, C(R ^L ) _₂ , and _CF₂ ; and

And each ^RL is independently H or _C1-2 alkyl.

In one embodiment, the compound of formula (A) does not include compounds selected from:

1 12-Diphenylmethyl-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

2 12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

3 12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

4 12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

5 12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

6 13-Diphenylmethyl-4-hydroxy-8,9,10,11-tetrahydro-7H,13H-pyridazino[1',6':4,5][1,2,4]triazino[1,2-a][1,2]diaza-3,5-dione;

7 13-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,10,11-tetrahydro-7H,13H-pyridazino[1',6':4,5][1,2,4]triazino[1,2-a][1,2]diaza-3,5-dione;

8(R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

9(S)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyn[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

10(9aR,10S)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

11(9aR,10R)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

12(9aS,10R)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

13(9aS,10S)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

14(9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

15(9aR,10R)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

16(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

17(9aS,10R)-10-((S)-(3-chlorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

18(10aS,11R)-11-diphenylmethyl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-3,5-dione;

19A 12-Diphenylmethyl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazin-6,8-dione;

19B 12-Diphenylmethyl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazin-6,8-dione;

20 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9-dihydro-7H,11H-pyrazolo[1,2-a]pyridazino[1,6-d][1,2,4]triazin-3,5-dione;

21 12-(1,1-diphenylethyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

22 12-(bis(2-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

23A 12-Diphenylmethyl-4-hydroxy-10-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

23B 12-Diphenylmethyl-4-hydroxy-10-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

24 12-Diphenylmethyl-4-hydroxy-7-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

25A 12-Diphenylmethyl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

25B 12-Diphenylmethyl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

26A 12-(6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazine[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

26B 12-(6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

27A 12-(6,11-dihydrodibenzo[b,e]oxa-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazine[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

27B 12-(6,11-dihydrodibenzo[b,e]oxa-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazine[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

28A 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

28B 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

29(S)-12-diphenylmethyl-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

30(S)-12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

31(R)-12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione;

32(9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

33(9aR,10S)-10-((R)-(3,4-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

34(9aR,10S)-10-((S)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

35(9aR,10S)-10-((R)-(2-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

36(9aR,10S)-10-((S)-(3,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

37(9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

38(9aR,10S)-10-((S)-(3,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

39(9aR,10S)-10-((R)-(2-fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

40(9aR,10S)-10-((R)-(3,5-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

41(9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

42(9aR,10S)-10-((R)-(2-fluorophenyl)(2-methoxyphenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

43(9aR,10S)-10-((R)-(2-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

44(9aR,10S)-10-(bis(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

45(9aR,10S)-10-((R)-(3,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

46(9aR,10S)-10-((R)-(2,6-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

47(9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

48(9aR,10S)-10-((R)-(2,6-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

49(9aR,10S)-10-((R)-(2,6-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

50(9aR,10S)-10-((S)-(3-fluorophenyl)(3,4,5-trifluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

51(9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

52(9aR,10S)-10-((R)-(3,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

53(9aR,10S)-10-((S)-(3,4-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

54(9aR,10S)-10-((S)-(3,5-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

55(9aR,10S)-10-((S)-(2-fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

56(9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

57(9aR,10S)-10-((S)-(2-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

58(9aR,10S)-10-((S)-(4-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

59(9aR,10S)-10-((S)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

60(9aR,10S)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

61(9aR,10S)-10-((S)-(2,6-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-3,5-dione;

62(9aR,10S)-10-((S)-(2,6-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

63(9aR,10S)-10-((S)-(2,6-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

64(9aR,10S)-10-((R)-(3-fluorophenyl)(3,4,5-trifluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

65(9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

66(9aR,10S)-10-((R)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

67(9aR,10R)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

68(9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

69(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

70(9aR,10S)-10-((S)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

71(9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

72(9aR,10S)-10-((R)-(2,3-difluorophenyl)(2,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

73(9aR,10R)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

74(9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

75(9aR,10S)-10-((S)-(3,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

76(9aR,10S)-10-((S)-(3,4-difluorophenyl)(3,5-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

77(9aR,10S)-10-((R)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

78(9aR,10S)-10-(bis(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

79(9aR,10S)-10-(bis(2,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

80(9aR,10S)-10-((R)-(2,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

81(9aR,10S)-10-((R)-(2,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

82(9aR,10S)-10-((R)-(2,5-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

83(9aR,10S)-10-((S)-(3,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

84(9aR,10S)-10-((R)-(2,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

85(9aR,10S)-10-((R)-(2,4-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

86(9aR,10S)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

87(9aR,10S)-10-((R)-(2,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

88(9aR,10S)-10-((R)-(2,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

89(9aR,10S)-10-((R)-(2,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

90(9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

91(9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

92(9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

93(9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

94(9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-2-(hydroxymethyl)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

95(9aR,10S)-10-((S)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

96(9aR,10S)-10-((R)-(3,4-difluorophenyl)(3,5-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

97(9aR,10S)-10-((R)-(3,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

98(9aR,10S)-10-((S)-(2,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

99(9aR,10S)-10-((S)-(2,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

100(9aR,10S)-10-((S)-(2,5-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

101(9aR,10S)-10-((R)-(3,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

102(9aR,10S)-10-((S)-(2,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

103(9aR,10S)-10-((S)-(2,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

104(9aR,10S)-10-((S)-(2,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

105(9aR,10S)-10-((S)-(2,4-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

106 10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

107 4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-10-yl)methyl)benzylnitrile;

108(9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

109(9aR,10S)-10-((R)-(3-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

110(9aR,10S)-10-((S)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

111(9aR,10S)-10-((R)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

112(9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

113(9aR,10S)-10-((S)-(3-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

114(9aR,10S)-10-((R)-(3-chlorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

115(9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

116(9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

117(7S,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

118(7S,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

119(7R,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

120(7R,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

121(8S,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

122(8R,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

123(10aR,11S)-11-diphenylmethyl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-3,5-dione;

124A 11-Diphenylmethyl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

124B 11-Diphenylmethyl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

125A 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

125B 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

126 11-Diphenylmethyl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-3,5-dione;

127 11-Diphenylmethyl-4-hydroxy-7-methyl-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione;

128(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-3-methylbutyrate;

129(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-3-methylbutyrate;

130(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-4-ylacetate;

131(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl isobutyrate;

132(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-4-ylisopropyl carbonate;

133 1-(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)ethyl ethyl carbonate;

134(S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazin-4-yl)oxy)methyl ethyl carbonate;

135(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(2-methoxyethyl)carbonate;

136 1-(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)ethyl ethyl carbonate;

137(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate;

138(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl carbonate;

139(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate;

140(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl carbonate;

141(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylisopropyl carbonate;

142(((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate;

143(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl neopentanoate;

144(S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-didariazino[1,2-a:1',6'-d][1,2,4]triazin-4-yl)oxy)methyl methyl carbonate;

145(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl L-valine ester;

146(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate;

147(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl(methyl)carbamate;

148 2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)(ethoxy)phosphoryl)oxy)methyl acetate; and

149 2-((((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropionate;

And pharmaceutically acceptable salts of these compounds.

Compounds of formula (A) in which G is not H can be used as prodrugs, which are readily converted in vivo into compounds in which G is H.

In one embodiment of the compound of formula (A), G is H.

In another embodiment of the compound of formula (A), G is selected from R 0 , –C(O)R 0 , –C( O )-OR 0 , –C(RG) 2 -OC( O )R 0 , –C(RG) 2 -OC(O)-OR 0 , –C(O)-N(R 0 ) 2  and –C( RG ) 2 -OC(O)N(R 0 )2 , wherein each R 0  is independently H or a group selected from: C 1 -C 6  alkyl, phenyl, pyridyl, C 3 -C 7  cycloalkyl, and 3-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members; and each R not being H is optionally substituted by one or two groups selected from: halogen, CN, -OH, amino, C 1-4 alkyl, COOR, phenyl, C1-4 alkoxy, C 1-4  haloalkyl, C 1-4  1-4 haloalkoxy groups, and 3-6 membered heterocycles containing one or two heteroatoms selected from N, O and S as ring members.

In some of the foregoing embodiments, G is selected from R 0 , –C(O)R 0 , –C(O)-OR 0 , –C( RG ) 2 -OC(O)R 0 , and –C( RG ) 2 -OC(O)-OR 0 , wherein each R 0  is independently H or C 1 -C 4  alkyl, and each RG is H or C 1 -C 4  alkyl. In some of these embodiments, each RG is H and R 0  is C 1 -C 4  alkyl.

In some of the foregoing embodiments, compound (A) has the following formula:

Or its pharmaceutically acceptable salt.

In some compounds of this formula, ^Z2 is _CH2 , ^Z3 is _CH2 or _CX2 , where X is a halogen, such as F, n is 0, 1 or 2, and each ^R3 is Me.

In another embodiment (Embodiment 1), the present invention provides a compound of formula (I):

Or its pharmaceutically acceptable salt, wherein:

^R1 is H, halogen, CN, COOR*, -CONR* ₂ or optionally a _C1 - _C6 alkyl group substituted with one or two groups selected from the following: –OR* and –NR* ₂ , _C1 - _C4 haloalkyl;

R* is independently H or optionally _C1 - _C6 alkyl substituted with –OR or –NR ₂ each time it appears;

^Z1 is N, and ^Z2 is C(R) ₂ ;

Or ^Z1 is CH, and ^Z2 is NR, O, S or _CH2 ;

^Z3 is _CH2 , Q, _{-CH2- CH2-} , -Q- _CH2- , _–CH2 -Q-, _-CH2 -Q- _CH2- , _-CH2 - _CH2 - _CH2- or _CX2 , where X is a halogen, such as F;

Q is selected from –NR-, O, S, SO and _SO2 ;

^R2 is selected from H, halogen, CN, _C1-4 alkyl, wherein the _C1-4 alkyl is optionally substituted by up to three independent groups selected from the following: halogen, CN, _C1-4 alkyl, -OR, _C1-4 haloalkoxy, _-NR2 and _C1-4 haloalkyl;

Each R ³ is a substituent optionally present on any carbon atom of the ring containing Z ² and Z ³ , and is independently selected from –OR, C _1-4 haloalkyl, C _1-4 haloalkoxy, oxo, CN, -NR ₂ , and C _1-4 alkyl optionally substituted by up to three groups independently selected from: halogen, CN, C _1-4 alkyl, -OR, C _1-4 haloalkoxy, -NR ₂ , and C _1-4 haloalkyl;

n is 0-2;

Ar ¹ and Ar ² each independently represent a phenyl or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S as ring members, and each is independently substituted by up to three groups selected from the following: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkyne and CN;

Ar ¹ and Ar ² are optionally linked together by a bridge of the formula –C(R ^L ) ₂ -L- to form a tricyclic group, wherein Ar ¹ and Ar ² are each optionally substituted by up to three independent groups selected from the following: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-4 alkyne and CN;

R is independently H or _C1 - _C4 alkyl each time it appears, said _C1 - _C4 alkyl being optionally substituted by up to three groups independently selected from the following: halogen, OH, oxo, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 haloalkoxy and _C1-4 haloalkyl;

L is selected from S, S = O, _SO₂ , O, NR, C(R ^L ) _₂ , and _CF₂ ; and

And each ^RL is independently H or _C1-2 alkyl.

In a preferred embodiment of any compound of formula (G) or formula (I) in the foregoing embodiments, if ^Z2 is NR, O or S, then ^Z3 is _CH2 , _CH2CH2 , _CH2CH2CH2 or _{CX2 ,} where X is _a halogen, such as _F.

The following embodiments describe and illustrate certain aspects of the present invention.

2. A compound according to embodiment 1, or any embodiment of formula (A), or a pharmaceutically acceptable salt thereof, wherein Z ¹ is CH.

3. A compound according to embodiment 1 or embodiment 2, or any embodiment of formula (A), or a pharmaceutically acceptable salt thereof, wherein ^Z1 is N.

4. A compound according to any one of embodiments 1-3, or any embodiment of formula (A), or a pharmaceutically acceptable salt thereof, wherein ^Z2 is _CH2 or _–CH2 - _CH2- .

5. A compound according to any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, wherein ^Z3 is _CH2 , _–CH2 - _CH2- , _-CH2 - _CH2 - _CH2- , _-CH2- , O-, O or _CX2 , wherein X is a halogen, such as F.

6. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments, wherein ^R1 is H.

7. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments, wherein ^R2 is H.

8. A compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments, wherein ^Ar1 and ^Ar2 are both phenyl and each is independently substituted by up to three groups selected from the group consisting of: halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C2-4 alkyne and CN.

9. Any compound of the foregoing embodiments, having the following formula:

Where Y represents a group selected from the following groups

Each Ry is independently selected from H, halogens, C 1-4 alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, C 2-4  alkynes, and CN.

Or its pharmaceutically acceptable salt.

10. The compound of embodiment 9, or a pharmaceutically acceptable salt thereof, having the following formula:

Where ^Z1 is N or CH; and

^Z3 is _CH2 , _–CH2 - _CH2- or _CX2 , where X is a halogen, such as F.

11. A compound of embodiment 1, or any embodiment of formula (A), wherein G is selected from:

And pharmaceutically acceptable salts of these compounds.

12. A compound of embodiment 1, or any embodiment of formula (A), wherein the compound is selected from:

And pharmaceutically acceptable salts of these compounds.

13. A compound of embodiment 1, or any embodiment of formula (A), selected from the group consisting of Examples 1-116, or a pharmaceutically acceptable salt thereof. Each example compound is a specific embodiment of the invention, and therefore the invention provides compounds selected from the following:

And pharmaceutically acceptable salts of these compounds.

