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 associated compounds as inhibitors of orthomyxovirus replication for treating influenza

Abstract

Providing methods for treating viral infections SOLUTION: The present invention refers to 10 - (di (phenyl) methyl) - 4-hydroxy-8, 9, 9a, 10-tetrahydro - 7H - pynolo [1'; 2': 4,5] pyrazino [1, 2-b] pyridazine-3, 5-dione derivatives of formula (A) and associated compounds as inhibitors of orthomyxovirus replication for the treatment of flu. The present invention provides compounds and prodrugs thereof that inhibit orthomyxovirus replication and are therefore useful for the treatment of viral infections caused by orthomyxoviruses. The invention further provides pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent viral infections caused by orthomyxoviruses.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 636,378, filed February 28, 2018, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention provides compounds and prodrugs thereof that inhibit orthomyxovirus replication and are therefore useful for treating viral infections caused by orthomyxoviruses. The present invention further provides pharmaceutical compositions containing these compounds and methods of using these compounds to treat or prevent viral infections caused by orthomyxoviruses. [Background technology]

[0002] background Orthomyxoviruses replicate in the nuclei of infected cells because they have a negative-sense, single-stranded RNA genome and lack a mechanism for generating cap structures to produce their own mRNA. Members of the Orthomyxoviridae family possess an RNA-dependent RNA polymerase with endonuclease activity that cleaves the capped 5'-terminal segments of cellular mRNAs; the RNA polymerase then uses the cleavage products as primers for viral mRNA synthesis. This process is known as cap snatching. This endonuclease has been recognized as a promising target for the development of antiviral agents effective against orthomyxoviruses. ACS Med. Chem. Letters, 2014, vol. 5, 61-64. Inhibitors of this endonuclease are disclosed, for example, in WO2015 / 038660, U.S. Pat. No. 8,987,441, WO2010 / 147068, and U.S. Patent Applications Nos. 2012 / 022251, 2013 / 0197219, 2014 / 256937, and 2015 / 0072982, which report that such inhibitors are useful for treating influenza infections in mammals. 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 generally infect humans. Influenza A is the most pathogenic of these pathogens in humans and often accounts for the majority of severe influenza cases during a typical influenza season. Even with widespread use of vaccines to reduce influenza incidence, influenza is estimated to cause as many as 40,000 deaths per year in the United States; therefore, there is a great need for effective antiviral therapeutics to treat influenza, particularly influenza A. The present invention provides compounds that inhibit the replication of orthomyxoviruses (including influenza A, B, and C). Without being bound by theory, it is believed that these compounds exert their antiviral effect by inhibiting the endonuclease function of the viral polymerase. Because this endonuclease is highly conserved in influenza A viruses (ibid.), the compounds are particularly useful for treating influenza A. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015 / 038660 [Patent Document 2] U.S. Patent No. 8,987,441 [Patent Document 3] International Publication No. 2010 / 147068 [Non-patent literature]

[0004] [Non-Patent Document 1] ACS Med.Chem.Letters,2014,vol.5,61-64 Summary of the Invention [Means for solving the problem]

[0005] Summary of the Invention In one aspect, the present invention provides a compound of formula (A): [ka] The present invention provides a compound of the formula:

[0006] In another aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 H, Halo, CN, COOR * , -CONR * 2, OR * and -NR * C1-C6 alkyl, C1-C4 haloalkyl optionally substituted with 1 or 2 groups selected from 2; R * is independently at each occurrence H or C1-C6 alkyl optionally substituted with -OR or -NR2; Z 1 is N and Z 2 Is C(R)2? Or Z 1 is CH and Z 2 is NR, O, S, or CH2; Z 3 is CH2, Q, -CH2-CH2-, -Q-CH2-, -CH2-Q-, -CH2-Q-CH2-, -CH2-CH2-CH2-, or CX2, where X is halo; Q is selected from -NR-, O, S, SO, and SO2; R 2 H, halo, CN, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 alkyl; Each R 3 is Z 2 and Z 3 is an optional substituent on any carbon atom of the ring, including -OR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, oxo, CN, -NR2, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 independently selected from alkyl; n is 0 to 2; Ar 1 and Ar 2 each independently represents phenyl or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S as ring members; halo, 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 is the formula -C(R L ) optionally interconnected by 2-L- bridges to form a tricyclic group, wherein Ar 1 and Ar 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 each optionally substituted with up to three groups independently selected from alkyne, and CN; R is independently at each occurrence H, or halo, OH, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C1~4 Haloalkoxy, and C 1~4 C1-C4 alkyl optionally substituted with up to 3 groups independently selected from haloalkyl; L is S, S=O, SO2, O, NR, C(R L )2, and CF2; Each R L are independently H or C 1~2 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0007] The present invention includes these compounds, pharmaceutically acceptable salts thereof, as well as compositions and combinations comprising these compounds (including pharmaceutically acceptable salts), and methods of use thereof, as further described herein.