14. A pharmaceutical composition comprising a compound of any one of the foregoing embodiments or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

15. A combination comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-13 or any of formula (A), and one or more therapeutically active co-agents.

16. A method of treating influenza, comprising administering to a subject in need a therapeutically effective amount of a compound of any one of embodiments 1-13 or any embodiment of formula (A), or a pharmaceutically acceptable salt thereof.

17. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-13 or any embodiment of formula (A), used as a medicine.

18. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-13 or any embodiment of formula (A), used for the treatment of influenza.

19. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-13 or any of formula (A) in the manufacture of a medicament for treating influenza.

In some embodiments, the compound of formula (A) is a compound of one of the following formulas:

Wherein G is H, or G is selected from ^R0 , –C(O) ^R0 , –C(O) ^-OR0 , –C( ^RG ) ₂ -OC(O) ^R0 and –C( ^RG ) ₂ -OC(O) ^-OR0 , wherein each ^R0 is independently H or _C1 - _C4 alkyl, and each ^RG is H or _C1 - _C4 alkyl. In some of these embodiments, each ^RG is H and ^R0 is _C1 - _C4 alkyl;

n is 0, 1, or 2;

Each ^R3 represents Me, OH, OMe, or a halogen; and Y represents

Each Ry is independently selected from F, Cl, Me, OMe, CF3 , OCF 3 , and CN; and each q is independently 0, 1, 2, or 3.

In some embodiments, the compound of formula (I) is a compound of one of the following formulas:

Where n is 0, 1, or 2;

Each ^R3 represents Me, OH, OMe, or a halogen; and Y represents

Each R ^_y is independently selected from H, F, Cl, Me, OMe, CF_₃ , OCF_₃ , and CN.

As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that a given compound of the present invention may exist in, including geometric isomers. It should be understood that substituents may be attached at the chiral center of a carbon atom. The term "chiral" refers to a molecule that is non-overlapping with its mirror-endor, while the term "chiral" refers to a molecule that is overlapping with its mirror-endor. Therefore, the present invention includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to denote suitable racemic mixtures. A "diastereomer" is a stereoisomer having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog "R-S" system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon atom may be specified by R or S. Compounds whose absolute conformation is unknown can be designated as (+) or (-) according to the direction (right-handed or left-handed) in which they rotate plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers or axes and can therefore produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in absolute stereochemistry.

Depending on the choice of starting materials and synthetic process, the compound may exist as one of the possible isomers or mixtures thereof, for example, as a pure optical isomer or as a mixture of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. This invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, its substituents may be E or Z configurations, unless otherwise specified. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration, unless otherwise specified. All tautomeric forms are also intended to be included.

In many cases, the compounds of the present invention are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or similar groups. As used herein, the terms "salt" or "salt class" refer to acid addition salts and basic addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means a salt that retains the biological effects and properties of the compounds of the present invention and generally has no biological or other disadvantages.

Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromoates, bicarbonates/carbonates, hydrogen sulfates/sulfates, camphor sulfonates, chlorides/hydrochlorides, chlorotheophyllinates, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronides, glucuronides, hippurates, hydroiodates/iodides, hydroxyethyl sulfonates, lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates/hydrogen phosphates/dihydrogen phosphates, polygalacturonic acids, propionates, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates. Other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, Pa. (1985); and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, edited by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

It can be formed from inorganic or organic bases into pharmaceutically acceptable base addition salts that may have inorganic or organic counterions.

The inorganic counterions of these alkali salts include, for example, ammonium salts and metals from columns I to XII of the periodic table. In some embodiments, the counterions are selected from sodium, potassium, ammonium, alkylammonium having 1-4 C1-C4 alkyl groups, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

Organic bases from which salts can be obtained include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Suitable organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic portion by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water, organic solvents, or mixtures of both. Generally, where feasible, non-aqueous media such as ethers, ethyl acetate, tetrahydrofuran, toluene, chloroform, dichloromethane, methanol, ethanol, isopropanol, or acetonitrile are preferred.

Any formula provided herein is also intended to represent both unlabeled forms of compounds (i.e., compounds in which all atoms exist at natural isotopic abundances rather than in isotopically enriched states) and isotopically enriched or labeled forms. Isotopically enriched or labeled compounds have the structures described by the formulas provided herein, except that at least one atom of the compound is replaced by an atom having an atomic mass or mass number different from that of naturally occurring atoms or atomic mass distributions. Examples of isotopes that can be incorporated into the enriched or labeled compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^15N , ^18F , ^31P , ^32P , ^35S , ^36Cl , and ^125I . This invention includes various isotopically labeled compounds as defined herein, for example, compounds in which radioactive isotopes (such as ^3H and ^14C ) or non-radioactive isotopes (such as ^2H and ^13C ) exist at levels significantly higher than the natural abundances of these isotopes. These isotopically labeled compounds can be used in metabolic studies (e.g., using ^14C ), reaction kinetic studies (e.g., using ^2H or ^3H ), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)) for drug or substrate tissue distribution assays, or in the treatment of patients with radiotherapy. Specifically, ^18F -labeled compounds may be particularly needed for PET or SPECT studies. The isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the examples and preparations below, replacing the unlabeled reagents used with suitable isotopically labeled reagents.

Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., ^₂H or D), can provide certain therapeutic advantages due to increased metabolic stability, such as prolonged half-life in vivo, reduced dose requirements, or improved therapeutic parameters. The concentration of these heavier isotopes (especially deuterium) can be defined by isotope enrichment factors. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance and the native abundance of a particular isotope. If the substituent in the compounds of this invention is deuterium, then such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (each specified deuterium atom contains 52.5% deuterium), at least 4000 (containing 60% deuterium), at least 4500 (containing 67.5% deuterium), at least 5000 (containing 75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 (containing 97% deuterium), at least 6600 (containing 99% deuterium), or at least 6633.3 (containing 99.5% deuterium).

Pharmaceutically acceptable solvates according to the invention include those in which the solvent in which crystallization can be substituted by isotopes (e.g., _D₂O , _d₆ -acetone, _d₆ -DMSO), as well as solvates having non-enriched solvents.

Compounds of the present invention (i.e., compounds of formula (I)) containing groups capable of acting as hydrogen bond donors and/or acceptors can form eutectics with suitable eutectic formers. These eutectics can be prepared from compounds of formula (I) by known eutectic formation methods. Such methods include grinding, heating, co-sublimation, eutectic melting of compounds of formula (I) with eutectic formers under crystallization conditions, or contacting compounds of formula (I) with eutectic formers in solution and separating the resulting eutectics. Suitable eutectic formers include those described in WO 2004/078163. Therefore, the present invention also provides eutectics comprising compounds of formula (I).

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and combinations thereof, which should be known to those skilled in the art for use in pharmaceutical compositions administered to human subjects (see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions should be considered.

The term "therapeuticly effective amount" of the compound of the present invention refers to an amount of the compound of the present invention that is capable of evoking a biological or medical response in a subject, such as being sufficient to reduce one or more symptoms, alleviate symptoms, delay or postpone disease progression, or prevent disease. In a non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention, when administered to a subject, that is capable of effectively reducing one or more symptoms associated with influenza virus infection, or shortening the duration of the symptomatic phase of influenza virus infection, or delaying the progression of influenza virus infection, or reducing or stopping the worsening of the condition caused by influenza virus infection.

In another non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the invention that, when applied to cells or tissues or non-cellular biological materials or media, is sufficient to cause a statistically significant reduction in the replication or proliferation rate of orthomyxovirus strains.

As used in this article, the term "subject" refers to an animal. Typically, a subject is a human.

As used herein, the terms “inhibition,” “inhibitory effect,” or “inhibitory” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

As used herein, the terms “treatment,” “treatment,” or “therapy” for any disease or disorder mean, in one embodiment, improving a disease or condition (i.e., slowing or preventing or reducing the progression of a disease or at least one of its clinical symptoms). In other embodiments, “treatment,” “treatment,” or “therapy” means reducing or improving at least one physical parameter, including those not identified by the patient. In still other embodiments, “treatment,” “treatment,” or “therapy” means regulating a disease or condition from a bodily (e.g., stabilization of a noticeable symptom) or physiological (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treatment,” “treatment,” or “therapy” means preventing or delaying the onset or progression of a disease or condition.

As used in this article, a subject “needs” such treatment if the subject will benefit from the treatment biologically, medically, or in terms of quality of life.

As used herein, the terms “a,” “an,” “the,” and similar expressions used in the context of this invention (especially in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise stated or clearly contradicted by the context.

All methods described herein may be performed in any suitable order unless otherwise stated or clearly contradicted by the context. Any and all embodiments/examples, or exemplary language (e.g., “for example” or “like”) used herein are merely for the purpose of better illustrating the invention and are not intended to limit the scope of the invention as claimed.

Any asymmetric atom (e.g., carbon, etc.) in one or more compounds of the present invention may exist in racemic or enantiomer-enriched forms, such as (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has any of the (R) or (S)- configurations with at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess; that is, for optically active compounds, it is generally preferred to use one enantiomer while substantially excluding the other enantiomer, and thus generally preferred to have at least 95% enantiomer purity. Substituents on atoms located at unsaturated double bonds may (if possible) exist in cis-(Z)- or trans-(E)- forms.

Accordingly, as used herein, the compounds of the present invention may be in the form of one of the possible isomers, rotational isomers, rotation-blocked isomers, tautomers, or mixtures thereof, for example, substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof. As used herein, “substantially pure” or “substantially free of other isomers” means that the product contains less than 5% by weight, preferably less than 2% by weight, of other isomers relative to the amount of the preferred isomer.

The resulting mixture of isomers can typically be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemates based on the physicochemical differences of the components, for example, by chromatography and/or fractional crystallization.

Racemic products or intermediates can typically be resolved into optically active enantiomers by known methods, such as by separating their diastereomeric salts, obtaining them with optically active acids or bases, and releasing optically active acidic or basic compounds. Specifically, the compounds of the present invention can thus be resolved into their optically active enantiomers using a basic moiety, for example, by stepwise crystallization of salts formed from optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-benzoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral stationary phase.

Furthermore, compounds of the present invention, including their salts, can also be obtained as their hydrates, or include other solvents used for their crystallization. Compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and non-solventized forms. The term "solvate" refers to a molecular complex of compounds of the present invention (including their pharmaceutically acceptable salts) having one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to the recipient, for example, water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, carriers and excipients approved (registered) for formulation of therapeutic agents for administration via similar routes of administration. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to routine pharmaceutical processing (e.g., sterilization) and/or may contain conventional inert diluents, lubricants, or buffers, and adjuvants, such as preservatives, stabilizers, humectants, emulsifiers, and buffers.

In one embodiment, the compounds of the present invention are formulated for oral delivery. Typically, these pharmaceutical compositions are tablets or gelatin capsules comprising an active ingredient (at least one compound of formula (I)) and one or more excipients selected from:

a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerin;

b) Lubricants, such as silica, talc, stearic acid, their magnesium or calcium salts, and/or polyethylene glycol; also included for tablets.

c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone; if required.

d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and/or

e) Adsorbents, colorants, flavoring agents, and sweeteners.

Tablets can be coated with film or casing according to methods known in the art.

Suitable compositions for oral administration include effective amounts of the compounds of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art of pharmaceutical composition manufacturing, and the compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically sound and palatable formulation. Tablets may contain a mixture of the active ingredient and pharmaceutically acceptable, non-toxic excipients suitable for tablet preparation. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delay-release materials such as glyceryl monostearate or glyceryl distearate can be used. Orally administered formulations can be prepared as hard gelatin capsules containing the active ingredient and an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules containing the active ingredient and water or an oily medium (such as peanut oil, liquid paraffin, or olive oil).

Some injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterile and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, osmotic pressure-regulating salts and/or buffers. Additionally, they may contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain about 0.1-75% or about 1-50% of the active ingredient.

Suitable compositions for transdermal administration comprise an effective amount of the compound of the present invention and a suitable carrier. Carriers suitable for transdermal delivery include absorbable, pharmacologically acceptable solvents to aid penetration of the host skin. For example, transdermal devices may be in the form of a bandage with a backing component, a reservoir containing the compound and optionally a carrier, an optional rate-control barrier for long-term, controlled delivery of the compound to the host skin at a predetermined rate, and components for securing the device to the skin.

Suitable compositions for topical application (e.g., to skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, such as those delivered via aerosols. These topical delivery systems may involve inhalation or intranasal administration, and may be suitable for treating influenza, for example, and may contain solubilizers, stabilizers, isotonic enhancers, buffers, and preservatives. They may be delivered in dry powder form (either alone or as a mixture (e.g., a dry mixture with lactose), or as mixed component particles (e.g., with phospholipids)) via aerosol spray from a pressurized container, pump, nebulizer, atomizer, or sprayer, or conventionally via a dry powder inhaler, with or without a suitable propellant.

The present invention also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may promote the degradation of certain compounds.

The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture components and under low-moisture or low-humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, the anhydrous compositions are packaged in suitable formulation boxes using materials known to prevent contact with water. Examples of suitable packaging include, but are not limited to, airtight foil, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

This invention also provides pharmaceutical compositions and dosage forms comprising one or more agents capable of reducing the degradation rate of compounds of this invention as active ingredients. These formulations are referred to herein as “stabilizers,” and include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers, or buffer salts.

Compounds of formula (I) in their free or salt forms exhibit considerable pharmacological properties, such as their ability to inhibit or prevent orthomyxovirus replication (as shown in the test data provided below), and thus demonstrate their potential for use as therapeutic or research compounds, for example, as tool compounds for studying orthomyxovirus replication, particularly influenza A, B, or C viruses. Therefore, the compounds of the present invention are intended for the treatment of orthomyxovirus infections, particularly influenza A, B, or C virus infections, especially in human subjects. In some embodiments, the subjects to be treated are humans who have been exposed to or are at risk of exposure to influenza virus infection. For example, the methods or compounds of the present invention can be used to treat subjects with pre-existing conditions (e.g., asthma or COPD) that would be significantly exacerbated by influenza virus infection before the onset of influenza infection symptoms; especially if they are at risk of exposure to influenza due to close contact with people who have or may have influenza (e.g., family members). In other embodiments, the subjects treated by the methods and compositions of the present invention are subjects diagnosed with symptoms consistent with influenza infection. In other implementations, the subject may be a human who has been found to be infected with influenza by a known diagnostic method, such as the Rapid Influenza Diagnostic Test (RIDT) or the reverse transcriptase PCT (RT-PCR) method used to detect the presence of influenza virus, regardless of whether they have typical influenza symptoms.

As a further embodiment, the present invention provides the use of compounds of formula (I) or any embodiment within the scope of formula (I) as described herein in a therapeutic context. In particular, the compounds are suitable for treating subjects who have or are at particularly high risk of having orthomyxovirus infections, especially influenza A, B, or C.

In another embodiment, the present invention provides a method for treating an orthomyxovirus-induced disease, comprising administering to a subject requiring such treatment a therapeutically effective amount of a compound of formula (I) or any embodiment within the range of formula (I) as described herein. In some embodiments, the compound of formula (I) is administered orally. In another embodiment, the disease is selected from influenza A, B, and C. The method generally comprises administering to a subject requiring this treatment an effective amount of a compound as described herein, or a pharmaceutical composition comprising an effective amount of such a compound. The compound may be administered using any suitable method as described herein, and may be administered at intervals, as may be chosen by the treating physician. In some embodiments, the compound or pharmaceutical composition is administered orally.

Therefore, as another embodiment, the present invention provides the use of compounds of formula (I) or any embodiment of such compounds described herein for the preparation of a medicament. In one particular embodiment, the medicament is used to treat orthomyxoviral infections, particularly influenza A, B, or C.

The compounds of the present invention may be administered simultaneously with, before, or after one or more therapeutic co-agents. The compounds of the present invention may be administered alone via the same or different routes of administration, or together with co-agents in the same pharmaceutical composition. Suitable co-agents for the compounds of the present invention include those with antiviral activity against influenza viruses, such as neuraminidase inhibitors, including oseltamivir, peramivir, zanamivir, and ranimivir, ranimivir caprylate, and adamantanes such as amantadine and rimantadine. Other co-agents for these methods include M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, favipiravir, influenza enzymes, ADS-8902, beraprost, ribavirin, CAS registration number 1422050-75-6, VX-787, Flu Mist Quadrivalent, Quadrivalent, and...

In one embodiment, the present invention provides a product comprising a compound of formula (I) and at least one other therapeutic co-agent, which is used as a combination formulation for simultaneous, single, or sequential use in treatment. In one embodiment, the treatment is for viral infection caused by orthomyxoviruses, particularly influenza A, B, or C. The product provided as a combination formulation includes a composition comprising a compound of formula (I) and at least one other therapeutic co-agent present in the same pharmaceutical composition; or a compound of formula (I) and at least one other therapeutic co-agent in a single form, for example, in kit form for treating a subject by the methods described herein.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and other therapeutic co-agents. Suitable co-agents include those with antiviral activity against influenza viruses, such as neuraminidase inhibitors including oseltamivir, peramivir, zanamivir, and ranimivir, and adamantanes such as amantadine and rimantadine. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). Other pharmaceutical compositions may contain one of suitable co-agents. In one embodiment, the kit comprises a device for individually containing the compositions, such as a container, dispensing vial, or dispensing foil pack. An example of such a kit is blister packs, typically used for packaging tablets, capsules, etc.

The kits of the present invention can be used to administer different dosage forms, such as oral or parenteral, to administer individual compositions at different dose intervals, or to titrate individual compositions against each other. To aid compliance, the kits of the present invention typically include instructions for use.

In the combination therapy of the present invention, the compounds and therapeutic co-agents of the present invention may be prepared and/or formulated by the same or different manufacturers. Additionally, the methods and therapeutic co-agents of the present invention may be incorporated into the combination therapy at the following stages: (i) before the combination product is made available to a physician (e.g., when the kit contains the compounds and other therapeutic agents of the present invention); (ii) spontaneously by the physician (or under the physician's guidance) shortly before administration; and (iii) by the patient themselves, for example, during the sequential administration of the compounds and therapeutic co-agents of the present invention.

Therefore, the present invention provides the use of the compound of formula (I) for treating viral infections caused by orthomyxovirus infection, particularly influenza, wherein the influenza virus may be influenza A, B, or C, wherein the preparation is for administration in conjunction with a therapeutic co-agent. Typically, in methods of using the compounds of the present invention, the influenza serotype is not identified prior to treatment. The present invention also provides the use of the therapeutic co-agent for treating diseases or conditions, wherein the medicament is administered in conjunction with the compound of formula (I).

The present invention also provides the use of the compound of formula (I) in a method for treating viral infections caused by orthomyxoviruses, particularly influenza A, B, or C, wherein the preparation of the compound of formula (I) is for administration in conjunction with a therapeutic co-agent. The present invention also provides the use of another therapeutic co-agent in a method for treating viral infections caused by orthomyxoviruses, particularly influenza A, B, or C, wherein the preparation of the therapeutic co-agent is for administration in conjunction with the compound of formula (I). The present invention also provides the use of the compound of formula (I) in a method for treating viral infections caused by orthomyxoviruses, particularly influenza A, B, or C, wherein the compound of formula (I) is administered in conjunction with a therapeutic co-agent. The present invention also provides the use of a therapeutic co-agent in a method for treating viral infections caused by orthomyxoviruses, particularly influenza viruses such as influenza A, B, or C, wherein the therapeutic co-agent is administered in conjunction with the compound of formula (I).

The present invention also provides the use of the compound of formula (I) for treating viral infections caused by orthomyxoviruses, particularly influenza viruses such as influenza A, B, or C, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating viral infections caused by orthomyxoviruses, particularly influenza A, B, or C, wherein the patient has previously (e.g., within 24 hours) been treated with a compound of formula (I).

In one embodiment, the therapeutic agent is selected from antiviral drugs believed to be useful in treating infections caused by influenza viruses, such as neuraminidase inhibitors including oseltamivir, peramivir, zanamivir, and ranimivir, as well as adamantanes such as amantadine and rimantadine.

The pharmaceutical compositions or combinations of the present invention may be unit dosage forms containing about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient for a human subject weighing about 50-70 kg. The therapeutically effective amount of the compound, pharmaceutical composition, or combination thereof is determined by the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient for preventing, treating, or inhibiting the progression of a disorder or disease.

Advantageously, the properties of the above-described dosages are demonstrated in in vitro and in vivo tests using mammalian (e.g., mouse, rat, dog, monkey) or isolated organs, tissues, and products thereof. The compounds of the invention can be administered in vitro in solution (e.g., aqueous solution), in vivo in enteral or parenteral form, and advantageously intravenously, for example, as a suspension or in aqueous solution. The in vitro dosage range can be between concentrations of about ^10⁻³ mol and ^10⁻⁹ mol. The effective therapeutic dose range in vivo can be between about 0.1-500 mg/kg or about 0.1-50 mg/kg, depending on the route of administration.

The present invention also includes methods for preparing compounds of formula (I) as described herein, and any variations thereof, wherein an intermediate product available at any stage is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under reaction conditions, or wherein the reaction components are used as their salt or as optically pure substances.

The compounds and intermediates of the present invention can also be converted into each other according to methods conventionally known to those skilled in the art.

The method for synthesizing compound (I) is as described in schemes A-D and illustrated in the examples herein. Scheme A describes a method for preparing the compound, wherein Z1 is N, Z2 is C(R)2, and Z3 is -CR2-CR2, and it should also be possible to synthesize compounds having other Z3 linkages. It begins with a 5-hydroxypyridazine-4-one-3-carboxylic acid compound, wherein the 5-hydroxyl group and the cyclic NH group are both protected by suitable protecting groups that can be easily removed. The carboxylic acid is condensed with a cyclic hydrazine linkage, providing two outer rings. After deprotection of the cyclic nitrogen, a central ring is formed by condensation with an aldehyde.

Option A.

Scheme B describes an alternative method for preparing the intermediates after step 1 of Scheme A.

Option B.

Schemes C and D describe methods for preparing compounds of formula (I), wherein ^Z1 is CR, ^Z2 is _CR2 and ^Z3 is _CR2 .

Option C.

Option D.

Using these synthetic methods and the provided examples, those skilled in the art can prepare compounds of formula (I).

Example

The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporation was carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (about 20-133 mbar). The structures of the final products, intermediates, and starting materials were determined by standard analytical methods, such as trace analysis and spectroscopic characterization, such as MS, IR, and NMR. Abbreviations used are those conventional in the art.

All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthetic methods known to those skilled in the art (Houben-Weyl, 4th edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21). Furthermore, considering the following examples, the compounds of the present invention can be produced by organic synthetic methods known to those skilled in the art.

abbreviation

ATP adenosine 5'-triphosphate

Bn benzyl

BOC tert-butylcarboxyl

br Wide peak

BSA (Bovine Serum Albumin)

d Double peak

dd double peak

DCM dichloromethane

DEAD Diethyl azodicarbonate

DBAD di-tert-butyl azodicarbonate

DIBAL-H diisobutylaluminum hydride

DIEA (Diethylisopropylamine)

DME 1,4-dimethoxyethane

DMF N,N-dimethylformamide

DMSO (dimethyl sulfoxide)

DTT (Dithiothreitol)

EDTA (ethylenediaminetetraacetic acid)

ESI Electrospray Ionization

EtOAc (ethyl acetate)

FCC Fast Column Chromatography

h hours

HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (1-)3-oxide

HOBt 1-hydroxy-7-azabenzotriazole

HPLC (High-Performance Liquid Chromatography)

IR infrared spectrum

LCMS (Liquid Chromatography and Mass Spectrometry)

MeOH (methanol)

MS mass spectrometry

MW microwave

m multiplet

min minutes

mL

m/z mass-to-charge ratio

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NMP (N-methylpyrrolidone)

NMR (Nuclear Magnetic Resonance)

ppm (parts per million)

PyBOP Benzotriazole-1-yloxytripyrrolidone hexafluorophosphate

rac racemic

rt room temperature

s Single peak

SEM(2-(trimethylsilyl)ethoxy)methyl

triple peak

TBDMS tert-butyldimethylsilyl

TBDPS tert-butyldiphenylsilyl

TFA (trifluoroacetic acid)

THF tetrahydrofuran

Tris·HCl tris(hydroxymethyl)aminomethane hydrochloride

Compound 1,1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride

At room temperature, ethyl 5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylate hydrochloride (50 g, 161 mmol: see US2015/0072982 A1) in MeOH (800 mL) was added to NaOH (26.4 g, 660 mmol). The mixture was stirred at room temperature for 10 min. Benzyl bromide (99 g, 579 mmol) was added and the mixture was stirred for 2 h. The reaction was concentrated, and water was added to the residue. The mixture was then acidified to pH 2 with 2 M HCl, resulting in the formation of a white precipitate. The white solid was collected by vacuum filtration and washed with water. The white solid collected on the filter was dried under vacuum to give 1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylate hydrochloride (57.5 g, 154 mmol, 96% yield), which was used directly without further purification. MS m/z 337.3 (M+1).

General Synthesis of Chiral N-CBZ Amino Alcohols

Step G-1: (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of bis(trimethylsilyl)aminolithium (1.0 M in THF, 78 mL, 78 mmol) was added dropwise to a solution of diethyl (4-fluorobenzyl)phosphonate (19.5 g, 79 mmol) in THF (100 mL) at 0 °C. The mixture was stirred at 0 °C for 20 min, followed by the dropwise addition of (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (15 g, 75 mmol) in THF (40 mL). The reaction mixture was stirred at 0 °C for 1 h, then slowly heated to room temperature over 1 h, and then stirred for another 2 h at room temperature. The reaction was quenched with water and extracted with EtOAc (twice). The combined organic extracts were washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R,E)-2-(4-fluorostyrene)pyrrolidine-1-carboxylic acid tert-butyl ester (11.65 g, colorless oil), 53%. MS m/z 236.3(M-tBu+H).

Step G-2: (R,E)-2-(4-fluorostyrene)pyrrolidine hydrochloride

At room temperature, HCl solution (4.0 M in dioxane, 29.6 mL, 118 mmol) was added to (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylic acid tert-butyl ester (11.5 g, 39.5 mmol) and stirred for 1 h. The reaction mixture was then concentrated to give crude (R,E)-2-(4-fluorostyryl)pyrrolidine hydrochloride, which was used for the next step without further purification. MS m/z 192.1 (MH ⁺ ).

Step G-3: (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylic acid benzyl ester

Benzyl chloroformate (6.8 mL, 47.4 mmol) was added dropwise at 0 °C to a solution of triethylamine (13.8 mL, 99.9 mmol) and (R,E)-2-(4-fluorostyryl)pyrrolidine hydrochloride (8.99 g, 39.5 mmol) in DCM (200 mL). The mixture was then heated to room temperature and stirred overnight. The reaction mixture was then diluted with additional DCM, washed successively with water and then with _brine , dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (11.6 g, colorless oil) in 90% yield for two steps. MS m/z 348.2 (M+Na) ^⁺ .

Step G-4: (R)-2-((2S,3S)-3-(4-fluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((2R,3R)-3-(4-fluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxylic acid benzyl ester

Sodium bicarbonate (4.52 g, 53.8 mmol) and mCPBA (70%, 13.3 g, 53.8 mmol) were added to a solution of (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylic acid benzyl ester (3.5 g, 10.8 mmol) in DCM (200 mL). The reaction mixture was stirred at room temperature for 2 h. An additional 50 mL of DCM was added and the mixture was stirred for another 1 _h . The reaction was quenched with water and extracted (twice) with DCM. The combined organic extracts were washed sequentially with saturated _{aqueous Na₂S₂O₃} solution, saturated aqueous _NaHCO₃ solution, and brine. The organic layer was then dried over _Na₂SO₄ , _filtered , and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded an inseparable mixture (2.25 g, colorless oil) of (R)-2-((2S,3S)-3-(4-fluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((2R,3R)-3-(4-fluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester, in 61% yield. The mixture was used in the next step without further purification. MS m/z 342.4 (MH ⁺ ).

Step G-5: (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester

At room temperature, cuprous(I)-dimethyl sulfide complex (452 mg, 2.20 mmol) was added to a mixture of (R)-2-((2S,3S)-3-(4-fluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((2R,3R)-3-(4-fluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (750 mg, 2.20 mmol) in THF (12 mL). The mixture was cooled to between -20 and -30 °C in an acetone bath with periodic additions of dry ice. A solution of (3-(trifluoromethyl)phenyl)magnesium bromide (0.25 M in THF, 35.2 mL, 8.79 mmol) was added dropwise. The mixture was stirred for 10 minutes and the temperature was raised to 0 °C. Two equivalents more of (3-(trifluoromethyl)phenyl)magnesium bromide were added and the mixture was stirred for an additional 30 minutes. The reaction was quenched with saturated _NH₄Cl aqueous solution and extracted with EtOAc (twice). The combined organic extracts were dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2S ₎ -2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (195 mg, colorless oil, first elution), 18% yield; and (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (440 mg, second elution), 41% yield. MS m/z 488.4 (MH ⁺ ).

Example 1. (9aR,10S)-10-((S)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester

At 0 °C, methanesulfonyl chloride (0.47 mL, 6.0 mmol) was added to a solution of (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (195 mg, 0.400 mmol) in pyridine (6 mL). After 5 minutes, the ice bath was removed and the reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed sequentially with 1N HCl aqueous solution, saturated _NaHCO3 aqueous solution, and brine. The organic layer was dried over _Na2SO4 , _filtered , and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (130 mg), 58% yield. MS m/z 566.4 (MH ⁺ ).

Step 2: (1R,2S)-2-(4-fluorophenyl)-1-((R)-pyrrolidone-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid hydrochloride

A solution of (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (130 mg, 0.23 mmol) in methanol (6 mL) and HCl (4.0 M in dioxane, 0.12 mL, 0.46 mmol) was purged with nitrogen. 10% palladium on carbon (98 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred at room temperature under the hydrogen balloon. After 2 hours, the reaction mixture was filtered through diatomaceous earth (celite), and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid hydrochloride, which was used in the next step without further purification. MS m/z 432.4 (MH ⁺ ).

Step 3: (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl ester

Huenig base (0.16 mL, 0.91 mmol) and HATU (112 mg, 0.29 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (84 mg, 0.25 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 15 minutes at room temperature, then a solution of crude methanesulfonic acid (1R,2S)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl ester hydrochloride (98 mg, 0.23 mmol) in DCM (2 mL) and 2 equivalents of Huenig base were added. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was then diluted with DCM and washed with water and brine. The organic layer was dried over _Na₂SO₄ , _filtered , and concentrated. Silica gel column chromatography (EtOAc/EtOH/heptane) yielded (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid (150 mg), 88% yield. MS m/z 750.5 (MH ⁺ ).

Step 4: (1R,2S)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl ester

A solution of (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl ester (150 mg, 0.200 mmol) in methanol (6 mL) was purged with nitrogen. 10% palladium on carbon (85 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred for 2 h at room temperature and under the hydrogen balloon. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to provide crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid, which was used in the next step without further purification. MS m/z 570.4 (MH ⁺ ).

Step 5: (9aR,10S)-10-((S)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (107 mg, 0.773 mmol) was added to a solution of crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl ester (110 mg, 0.19 mmol) in DMF (3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give formate of (9aR,10S)-10-((S)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (56 mg, 0.11 mmol, white solid), in a two-step 55% yield. ¹ H NMR (400MHz, MeOD) δppm 7.63 (dd, J=8.63, 5.21Hz, 2H) 7.37 (br d, J＝7.24Hz, 1H) 7.23-7.33 (m, 4H) 7.18 (t, J＝8.68Hz, 2H) 5.77 (dd, J＝9.59, 3.62Hz, 1H) 4.72 (d, J＝9.63Hz, 1H )4.44-4.58(m,1H)3.82-3.95(m,1H)3.62-3.76(m,1H)2.02-2.13(m,2H)1.73-1.96(m,2H)1.54-1.71(m,1H). MS m/z 474.4 (MH ⁺ ).

Table 1a. Other compounds can be prepared using commercially available reagents by the method of Example 1.

Compound 2.(9aR,10S)-10-((R)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Prepared using commercially available reagents via the general method described in Example 1. LCMS (m/z): 442.5 (MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.87–7.72 (m, 1H), 7.53–7.36 (m, 2H), 7.24 (s, 1H), 7.16–7.04 (m, 1H), 6.89 (td, J = 8.6, 2.5 Hz, 1H), 6.85–6.72 (m, 2H), 5.71 (dd, J = 10.0, 3.6 Hz, 1H). 4.71(d, J＝10.0Hz, 1H), 4.46(dd, J＝10.7, 5.2Hz, 1H), 3.75–3.64(m, 1H), 3.62–3.50(m, 1H), 1.89(dd , J=12.6, 6.4Hz, 1H), 1.79 (dt, J=12.3, 5.9Hz, 1H), 1.73–1.59 (m, 1H), 1.31 (qd, J=11.5, 6.6Hz, 1H).

Example 20. (9aR,10S)-10-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester

At 0 °C, benzyl (440 mg, 0.90 mmol) of (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (8 mL) was added to a solution of pyridine (1.1 mL, 13.5 mmol). After 5 minutes, the ice bath was removed and the reaction was stirred at room temperature for ₂ h. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed sequentially with 1N HCl aqueous solution, saturated _NaHCO3 aqueous solution, and brine. The organic layer was dried over _Na2SO4 , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (450 mg) in 88% yield. MS m/z 566.5 (MH ⁺ ).

Step 2: (1R,7aR)-1-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one

A solution of (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (450 mg, 0.796 mmol) in pyridine (8 mL) was heated at 155 °C for 3 h in a microwave reactor. Silica gel column chromatography (EtOAc/heptane) yielded (1R,7aR)-1-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (175 mg), 58% yield. MS m/z 380.5 (MH ⁺ ).

Step 3: (1R,2R)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl-1-ol hydrochloride

A solution of (1R,7aR)-1-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (175 mg, 0.461 mmol) in dioxane (2.5 mL) was added, and the mixture was heated in a sealed tube at 95 °C for 2 days until the reaction was complete. The reaction was then concentrated to give crude (1R,2R)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl-1-ol hydrochloride, which was used for the next step without further purification. MS m/z 354.3 (MH ⁺ ).

Step 4: 1-Benzyl-5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carbonyl)pyridazine-4(1H)-one

Huenig base (0.32 mL, 1.8 mmol) and HATU (224 mg, 0.589 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (168 mg, 0.498 mmol) in DCM (4 mL) at room temperature. The mixture was stirred for 15 minutes at room temperature, then a solution of crude (1R,2R)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl-1-ol hydrochloride (160 mg, 0.453 mmol) in DCM (4 mL) and Huenig base (0.32 mL, 1.8 mmol) were added. The mixture was stirred for 60 minutes at room temperature. The mixture was then diluted with DCM and washed _with water and brine. The organic layer was dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/EtOH/heptane) yielded 1-benzyl-5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carbonyl)pyridazine-4(1H)-one (290 mg, 0.432 mmol), 95% yield. MS m/z 672.7 (MH ⁺ ).

Step 5: (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl ester

Methanesulfonyl chloride (0.52 mL, 6.7 mmol) was added to a solution of 1-benzyl-5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)-one (300 mg, 0.447 mmol) in 2,6-dimethylpyridine (6 mL) in an ice bath. After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then partitioned between DCM and water. The DCM layer was separated and washed sequentially with 1N HCl aqueous solution, saturated _NaHCO3 aqueous solution, and brine. The DCM layer was then dried over _Na2SO4 , _filtered , and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid (280 mg, 0.373), 84% yield. MS m/z 750.7 (MH ⁺ ).

Step 6: (1R,2R)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl ester

To a solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid (280 mg, 0.373 mmol) in methanol (10 mL), HCl (4.0 M in dioxane, 0.19 mL, 0.75 mmol) was added, and the solution was then purged with nitrogen. 10% palladium on carbon (199 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred for 2 h at room temperature and under the hydrogen balloon. More palladium on carbon (199 mg) was added and stirred for an additional 3 h at room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2R)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonic acid, which was used in the next step without further purification. MS m/z 570.5 (MH ⁺ ).

Step 7: (9aR,10S)-10-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (204 mg, 1.48 mmol) was added to a solution of crude (1R,2R)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl ester (210 mg, 0.369 mmol) in DMF (6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give formate of (9aR,10S)-10-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione (30 mg, 0.112 mmol, white solid). Two-step, 30% yield. ¹ H NMR (400MHz, MeOD) δppm 7.88 (br s, 2H) 7.62 (br s, 2H) 7.36-7.48 (m, 1H) 6.89-7.05 (m, 2H) 6.82 (br t, J=8.41Hz, 2H) 5.83 (br d, J=8.02Hz, 1H) 4.52 (br s, 1H) 3.80-3.92 (m, 1H) 3.62-3.74 (m, 1H) 2.03-2.12 (m, 1H) 1.78-1.98 (m, 2H) 1.49-1.66 (m, 1H).MS m/z 474.4 (MH ⁺ ).

Table 1b. Other compounds can be prepared using commercially available reagents according to the method of Example 20.

Compounds E-1: (R)-2-((2S,3S)-3-(2,3-difluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and E-2: (R)-2-((2R,3R)-3-(2,3-difluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxylic acid benzyl ester

Step 1: Diethyl (2,3-difluorobenzyl)phosphonate

A mixture of triethyl phosphite (26.6 mL, 152 mmol) and 2,3-difluorobenzyl bromide (18.43 mL, 145 mmol) was heated at 145 °C for 3 hours, then cooled to room temperature. Toluene (~50 mL) was added, and the mixture was concentrated to give crude (2,3-difluorobenzyl)phosphonate diethyl ester (41 g, colorless oil), which was used for the next step without further purification. MS m/z 265.3 (MH ⁺ ).

Step 2: (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylic acid tert-butyl ester

Lithium bis(trimethylsilyl)amino (1.0 M in THF, 26.3 mL, 26.3 mmol) was added dropwise to a solution of diethyl 2,3-difluorobenzylphosphonate (7.13 g, 25.1 mmol) in THF (84 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, followed by the dropwise addition of (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 25.1 mmol). The reaction mixture was stirred in an ice bath for 1 h, then slowly heated to room temperature for 1 h, and then stirred for an additional 2 h at room temperature. The reaction was quenched with water and extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated. _Silica gel column chromatography (EtOAc/heptane) yielded (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.87 g, white solid), 88% yield. MSm/z 254.3(M-tBu+H).

Step 3: (R,E)-2-(2,3-difluorostyryl)pyrrolidine hydrochloride

At room temperature, HCl solution (4.0 M in dioxane, 19.6 mL, 78 mmol) was added to (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.07 g, 19.6 mmol) and stirred for 1 h. The reaction mixture was then concentrated to give crude (R,E)-2-(2,3-difluorostyryl)pyrrolidine hydrochloride, which was used for the next step without further purification. MS m/z 210.2 (MH ⁺ ).

Step 4: (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylic acid benzyl ester

Benzyl chloroformate (3.1 mL, 21.6 mmol) was added dropwise at 0 °C to a solution of triethylamine (6.84 mL, 49.1 mmol) and (R,E)-2-(2,3-difluorostyryl)pyrrolidine hydrochloride (4.11 g, 19.6 mmol) in DCM (98 mL). The mixture was then heated to room temperature and stirred overnight. The reaction mixture was then diluted with additional DCM, washed successively with water and then with _brine , dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylic acid benzyl ester (6.67 g, colorless oil) in 99% yield over two steps. MS m/z 344.3 (MH ⁺ ).

Step 5: E-1:(R)-2-((2S,3S)-3-(2,3-difluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and E-2:(R)-2-((2R,3R)-3-(2,3-difluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxylic acid benzyl ester

Add mCPBA (21.2 g, 86 mmol) to (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylic acid benzyl ester (5.9 g, 17.2 mmol) in DCM (286 mL). Stir the reaction mixture overnight at room temperature. Quench the reaction with water and extract with DCM (twice). Wash the combined organic extracts sequentially with saturated _{Na₂S₂O₃ aqueous} solution, saturated _NaHCO₃ aqueous solution, and brine. Then dry the organic layer with _Na₂SO₄ , _{filter ,} and concentrate. Silica gel column chromatography (EtOAc/heptane) yielded a non-separable mixture (5.16 g, colorless oil) of (R)-2-((2S,3S)-3-(2,3-difluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxybenzyl ester (E-1) and (R)-2-((2R,3R)-3-(2,3-difluorophenyl)ethylene oxide-2-yl)pyrrolidine-1-carboxybenzyl ester (E-2) in 84% yield. The mixture was used in the next step without further purification.

Compound 3.(9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester

At room temperature, cuprous(I)-dimethyl sulfide complex (286 mg, 1.39 mmol) was added to a mixture of (R)-2-((2S,3S)-3-(2,3-difluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((2R,3R)-3-(2,3-difluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (500 mg, 1.39 mmol) in THF (8 mL). The mixture was cooled to between -20 and -30 °C in an acetone bath with periodic additions of dry ice. A solution of (4-fluorophenyl) magnesium bromide (1.0 M in THF, 8.35 mL, 8.35 mmol) was added dropwise. The mixture was stirred for 10 minutes and the temperature was raised to 0 °C. Two equivalents more of (4-fluorophenyl) magnesium bromide were added and the mixture was stirred for an additional 30 minutes. The reaction was quenched with a saturated aqueous solution of _NH₄Cl and extracted with EtOAc (twice). The combined organic extracts were dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2R ₎ -2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (88 mg, colorless oil, first elution), 14% yield; and (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (350 mg, second elution), 55% yield. MS m/z 456.4 (MH ⁺ ).

Step 2: (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)ethyl)pyrrolidine-1-carboxylic acid benzyl ester

At 0 °C, benzyl (0.23 mL, 2.9 mmol) of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid ester (88 mg, 0.19 mmol) was added to a solution of pyridine (2.5 mL). After 5 minutes, the ice bath was removed and the reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed sequentially with 1N HCl _aqueous solution, saturated _NaHCO3 aqueous solution, and brine. The organic layer was dried over _Na2SO4 , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)ethyl)pyrrolidine-1-carboxylic acid ester (85 mg), 82% yield. MS m/z 534.5 (MH ⁺ ).

Step 3: (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)ethyl methanesulfonic acid hydrochloride

A solution of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methanesulfonyl)oxy)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (85 mg, 0.16 mmol) in methanol (4 mL) and HCl (4.0 M in dioxane, 0.080 mL, 0.32 mmol) was purged with nitrogen. 10% palladium on carbon (68 mg, 0.064 mmol) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred at room temperature under the hydrogen balloon. After 2 hours, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)ethyl methanesulfonic acid hydrochloride, which was used in the next step without further purification. MS m/z 400.4 (MH ⁺ ).

Step 4: (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)ethyl ester

Huenig base (0.11 mL, 0.62 mmol) and HATU (77 mg, 0.20 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (57 mg, 0.17 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 15 minutes at room temperature, and then a solution of crude methanesulfonic acid (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)ethyl ester hydrochloride (62 mg, 0.16 mmol) in DCM (2 mL) and 2 equivalents of Huenig base were added. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was then diluted with DCM and washed with water and brine. The organic layer was dried over _Na₂SO₄ , _filtered , and concentrated. Silica gel column chromatography (EtOAc/EtOH/heptane) yielded (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)ethyl methanesulfonate (100 mg), 90% yield. MS m/z 718.6 (MH ⁺ ). Step 5: (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)ethyl methanesulfonate

A solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)ethyl ester (100 mg, 0.139 mmol) in methanol (6 mL) was purged with nitrogen. 10% palladium on carbon (59 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred for 1 h at room temperature and under the hydrogen balloon. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to provide crude (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)ethyl methanesulfonic acid, which was used in the next step without further purification. MS m/z 538.3 (MH ⁺ ).

Step 6: (9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (76 mg, 0.551 mmol) was added to a solution of crude (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)ethyl ester (74 mg, 0.138 mmol) in DMF (3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give formate of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (24 mg, 0.049 mmol, white solid), in a two-step yield of 36%. ^¹H NMR (400 MHz, _CD₃OD ) δppm 7.79–7.65 (m, 1H), 7.42 (s, 1H), 7.37–7.21 (m, 2H), 7.02 (dd, J=8.6, 5.3Hz, 2H), 6.8 5 (t, J=8.7Hz, 2H), 5.79 (dd, J=9.6, 3.7Hz, 1H), 4.74 (d, J=9.6Hz, 1H), 4.62 (s, 1H), 4 0.53 (dt, J = 10.2, 4.8 Hz, 1H), 3.90 (dd, J = 12.7, 8.8 Hz, 1H), 3.65 (td, J = 11.1, 7.0 Hz, 1H), 2.04 (ddt, J = 38.5, 18.2, 6.4 Hz, 2H), 1.94 (s, 1H), 1.51 (qd, J = 11.7, 6.7 Hz, 1H). MS m/z 442.4 (MH ⁺ ). Compound 4.(9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione

Step 1: (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester

At room temperature, cuprous(I)-dimethyl sulfide complex (3.65 g, 17.7 mmol) was added to a mixture of (R)-2-((2S,3S)-3-(2,3-difluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((2R,3R)-3-(2,3-difluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (5.8 g, 16.1 mmol) in THF (161 mL). The mixture was cooled to between -20 and -30 °C by periodic addition of dry ice in an acetone bath. A phenyl magnesium bromide solution (1.0 M in THF, 97 mL, 97 mmol) was added dropwise. The mixture was stirred for 10 min, then heated to 0 °C and stirred for an additional 1 h. The reaction was quenched with a saturated aqueous _NH₄Cl solution and extracted with EtOAc (twice). The combined organic extracts were dried _{over Na₂SO₄} , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) provided (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester (1.5 g, colorless oil, first elution) in 13% yield; and (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester (2.5 g, second elution) in 35% yield. MS m/z 438.5 (MH ⁺ ).

Step 2: (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-((methanesulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester

At 0 °C, benzyl (900 mg, 2.06 mmol) of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylic acid was added to a solution of pyridine (21 mL) with methanesulfonyl chloride (1.92 mL, 24.7 mmol). After 5 minutes, the ice bath was removed and the reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed sequentially with 1N HCl _aqueous solution, saturated _NaHCO3 aqueous solution, and brine. The organic layer was dried over _Na2SO4 , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-((methanesulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester (700 mg) in 66% yield. MS m/z 516.5 (MH ⁺ ).

Step 3: (1R,2R)-2-(2,3-difluorophenyl)-2-phenyl-1-((R)-pyrrolidine-2-yl)ethyl methanesulfonic acid hydrochloride

A solution of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-((methanesulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylic acid benzyl ester (700 mg, 1.36 mmol) in methanol (27 mL) and HCl (4.0 M in dioxane, 0.68 mL, 2.7 mmol) was purged with nitrogen. 10% palladium on carbon (722 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred at room temperature under the hydrogen balloon. After 30 minutes, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2R)-2-(2,3-difluorophenyl)-2-phenyl-1-((R)-pyrrolidine-2-yl)ethyl methanesulfonate hydrochloride, which was used for the next step without further purification. MS m/z 382.4 (MH ⁺ ).

Step 4: (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-phenylethyl ester

Huenig base (0.95 mL, 5.46 mmol) and HATU (674 mg, 1.77 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (559 mg, 1.5 mmol) in DCM (7 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes, and then a solution of crude methanesulfonic acid (1R,2R)-2-(2,3-difluorophenyl)-2-phenyl-1-((R)-pyrrolidine-2-yl)ethyl ester hydrochloride (570 mg, 1.36 mmol) in DCM (2 mL) and 1.1 equivalents of Huenig base were added. The mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with DCM and washed with water and brine. The organic layer was dried over _Na₂SO₄ , _filtered , and concentrated. Silica gel column chromatography (EtOAc/EtOH/heptane) yielded (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-phenylethyl ester (900 mg), 94% yield. MS m/z 700.6 (MH ⁺ ).

Step 5: (1R,2R)-2-(2,3-difluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-phenylethyl methanesulfonic acid

A solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-phenylethyl ester (900 mg, 1.29 mmol) in methanol (26 mL) was purged with nitrogen. 10% palladium on carbon (684 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred for 1 h at room temperature and under the hydrogen balloon. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to provide crude methanesulfonic acid (1R,2R)-2-(2,3-difluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-phenylethyl ester, which was used in the next step without further purification. MS m/z 520.4 (MH ⁺ ). Step 6: (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (535 mg, 3.87 mmol) was added to a solution of crude methanesulfonic acid (1R,2R)-2-(2,3-difluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-phenylethyl ester (670 mg, 1.29 mmol) in DMF (13 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (259 mg, 0.606 mmol, white solid), in a two-step yield of 47%. (400MHz, DMSO-d6) δ7.84 (t, J=7.1Hz, 1H), 7.37 (ddt, J=16.0, 13.4, 8.1Hz, 2H), 7.2 1(s, 1H), 7.14–7.03(m, 3H), 6.98–6.85(m, 2H), 5.77(dd, J=9.6, 3.7Hz, 1H), 4.64(d, J=9.6Hz, 1H), 4.50 (dt, J=10.0, 5.1Hz, 1H), 3.73 (dd, J=12.0, 8.4Hz, 2H), 1.92 (ddt , J=30.6, 12.3, 6.1Hz, 2H), 1.74 (q, J=8.3, 6.0Hz, 1H), 1.34 (qd, J=11.6, 6.6Hz, 1H). MS m/z 424.4 (MH ⁺ ).

Compound 5.(9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1: (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester

At room temperature, cuprous(I)-dimethyl sulfide complex (2.83 g, 13.8 mmol) was added to a mixture of (R)-2-((2S,3S)-3-(2,3-difluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester and (R)-2-((2R,3R)-3-(2,3-difluorophenyl)ethyleneoxy-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (4.95 g, 13.8 mmol) in THF (120 mL). The mixture was cooled to between -20 and -30 °C by periodic addition of dry ice in an acetone bath. A solution of (3-fluorophenyl) magnesium bromide (1.0 M in THF, 55.1 mL, 55.1 mmol) was added dropwise. The mixture was stirred for 10 minutes, then heated to 0 °C and stirred for an additional 15 minutes. Two equivalents more of (3-fluorophenyl) magnesium bromide were added and the mixture was stirred for an additional 30 minutes. The reaction was quenched with a saturated aqueous solution of _NH₄Cl and extracted with EtOAc (twice). The combined organic extracts were dried over _Na₂SO₄ , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2R ₎ -2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (1.4 g, colorless oil, first eluted), 10% yield; and (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (3.2 g, second eluted), 51% yield. MS m/z 456.4 (MH ⁺ ). Step 2: (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((methanesulfonyl)oxy)ethyl)pyrrolidine-1-carboxylic acid benzyl ester

At 0 °C, methanesulfonyl chloride (1.62 mL, 20.7 mmol) was added to a solution of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylic acid ester (1.4 g, 1.38 mmol) in pyridine (20 mL). After 5 minutes, the ice bath was removed and the reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed sequentially with 1N HCl aqueous solution, saturated _{NaHCO3 aqueous} solution, and brine. The organic layer was dried over _Na2SO4 , filtered, and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((methanesulfonyl)oxy)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (575 mg), 78% yield. MS m/z 534.4 (MH ⁺ ).

Step 3: (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidine-2-yl)ethyl methanesulfonic acid hydrochloride

A solution of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((methanesulfonyl)oxy)ethyl)pyrrolidine-1-carboxylic acid benzyl ester (575 mg, 1.08 mmol) in methanol (15 mL) and HCl (4.0 M in dioxane, 0.54 mL, 2.2 mmol) was purged with nitrogen. 10% palladium on carbon (459 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred at room temperature under the hydrogen balloon. After 2 h, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidine-2-yl)ethyl ester hydrochloride, which was used for the next step without further purification. MS m/z 400.4 (MH ⁺ ). Step 4: (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)ethyl ester

Huenig base (0.75 mL, 4.3 mmol) and HATU (532 mg, 1.40 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (398 mg, 1.18 mmol) in DCM (6 mL) at room temperature. The mixture was stirred for 15 minutes at room temperature, and then a solution of crude methanesulfonic acid (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidine-2-yl)ethyl ester hydrochloride (430 mg, 1.08 mmol) in DCM (6 mL) and 1.1 equivalents of Huenig base were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with DCM and washed with water and brine. The organic layer was dried over _Na₂SO₄ , _filtered , and concentrated. Silica gel column chromatography (EtOAc/EtOH/heptane) yielded (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)ethyl methanesulfonic acid (735 mg), 95% yield. MS m/z 718.6 (MH ⁺ ).

Step 5: Ethyl (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)methanesulfonic acid

A solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridine-3-carbonyl)pyrrolidine-2-yl)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)ethyl ester (735 mg, 1.02 mmol) in methanol (15 mL) was purged with nitrogen. 10% palladium on carbon (436 mg) was added and a hydrogen balloon was attached. The flask was purged and refilled with hydrogen (3 times), and then vigorously stirred for 1 h at room temperature and under the hydrogen balloon. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH. The filtrate was concentrated to provide crude (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)ethyl methanesulfonic acid, which was used in the next step without further purification. MS m/z 538.5 (MH ⁺ ).

Step 6: (9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (566 mg, 4.09 mmol) was added to a solution of crude (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidine-2-yl)ethyl methanesulfonic acid (550 mg, 1.02 mmol) in DMF (20 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (252 mg, 0.571 mmol, white solid), in a two-step 56% yield. (400MHz, MeOD) δppm 7.74 (brt, J=6.99Hz, 1H) 7.40 (s, 1H) 7.37 (br s, 1H) 7.23-7.36 (m, 1H) 7.06-7.16 (m, 1H) 6.82-6.91 (m, 1H) 6.72-6.81 (m, 2H) 5.81 (dd, J=9.61, 3.59Hz, 1H) 4.76 (d, J=9.63Hz, 1H) 4.61 (br s, 1H) 4.48-4.55 (m, 1H) 3.84-3.94 (m, 1H) 3.65 (td, J = 11.25, 7.38Hz, 1H) 2.04- 2.14 (m, 1H) 1.95-2.03 (m, 1H) 1.80-1.92 (m, 1H) 1.50 (qd, J=11.67, 6.80Hz, 1H). MS m/z 442.4(MH ⁺ )

Example 30. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate

Step 1. Iodomethyl methyl carbonate

Sodium iodide (1.81 g, 12 mmol) was added to a solution of chloromethyl methyl carbonate (1 g, 8 mmol) in acetone (4 ml). The yellow suspension was then stirred overnight at 40 °C. The reaction was cooled to room temperature and concentrated. The residue was diluted with water and an aqueous solution of sodium thiosulfate, and then extracted with DCM. The organic layer was washed with brine, _dried over _Na₂SO₄ , filtered, and concentrated to give crude iodomethyl methyl carbonate (1.27 g, 5.88 mmol, 73% yield) as a yellow oil. It was used without further purification.

Step 2. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate

Potassium carbonate (499 mg, 3.61 mmol) and iodomethyl methyl carbonate (520 mg, 2.41 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (510 mg, 1.21 mmol) in DMF (volume: 8.6 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, followed by stirring at room temperature for another hour. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate (367 mg, 0.710 mmol, white solid), ⁵⁹ % yield. NMR (500 MHz, methanol-d4) δ 7.72 (s, 1H), 7.47 (t, J = 2.2 Hz, 1H), 7.39–7.21 (m, 2H), 7.13 (d, J = 8.6 Hz, 3H), 7.00 (d, J = 7.3 Hz, 2H), 5.81 (t, J = 4.2 Hz, 1H), 5.76 (d, J = 10.2 Hz, 1H), 5. 71–5.65 (m, 1H), 4.66–4.59 (m, 1H), 4.53 (s, 1H), 3.85 (t, J=2.2Hz, 3H), 3.78 (t, J=10 .3Hz, 1H), 3.63 (q, J=10.4Hz, 1H), 2.11–1.95 (m, 2H), 1.85 (s, 1H), 1.56–1.44 (m, 1H). MS m/z 512.4 (MH ⁺ ).

Example 31. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl isobutyrate

Triethylamine (0.040 mL, 0.28 mmol) was added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (40 mg, 0.094 mmol) in DCM (1 mL), followed by isobutyryl chloride (0.020 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated. The residue was dissolved in DMSO and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl isobutyrate (26 mg, 0.052 mmol, white solid), ⁵⁵ % yield. NMR (400MHz, DMSO-d6) δ7.82 (t, J=7.1Hz, 1H), 7.37 (dddd, J=21.7, 15.9, 11.5, 4.8H z, 3H), 7.20–7.02 (m, 3H), 6.88 (s, 2H), 5.78 (d, J=10.1Hz, 1H), 4.52 (dd, J=10.1, 4. 9Hz, 2H), 3.62 (dd, J=12.1, 8.0Hz, 1H), 3.48 (td, J=11.0, 6.6Hz, 1H), 2.77 (hept, J= 7.1Hz, 1H), 1.84 (dd, J=11.8, 6.1Hz, 2H), 1.66 (s, 1H), 1.22 (dd, J=7.2, 3.9Hz, 6H). MS m/z 494.5 (MH ⁺ ).

Example 32. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl isobutyrate

Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (141 mg, 0.85 mmol), and methyl isobutyrate (116 mg, 0.85 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (60 mg, 0.142 mmol) in DMF (volume: 1.4 mL) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl isobutyrate (19 mg, 0.036 mmol, white solid), 25% yield. ¹ H NMR (400MHz, DMSO-d6) δ7.83 (t, J=7.1Hz, 1H), 7.46–7.27 (m, 3H), 7.18–7.03 (m, 3H), 6.96–6.83 (m, 2H), 5.84–5.67 (m, 2H), 5.60 (d, J=6.3 Hz, 1H), 4.52–4.31 (m, 2H), 3.67–3.38 (m, 2H), 2.02–1.76 (m, 2H), 1.66 (d, J=11.3Hz, 1H), 1.45–1.17 (m, 1H), 1.09 (dd, J=7.0, 1.1Hz, 6H). MS m/z524.3(MH ⁺ ).

Example 33.1-(((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethyl methyl carbonate

Potassium carbonate (98 mg, 0.71 mmol), potassium iodide (118 mg, 0.71 mmol), 18-crown-6 (12 mg, 0.05 mmol), and 1-chloroethyl methyl carbonate (98 mg, 0.71 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (50 mg, 0.118 mmol) in DMF (volume: 1 mL) at room temperature. The mixture was stirred at 60 °C for 4 h. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give 1-(((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethyl methyl carbonate (12 mg, 0.022 mmol, white solid), ¹⁹ % yield. NMR (500MHz, chloroform-d) δ7.40 (t, J=6.9Hz, 1H), 7.34 (s, 1H), 7.28-7.12 (m, 5H), 7.01 (d, J=7.0 Hz, 2H), 6.70 (q, J=5.3Hz, 1H), 5.37 (dd, J=10.5, 3.4Hz, 1H), 4.59 (d, J=10.5Hz, 1H), 4.37 (ddd, J=10.1, 6.3, 3.4Hz, 1H), 3.93-3.85 (m, 4H), 3.64 (td, J=11.2, 6.6Hz, 1H), 2.00 (dt, J=13.0, 6.8Hz, 1H), 1.92 (dt, J=12.9, 6.4Hz, 1H), 1.84-1.72 (m, 4H), 1.51-1.40 (m, 1H).MS m/z 526.3 (MH ⁺ ).

Example 34. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-ylisopropyl carbonate

To a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione (60 mg, 0.14 mmol) in DCM (2 mL), Huenig base (0.074 mL, 0.43 mmol) was added, followed by isopropyl chloroformate (0.18 mL, 0.18 _mmol ). The reaction mixture was stirred at room temperature for 2 h and then diluted with ethyl acetate. The mixture was washed with water, and the organic layer was dried over _Na₂SO₄ , filtered, and concentrated. The residue was dissolved in DMSO and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-ylisopropyl carbonate (17 mg, 0.032 mmol, white solid), 23% yield. ¹ H NMR (500MHz, DMSO-d6) δppm 7.86 (br t, J＝6.92Hz, 1H) 7.34-7.49 (m, 3H) 7.10-7.17 (m, 3H) 6.88-6.95 (m, 2H) 5.82 (dd, J＝10.23, 3.37Hz, 1H) 4.90 (dt, J＝12.44, 6.13Hz, 1H) 4.54-4.59 (m, 2H) 3.63-3.70 (m, 1H) 3.45-3.63 (m, 1H) 1.84-1.94 (m, 2H) 1.65-1.83 (m, 1H) 1.18-1.37 (m, 7H). MS m/z 510.4 (MH ⁺ ).

Example 35. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate

Triethylamine (0.13 mL, 0.95 mmol) was added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (50 mg, 0.12 mmol) in DCM (1.2 mL), followed by DMAP (7 mg, 0.06 mmol) and dimethylcarbamoyl chloride (0.065 mL, 0.71 mmol). The reaction mixture was stirred overnight at room temperature, filtered, and then concentrated. The residue was dissolved in DMSO and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate (32 mg, 0.064 mmol, white solid), 54% yield. ¹ H NMR (500MHz, methanol-d4) δ7.72 (br m, 1H), 7.49 (br s, 1H), 7.34 (m, 1H), 7.29 (m, 1H), 7.15 (m, 3H), 7.01 (m, 2H), 5.81 (br m, 1H), 4.67 (m, 1H), 4.58 (br m, 1H), 3.81 (m, 1H), 3.60 (br m, 1H), 3.15 (br s, 3H), 3.02 (br s, 3H), 2.01 (br m, 2H), 1.85 (br m, 1H), 1.49 (br m, 1H). MSm/z 495.3 (MH ⁺ ).

Example 36. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl-4-methylpiperazine-1-carboxylic acid ester

Step 1. 4-Methylpiperazine-1-carboxylic acid methyl ester

Chloromethyl chloroformate (0.2 mL, 2.25 mmol) was added to a solution of 1-methylpiperazine (0.51 mL, 4.6 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 3 h. The reaction was quenched with 5% _NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over _Na2SO4 , filtered, and concentrated to give crude 4-methylpiperazine _- 1-carboxylic acid chloromethyl ester, which was used in the next step without further purification. MS m/z 193.5 (MH ⁺ ).

Step 2. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl-4-methylpiperazine-1-carboxylic acid ester

Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (94 mg, 0.57 mmol), and 4-methylpiperazine-1-carboxylic acid chloromethyl ester (109 mg, 0.57 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (60 mg, 0.142 mmol) in DMF (1 mL) at room temperature. The mixture was stirred for 3 h at room temperature. An additional 4-methylpiperazine-1-carboxylic acid chloromethyl ester (109 mg, 0.57 mmol) was added, and the mixture was stirred overnight. The reaction mixture was filtered through a 1 μm filter and purified by SFC ( _CO₂ /MeOH). The product fractions were combined, freeze-dried, and lyophilized to give (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl-4-methylpiperazine-1-carboxylic acid ester (8 mg, 0.013 mmol, white solid), ⁹ % yield. NMR (500MHz, DMSO-d6) δ7.87 (t, J=7.0Hz, 1H), 7.47-7.31 (m, 3H), 7.21-7.07 (m, 3H), 7.0 1-6.85 (m, 2H), 5.83-5.70 (m, 2H), 5.61 (d, J=6.4Hz, 1H), 4.50 (dd, J=13.9, 7.2Hz, 2H), 3 .70-3.59 (m, 1H), 3.54 (td, J=11.2, 6.6Hz, 1H), 3.38 (d, J=5.6Hz, 4H), 2.30 (s, 4H), 2.20 (s, 3H), 1.98-1.82 (m, 2H), 1.70 (d, J=15.9Hz, 1H), 1.30 (ddd, J=17.8, 15.4, 9.0Hz, 1H). MS m/z 580.4 (MH ⁺ ).

Example 37. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)methyl L-valine ester

Step 1. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(tert-butoxycarbonyl)-L-valine ester

To a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (80 mg, 0.19 mmol) in DMF (volume: 1.8 mL) _{, K₂CO₃} (78 mg, 0.57 mmol) and KI (94 mg, 0.57 mmol) were added. The mixture was cooled to 0 °C and (tert-butyloxycarbonyl)-L-valine chloromethyl ester (151 mg, 0.57 mmol) was added. The reaction was stirred overnight at room temperature and then diluted with EtOAc. The organic layer was washed with water, dried over _Na₂SO₄ , filtered _, and concentrated. Silica gel column chromatography (DCM/MeOH) yielded (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(tert-butoxycarbonyl)-L-valine ester (90 mg), 73% yield. MS m/z 654.2 (MH ⁺ ).

Step 2. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl L-valine ester

HCl (0.7 mL, 2.8 mmol, 4.0 M in dioxane, 460 μL) was added dropwise to a solution of (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(tert-butoxycarbonyl)-L-valine ester (90 mg, 0.138 mmol) in dioxane (460 μL) at 0 °C. The mixture was stirred at 0 °C for 5 h and maintained at 0 °C overnight. The reaction was concentrated and the residue was purified by reversed-phase HPLC to give formate of (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl L-valine ester (14 mg), 14% yield. ¹ H NMR (500MHz, methanol-d4) δ7.74 (m, 1H), 7.51 (s, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.15 (m, 3H), 7.01 (m, 2H), 5.93 (d, J = 6Hz, 1H), 5.78 (m, 1H), 5.73 (m, J = 6Hz, 1H), 4.64(m, 1H), 4.54(m, 1H), 3.80(m, 1H), 3.65(m, 1H), 2.15(m, 1H), 2.03 (m, 2H), 1.87 (m, 1H), 1.53 (m, 1H), 1.04 (d, J=7Hz, 3H), 0.98 (d, J=7Hz, 3H). MS m/z 553.3(M+1).

Example 38. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (49 mg, 0.35 mmol) and iodomethane (67 mg, 0.47 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (50 mg, 0.12 mmol) in DMF (volume: 1 mL) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (20 mg, 0.046 mmol, white solid), 39% yield. ^{The 1H} of the monohydrate... NMR (500 MHz, chloroform-d) δ 7.52–7.45 (m, 2H), 7.28–7.22 (m, 1H), 7.21–7.14 (m, 1H), 7.14–7.09 (m, 3H), 7.05–6.99 (m, 2H), 5.41 (dd, J = 9.2, 3.3 Hz, 1H), 4.64 (d, J = 9.2 Hz, 1H), 4.41 (ddd, J = 1 0.1, 6.5, 3.4Hz, 1H), 4.04 (s, 3H), 3.94-3.85 (m, 1H), 3.73 (td, J=11.3, 6.7Hz, 1H), 2.11 (d t, J=13.2, 6.9Hz, 1H), 2.00 (dt, J=12.8, 6.6Hz, 1H), 1.94-1.80 (m, 1H), 1.65-1.53 (m, 3H). MS m/z 438.2 (MH ⁺ ).

Example 39. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-3-methoxy-3-methylbutyrate

Huenig base (0.10 mL, 0.57 mmol) and HATU (70 mg, 0.18 mmol) were added to a solution of 3-methoxy-3-methylbutyric acid (21 mg, 0.16 mmol) in DMF (1 mL) at room temperature. The mixture was stirred for 15 minutes at room temperature, and then a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione (60 mg, 0.14 mmol) and Huenig base (0.027 mL, 0.16 mmol) in DMF (1 mL) was added. The reaction mixture was stirred overnight at room temperature, filtered, and then purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl 3-methoxy-3-methylbutyrate (5 mg, 0.008 mmol, white solid), 6% yield. ^¹H NMR (500 MHz, methanol-d⁴) δ 7.71 (m, 1H), 7.47 (s, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.14 (m, 3H), 6.99 (m, 2H), 5.80 (m, 1H), 4.66 (m, 1H), 4.58 (m, 1H), 3.80 (m, 1H), 3.62 (m, 1H), 3.36 (s, 3H, overlap), 2.90 (s, 2H), 2.02 (m, 2H), 1.86 (m, 1H), 1.51 (m, 1H), 1.43 (s, 6H). MS m/z 538.2 ( ^MH⁺ ).

Example 40. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-2-methoxy-2-methylpropionate

A mixture of 2-methoxy-2-methylpropionic acid (56 mg, 0.47 mmol) and oxalyl chloride (115 μl, 1.31 mmol) was gently heated at 50 °C for 5 min. The mixture was kept at room temperature for 1 h, and then at 40 °C for 30 min. Excess oxalyl chloride was removed under reduced pressure. The residue was added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione (40 mg, 0.094 mmol) and trimethylamine (0.040 mL, 0.28 mmol) in DCM (1 mL) and stirred at room temperature for 2 days. The reaction mixture was filtered and then purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl 2-methoxy-2-methylpropionate (28 mg, 0.052 mmol, white solid), 56% yield. ¹ HNMR (400MHz, DMSO-d6) δ7.83 (t, J=7.1Hz, 1H), 7.50–7.25 (m, 3H), 7.18–7.02 (m, 3H), 6.88 (s, 2H), 5.79 (s, 1H), 4.67 –4.40 (m, 2H), 3.63 (t, J=9.9Hz, 1H), 3.49 (td, J=11.0, 6.5Hz, 1H), 1.94–1.77 (m, 2H), 1.47 (s, 5H), 1.32–1.11 (m, 1H). MS m/z 524.3 (MH ⁺ ).

Example 41. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl 2-methoxy-2-methylpropionate

Step 1. Chloromethyl 2-methoxy-2-methylpropionate

A mixture of 2-methoxy-2-methylpropionic acid (1 g, 8.5 mmol), _NaHCO3 (2.84 g, 33.9 mmol), tetrabutylammonium hydrogen sulfate (0.287 g, 0.847 mmol), and chloromethyl chlorosulfonate (0.942 mL, 9.31 mmol) in 20 mL of water:dichloromethane (1:1) was stirred at room temperature for 1 hour. The organic phase was separated and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under vacuum to obtain crude chloromethyl 2-methoxy-2-methylpropionic acid (1 g, colorless liquid), which was used without further purification.

Step 2. (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl 2-methoxy-2-methylpropionate

Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (141 mg, 0.85 mmol), and chloromethyl 2-methoxy-2-methylpropionate (142 mg, 0.85 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (60 mg, 0.142 mmol) in DMF (1.4 mL) at room temperature. The mixture was stirred overnight. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)methyl 2-methoxy-2-methylpropionate (8 mg, 0.015 mmol, white solid), 10% yield. ¹ H NMR (400MHz, DMSO-d6) δ7.83 (t, J=7.0Hz, 1H), 7.51–7.25 (m, 3H), 7.17–6.95 (m, 3H), 6.99–6.84 (m, 2H), 5.85–5.69 (m, 2H), 5.68 (d, J=6 .3Hz, 1H), 4.58–4.32 (m, 2H), 3.68–3.41 (m, 2H), 3.15 (s, 3H), 1.86 (dt, J=12.3, 6.5Hz, 2H), 1.64 (q, J=17.2, 13.7Hz, 1H), 1.31 (s, 6H). MS m/z 554.3 (MH ⁺ ).

Example 42.2-((((((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)methyl-2-methylpropionate

Step 1. Methyl 2-(((chloromethoxy)carbonyl)oxy)-2-methylpropionate

At 0 °C, pyridine (0.5 mL, 1.3 mmol) and methyl 2-hydroxy-2-methylpropionate (600 mg, 5.08 mmol) were added to a solution of methyl chloroformate (600 mg, 4.65 mmol) in DCM (10 mL). The mixture was stirred at 0 °C for 1 h, and then at room temperature for 2 h. The reaction was quenched with _2N HCl aqueous solution and extracted with DCM. The organic layer was dried over _Na₂SO₄ , filtered, and concentrated to give crude methyl 2-(((chloromethoxy)carbonyl)oxy)-2-methylpropionate, which was used in the next step without further purification.

Step 2.2-((((((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)methyl-2-methylpropionate

Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (94 mg, 0.57 mmol), and methyl 2-(((chloromethoxy)carbonyl)oxy)-2-methylpropionate (30 mg, 0.14 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (60 mg, 0.142 mmol) in DMF (0.5 mL) at room temperature. The mixture was stirred for 4 h at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give methyl 2-((((((9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropionate (9 mg, 0.015 mmol, white solid), 11% yield. ¹ H NMR (500MHz, DMSO-d6) δ7.87 (s, 1H), 7.39 (d, J = 23.5Hz, 3H), 7.12 (d, J = 4.0Hz, 3H), 6.94 (d, J = 7.8Hz, 2H), 5 .84–5.58(m, 3H), 4.50(d, J=10.0Hz, 2H), 3.68(m, 5H), 1.88(s, 2H), 1.70(s, 1H), 1.57(s, 6H), 1.29(s, 1H). MS m/z 598.2 (MH ⁺ ).

Example 43. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-((5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxy)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Step 1. 4-(iodomethyl)-5-methyl-1,3-dioxacyclopenten-2-one

Sodium iodide (1.51 g, 10.1 mmol) was added to a solution of 4-(chloromethyl)-5-methyl-1,3-dioxacyclopenten-2-one (500 mg, 3.37 mmol) in butanone (10 mL) at room temperature, and the mixture was stirred at 60 °C for 90 min. The reaction was filtered and concentrated. Silica gel column chromatography (EtOAc/heptane) yielded 4-(iodomethyl)-5-methyl-1,3-dioxacyclopenten-2-one (622 mg, 2.59 mmol) in 77% yield. MS m/z 241.0 (MH ⁺ ).

Step 2. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-((5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxy)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

Potassium carbonate (41 mg, 0.30 mmol) and 4-(iodomethyl)-5-methyl-1,3-dioxane-2-one (57 mg, 0.24 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (50 mg, 0.12 mmol) in DMF (1 mL) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and then lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-((5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxy)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione (32 mg, 0.059 mmol, white solid), 50 ^% yield. NMR (400MHz, chloroform-d) δ7.49-7.40(m, 2H), 7.25-7.19(m, 1H), 7.19-7.07(m, 4H), 7.03-6.96(m, 2H), 5. 41 (dd, J=9.4, 3.3Hz, 1H), 5.18 (d, J=13.3Hz, 1H), 5.10 (d, J=13.3Hz, 1H), 4.60 (d, J=9.3Hz, 1H), 4. 38 (ddd, J=10.0, 6.4, 3.3Hz, 1H), 3.92-3.83 (m, 1H), 3.68 (td, J=12.1, 11.3, 6.7Hz, 1H), 2.17 (s, 3H ), 2.08 (dt, J=13.1, 6.7Hz, 1H), 1.97 (dt, J=13.5, 6.2Hz, 1H), 1.92-1.78 (m, 1H), 1.57-1.48 (m, 1H). MS m/z 536.2 (MH ⁺ ).

Example 44. (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-4-yl-4-methylpiperazine-1-carboxylic acid ester

Potassium carbonate (98 mg, 0.71 mmol) and 4-methylpiperazine-1-carbonyl chloride (58 mg, 0.35 mmol) were added to a solution of (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (60 mg, 0.14 mmol) in DMF (1.5 mL) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered through a 1 μm filter and purified by reversed-phase HPLC. The product fractions were combined, freeze-dried, and lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-4-methylpiperazine-1-carboxylic acid ester (63 mg, 0.11 mmol, white solid), 81% yield. ¹ H NMR (400MHz, MeOD) δppm 7.70 (br s, 1H) 7.45 (br s, 1H) 7.23-7.38 (m, 2H) 7.04-7.20 (m, 3H) 6.90-7.04 (m, 2H) 5.81 (br s, 1H) 4.64 (d, J = 10.17Hz, 1H) 4.56 (br s, 1H) 3.68-3.89 (m, 3H) 3.43-3.66 (m, 3H) 2.70 (br s, 4H) 2.44 (br s, 3H) 1.92-2.08 (m, 2H) 1.75-1.89 (m, 1H) 1.47 (br s, 1H). MS m/z 550.5 (MH ⁺ ). Table 1c. Other examples can be prepared using commercially available reagents and compounds 2-5 by the methods described above.

Biological assays and data

The activity of the compounds according to the invention can be evaluated by the following in vitro and in vivo methods. Using the assays described herein, the compounds of the invention exhibited inhibitory potency according to Table 2. In Table 2, + represents ≥1 μM; ++ represents <1 μM and ≥0.1 μM; and +++ represents <0.1 μM.

Influenza virus small genome sequencing (RNP assay)

For the small genome reporter assay of influenza A virus, 293T cells were transfected with expression vectors encoding PB2, PB1, PA, and NP proteins and influenza A fluorescent enzyme reporter plasmids. Cells were harvested in Dulbecco modified Eagles medium (DMEM, phenol red-free, supplemented with 10% heat-inactivated FBS (fetal bovine serum), 1% sodium pyruvate, and 1% L-glutamine (Cellgro, Manassas, VA)). Five plasmids were transfected with Fugene 6 transfection reagent (Promega, Madison, WI) in a ratio of 1:3 DNA (μg): Fugene 6 (μl) on (Gibco, Carlsbad, CA). Transfection was performed in 384 wells at a cell density of 1.8 × ^10⁴ cells/well. Two hours after transfection, the compound was added, and the plates were incubated at 37°C and 5% _CO₂ for 48 hours. After incubation, cells were lysed, and quantitative luciferase production was achieved by adding Britelite (Perkin-Elmer, Waltham, MA). For cytotoxicity measurements, Promega (Madison, WI) was added to the treated cells according to the manufacturer's instructions.

Table 2. Activity of selected compounds against various influenza strains as determined using RNP.

Claims (28)

1. Compound of formula (A): Or its pharmaceutically acceptable salt, wherein: Y is a group in the following formula The dashed lines represent the bonds connecting this group to formula (A); G is H or selected from the following groups: R 0 , –C(O)R 0 , –C(O)-OR 0 , –C( RG ) 2 -OC(O)R 0 , –C( RG ) 2 -OC(O)-OR 0 , –P(＝O)(OR 0 ) 2 , –(CR G ) 2 -OP(＝O)(OR0)  2 , –C(O)-N(R 0 ) 2  and –C( RG ) 2 -OC(O)N(R 0 )2 . Each R 0  is independently H or a group selected from the following: C <sub>1 -C 6  alkyl, phenyl, pyridyl, C<sub> 3 -C 7  cycloalkyl, and 3-6-membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members; and each R 0  that is not H is optionally substituted with one or two groups selected from the following: halogen, CN, -OH, amino, C 1-4 alkyl, COOR, phenyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, and 3-6-membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members, and is optionally substituted with one or two groups selected from the following: halogen, CN, -OH, oxo, amino, C 1-4 alkyl, phenyl, C 1-4  alkoxy, C 1-4  haloalkyl, and C 1-4 haloalkoxy; Furthermore, each RG is independently selected from H and C1-4 alkyl groups; R1 is H, halogen, CN, COOR*, -CONR* 2 or optionally a C1 - C6 alkyl group substituted with one or two groups selected from the following groups: halogen, –OR* and –NR* 2 ; R* is independently H or optionally C1 - C6 alkyl substituted with –OR or –NR 2 each time it appears; Z1 is N, and Z2 is C(R) 2 ; Or Z1 is CH, and Z2 is NR, O, S or CH2 ; Z3 is CH2 , Q, -CH2- CH2- , -Q- CH2- , –CH2 -Q-, -CH2 -Q- CH2- , -CH2 - CH2 - CH2- or CX2 , where X is a halogen; Q is selected from –NR-, O, S, SO and SO2 ; R2 is selected from H, halogen, CN, C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by up to three independent groups selected from the following: halogen, CN, C1-4 alkyl, -OR, C1-4 haloalkoxy, -NR2 , and C1-4 haloalkyl; Each R 3 is a substituent optionally present on any carbon atom of the ring containing Z 2 and Z 3 , and is independently selected from halogen, –OR, C 1-4 haloalkyl, C 1-4 haloalkoxy, oxo, CN, -NR 2 , and C 1-4 alkyl optionally substituted by up to three groups independently selected from: halogen, CN, C 1-4 alkyl, -OR, C 1-4 haloalkoxy, -NR 2 , and C 1-4 haloalkyl; n is 0-2; Ar 1 and Ar 2 each independently represent a phenyl or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S as ring members, and Ar 1 and Ar 2 each independently are substituted by up to three groups selected from the following groups: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkyne and CN; Ar 1 and Ar 2 are optionally linked together by a bridge of the formula –C(R L ) 2 -L- to form a tricyclic group, wherein Ar 1 and Ar 2 are each optionally substituted by up to three independent groups selected from the following: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkyne and CN; R is independently H or C1 - C4 alkyl each time it appears, said C1 - C4 alkyl being optionally substituted by up to three groups independently selected from the following: halogen, OH, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy and C1-4 haloalkyl; L is selected from S, S = O, SO₂ , O, NR, C(R L ) ₂ , and CF₂ ; and And each RL is independently H or C1-2 alkyl; provided that the compound is not selected from the following compounds: 1 12-Diphenylmethyl-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 2 12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 3 12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 4 12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 5 12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 6 13-Diphenylmethyl-4-hydroxy-8,9,10,11-tetrahydro-7H,13H-pyridazino[1',6':4,5][1,2,4]triazino[1,2-a][1,2]diaza-3,5-dione; 7 13-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,10,11-tetrahydro-7H,13H-pyridazino[1',6':4,5][1,2,4]triazino[1,2-a][1,2]diaza-3,5-dione; 8(R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 9(S)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyn[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 10(9aR,10S)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 11(9aR,10R)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 12(9aS,10R)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 13(9aS,10S)-10-diphenylmethyl-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 14(9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 15(9aR,10R)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 16(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 17(9aS,10R)-10-((S)-(3-chlorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 18(10aS,11R)-11-diphenylmethyl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-3,5-dione; 19A 12-Diphenylmethyl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazin-6,8-dione; 19B 12-Diphenylmethyl-7-hydroxy-3,4,12,12a-tetrahydro-2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazin-6,8-dione; 20 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9-dihydro-7H,11H-pyrazolo[1,2-a]pyridazino[1,6-d][1,2,4]triazin-3,5-dione; 21 12-(1,1-diphenylethyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 22 12-(bis(2-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 23A 12-Diphenylmethyl-4-hydroxy-10-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 23B 12-Diphenylmethyl-4-hydroxy-10-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 24 12-Diphenylmethyl-4-hydroxy-7-methyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 25A 12-Diphenylmethyl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 25B 12-Diphenylmethyl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 26A 12-(6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazine[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 26B 12-(6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 27A 12-(6,11-dihydrodibenzo[b,e]oxa-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazine[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 27B 12-(6,11-dihydrodibenzo[b,e]oxa-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazine[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 28A 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thia-11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazin-3,5-dione; 28B 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thia-11 29(S)-12-diphenylmethyl-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazin-3,5-dione; 30(S)-12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 31(R)-12-(bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,10-tetrahydro-12H-didarazyno[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 32(9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 33(9aR,10S)-10-((R)-(3,4-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 34(9aR,10S)-10-((S)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 35(9aR,10S)-10-((R)-(2-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 36(9aR,10S)-10-((S)-(3,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 37(9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 38(9aR,10S)-10-((S)-(3,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 39(9aR,10S)-10-((R)-(2-fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 40(9aR,10S)-10-((R)-(3,5-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 41(9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 42(9aR,10S)-10-((R)-(2-fluorophenyl)(2-methoxyphenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 43(9aR,10S)-10-((R)-(2-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 44(9aR,10S)-10-(bis(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 45(9aR,10S)-10-((R)-(3,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 46(9aR,10S)-10-((R)-(2,6-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 47(9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 48(9aR,10S)-10-((R)-(2,6-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 49(9aR,10S)-10-((R)-(2,6-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 50(9aR,10S)-10-((S)-(3-fluorophenyl)(3,4,5-trifluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 51(9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 52(9aR,10S)-10-((R)-(3,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 53(9aR,10S)-10-((S)-(3,4-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 54(9aR,10S)-10-((S)-(3,5-difluorophenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 55(9aR,10S)-10-((S)-(2-fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 56(9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 57(9aR,10S)-10-((S)-(2-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 58(9aR,10S)-10-((S)-(4-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 59(9aR,10S)-10-((S)-(3-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 60(9aR,10S)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 61(9aR,10S)-10-((S)-(2,6-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-3,5-dione; 62(9aR,10S)-10-((S)-(2,6-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 63(9aR,10S)-10-((S)-(2,6-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 64(9aR,10S)-10-((R)-(3-fluorophenyl)(3,4,5-trifluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 65(9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 66(9aR,10S)-10-((R)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 67(9aR,10R)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 68(9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 69(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 70(9aR,10S)-10-((S)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 71(9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 72(9aR,10S)-10-((R)-(2,3-difluorophenyl)(2,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 73(9aR,10R)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 74(9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 75(9aR,10S)-10-((S)-(3,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 76(9aR,10S)-10-((S)-(3,4-difluorophenyl)(3,5-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 77(9aR,10S)-10-((R)-(3,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 78(9aR,10S)-10-(bis(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 79(9aR,10S)-10-(bis(2,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 80(9aR,10S)-10-((R)-(2,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 81(9aR,10S)-10-((R)-(2,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 82(9aR,10S)-10-((R)-(2,5-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 83(9aR,10S)-10-((S)-(3,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 84(9aR,10S)-10-((R)-(2,5-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 85(9aR,10S)-10-((R)-(2,4-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 86(9aR,10S)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 87(9aR,10S)-10-((R)-(2,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 88(9aR,10S)-10-((R)-(2,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 89(9aR,10S)-10-((R)-(2,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 90(9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 91(9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 92(9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 93(9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 94(9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-2-(hydroxymethyl)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 95(9aR,10S)-10-((S)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 96(9aR,10S)-10-((R)-(3,4-difluorophenyl)(3,5-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 97(9aR,10S)-10-((R)-(3,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 98(9aR,10S)-10-((S)-(2,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 99(9aR,10S)-10-((S)-(2,5-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 100(9aR,10S)-10-((S)-(2,5-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 101(9aR,10S)-10-((R)-(3,5-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 102(9aR,10S)-10-((S)-(2,4-difluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 103(9aR,10S)-10-((S)-(2,4-difluorophenyl)(phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 104(9aR,10S)-10-((S)-(2,4-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 105(9aR,10S)-10-((S)-(2,4-difluorophenyl)(3,4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 106 10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 107 4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-10-yl)methyl)benzylnitrile; 108(9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 109(9aR,10S)-10-((R)-(3-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 110(9aR,10S)-10-((S)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 111(9aR,10S)-10-((R)-(2-bromophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 112(9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 113(9aR,10S)-10-((S)-(3-chlorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 114(9aR,10S)-10-((R)-(3-chlorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 115(9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 116(9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 117(7S,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 118(7S,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 119(7R,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 120(7R,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 121(8S,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 122(8R,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 123(10aR,11S)-11-diphenylmethyl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-3,5-dione; 124A 11-Diphenylmethyl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 124B 11-Diphenylmethyl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 125A 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 125B 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 126 11-Diphenylmethyl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-3,5-dione; 127 11-Diphenylmethyl-4-hydroxy-7-methyl-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 128(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-3-methylbutyrate; 129(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl-3-methylbutyrate; 130(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-4-ylacetate; 131(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl isobutyrate; 132(9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-4-ylisopropyl carbonate; 133 1-(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)ethyl ethyl carbonate; 134(S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazin-4-yl)oxy)methylethyl carbonate; 135(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)methyl(2-methoxyethyl) carbonate; 136 1-(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)ethyl ethyl carbonate; 137(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate; 138(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl carbonate; 139(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate; 140(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl carbonate; 141(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylisopropyl carbonate; 142(((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylmethyl carbonate; 143(((9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl neopentanoate; 144(S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro-12H-dipyridazin[1,2-a:1',6'-d][1,2,4]triazin-4-yl)oxy)methyl methyl carbonate; 145(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazinolo[1,2-b]pyridazin-4-yl)oxy)methyl L-valine ester; 146(9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate; 147(((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methylethyl(methyl)carbamate; 148 2-(((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)(ethoxy)phosphoryl)oxy)methyl acetate; and 149 2-((((((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropionate; And pharmaceutically acceptable salts of these compounds. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... G is H. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein... G is selected from R 0 , –C(O)R 0 , –C(O)-OR 0 , –C( RG ) 2 -OC(O)R 0 , –C( RG ) ₂ -OC(O) -OR₀ , –C(O)-N( R₀ ) ₂ and –C( RG ) ₂ -OC(O)N( R₀ ) ₂ , wherein each R₀ is independently H or C₁ - C₄ alkyl, said C₁ - C₄ alkyl being optionally substituted with one or two groups selected from: halogen, CN, -OH, amino, C₁ -4 alkyl, phenyl, C₁ -4 alkoxy, C₁ -4 haloalkyl, C₁ -4 haloalkoxy, and 3-6 membered heterocycles containing one or two heteroatoms selected from N, O and S as ring members. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein... G is selected from R0 , –C(O) R0 , –C(O) -OR0 , –C( RG ) 2 -OC(O) R0 and –C( RG ) 2 -OC(O) -OR0 , wherein each R0 is independently H or a group selected from C1 - C4 alkyl, and each RG is H or C1 - C4 alkyl. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein G is selected from –C(O) RO , –C(O) -ORO , –CH2 -OC(O) RO and –CH2 -OC(O) -ORO , wherein each RO is a C1 - C4 alkyl group. 6. The compound according to any one of claims 1-5, wherein it has the following formula: Or its pharmaceutically acceptable salt. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein... Z2 is CH2 , Z3 is CH2 or CX2 , where X is a halogen, n is 0, 1 or 2, and each R3 is Me. 8. The compound of claim 1, wherein the compound is of formula (I): Or its pharmaceutically acceptable salt, wherein: R1 is H, halogen, CN, COOR*, -CONR* 2 or optionally a C1 - C6 alkyl group substituted with one or two groups selected from the following: –OR* and –NR* 2 , C1 - C4 haloalkyl; R* is independently H or optionally C1 - C6 alkyl substituted with –OR or –NR 2 each time it appears; Z1 is N, and Z2 is C(R) 2 ; Or Z1 is CH, and Z2 is NR, O, S or CH2 ; Z3 is CH2 , Q, -CH2- CH2- , -Q- CH2- , –CH2 -Q-, -CH2 -Q- CH2- , -CH2 - CH2 - CH2- or CX2 , where X is a halogen; Q is selected from –NR-, O, S, SO and SO2 ; R2 is selected from H, halogen, CN, C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by up to three independent groups selected from the following: halogen, CN, C1-4 alkyl, -OR, C1-4 haloalkoxy, -NR2 and C1-4 haloalkyl; Each R 3 is a substituent optionally present on any carbon atom of the ring containing Z 2 and Z 3 , and is independently selected from –OR, C 1-4 haloalkyl, C 1-4 haloalkoxy, oxo, CN, -NR 2 , and C 1-4 alkyl optionally substituted by up to three groups independently selected from: halogen, CN, C 1-4 alkyl, -OR, C 1-4 haloalkoxy, -NR 2 , and C 1-4 haloalkyl; n is 0-2; Ar 1 and Ar 2 each independently represent a phenyl or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S as ring members, and each is independently substituted by up to three groups selected from the following: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkyne and CN; Ar 1 and Ar 2 are optionally linked together by a bridge of the formula –C(R L ) 2 -L- to form a tricyclic group, wherein Ar 1 and Ar 2 are each optionally substituted by up to three independent groups selected from the following: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkyne and CN; R is independently H or C1 - C4 alkyl each time it appears, said C1 - C4 alkyl being optionally substituted by up to three groups independently selected from the following: halogen, OH, oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy and C1-4 haloalkyl; L is selected from S, S = O, SO₂ , O, NR, C(R L ) ₂ , and CF₂ ; and And each RL is independently H or C1-2 alkyl. 9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Z1 is CH. 10. The compound according to claim 1 or claim 8, or a pharmaceutically acceptable salt thereof, wherein Z1 is N. 11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Z2 is CH2 . 12. The compound according to any one of claims 1-6 or 8-11, or a pharmaceutically acceptable salt thereof, wherein Z3 is CH2 , –CH2 - CH2- , -CH2- CH2 - CH2- , -CH2 - O- , O or CX2 , wherein X is a halogen. 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein Z3 is CH2 or CX2 , and X is a halogen. 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 or 8-13, wherein R1 is H. 15. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R2 is H. 16. The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein Ar1 and Ar2 are both phenyl groups and are each independently substituted by up to three groups selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C2-4 alkyne and CN. 17. The compound according to any one of claims 1-15, wherein it has the following formula: Where Y represents a group selected from the following groups. Each R y is independently selected from halogens, C 1-4  alkyl groups, C 1-4  haloalkyl groups, C  1-4 alkoxy groups, C 1-4  haloalkoxy groups, C 2-4  alkynes, and CN; and Each q is independently 0, 1, 2, or 3; Or its pharmaceutically acceptable salt. 18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, having the following formula: Where Z1 is N or CH; and Z3 is CH2 or –CH2 - CH2- or CX2 , where X is a halogen. 19. The compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein Ar1 and Ar2 are both phenyl, and Ar1 and Ar2 are independently and optionally substituted by one or three independently selected groups from: F, Cl and C1 - C4 alkyl. 20. The compound according to any one of the preceding claims, wherein G is selected from: And pharmaceutically acceptable salts. 21. The compound of any one of the preceding claims, wherein the compound is selected from: And pharmaceutically acceptable salts of these compounds. 22. The compound of claim 1, wherein the compound is selected from the group consisting of: And its pharmaceutically acceptable salts. 23. A pharmaceutical composition comprising a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 24. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active co-agents. 25. A method of treating influenza, comprising administering to a subject in need a therapeutically effective amount of any one of claims 1-22 or a pharmaceutically acceptable salt thereof. 26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, used as a medicine. 27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, for the treatment of influenza. 28. Use of any compound of claims 1-22 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating influenza.