[0008] The compounds of formula (A) are inhibitors of influenza virus endonuclease function and inhibit influenza virus replication, as demonstrated by the data provided herein. Thus, these compounds are useful for treating or preventing orthomyxovirus infections in mammals susceptible to such infections, and are particularly useful for treating influenza virus infections in humans. These compounds are also useful for inhibiting intracellular replication of orthomyxoviruses, including influenza viruses.

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (A) in admixture with at least one pharmaceutically acceptable carrier or excipient, and optionally in admixture with two or more pharmaceutically acceptable carriers or excipients. The aforementioned compounds may also be used as pharmaceutically acceptable salts.

[0010] In another aspect, the present invention provides a method of treating a subject infected with influenza A, B, or C, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula (A) described herein or any subgenus or species thereof, or a pharmaceutical composition comprising such a compound. The subject can be a mammal, preferably a human, although the compounds and methods of the present invention are also suitable for treating other species infected with influenza A, influenza B, or influenza C, as well as other orthomyxoviruses. The present invention relates to the compounds of Formula (A) and subgenus of Formula (I) described herein, and all stereoisomers (including diastereoisomers and enantiomers), except where a particular isomer is expressly stated, as well as tautomers and isotopically enriched versions (including deuterium-substituted forms) thereof, and pharmaceutically acceptable salts of these compounds. The compounds of the present invention also include polymorphic forms of the compounds of formula (A) (or subformulas thereof) and salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description Unless otherwise stated, the following definitions apply:

[0012] As used herein, the term "halogen" or "halo" refers to fluorine, bromine, chlorine, or iodine, and typically refers to fluorine or chlorine, particularly when attached to an alkyl group, and further includes bromine or iodine when present on an aryl or heteroaryl group.

[0013] As used herein, unless otherwise specified, the term "heteroatom" refers to a nitrogen atom (N), an oxygen atom (O), or a sulfur atom (S).

[0014] As used herein, the term "alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety having up to 10 carbon atoms. Unless otherwise specified, alkyl refers to a hydrocarbon moiety having 1 to 6 carbon atoms. Representative examples of alkyl 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, and n-decyl. A substituted alkyl is an alkyl group containing one or more substituents (e.g., 1, 2, or 3 substituents) in place of a hydrogen, up to the number of hydrogens present on the unsubstituted alkyl group. Suitable substituents for alkyl groups, unless otherwise specified, include halogen, CN, oxo, hydroxy, C 1~4 Alkoxy, substituted or unsubstituted C 3~6 Cycloalkyl, substituted or unsubstituted phenyl, amino, (C 1~4 alkyl)amino, di(C 1~4 Alkyl)amino, C 1~4 Alkylthio, C 1~4 Alkylsulfonyl, -C(=O)-C 1~4 Alkyl, COOH, COO(C 1~4 alkyl), -O(C=O)-C 1~4 Alkyl, -NHC(=O)C 1~4 Alkyl, and -NHC(=O)OC 1~4 alkyl groups, where the substituents of the substituted cycloalkyl or phenyl are up to three groups selected from Me, Et, -OMe, -OEt, CF3, halo, CN, OH, and NH2.

[0015] As used herein, the term "alkylene" refers to a divalent alkyl group having 1 to 10 carbon atoms and two open valencies for attachment to another feature. Unless otherwise provided, alkylene refers to a moiety having 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and 2,2-dimethylbutylene. A substituted alkylene is an alkylene group containing one or more (e.g., 1, 2, or 3) substituents; unless otherwise specified, suitable substituents for alkylene groups are selected from those listed above for alkyl groups.

[0016] As used herein, the term "haloalkyl" refers to an alkyl, as defined herein, substituted with one or more halo groups. A haloalkyl can be a monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl (including perhaloalkyl). A monohaloalkyl can have one chloro or fluoro within the alkyl group. Chloro and fluoro are generally present as substituents on an alkyl or cycloalkyl group; fluoro, chloro, and bromo are present in aryl or heteroaryl groups. A haloalkyl group is often present on the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups on the alkyl. Typically, a polyhaloalkyl contains up to 12, 10, 8, 6, 4, 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhalo-alkyl refers to an alkyl in which all hydrogen atoms have been replaced with halo atoms (e.g., trifluoromethyl).

[0017] As used herein, the term "alkoxy" refers to alkyl-O-, where alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Typically, an alkoxy group has 1 to 6 carbon atoms, more usually 1 to 4 carbon atoms.

[0018] A "substituted alkoxy" is an alkoxy group that contains one or more (such as 1, 2, or 3) substituents on the alkyl portion of the alkoxy. Unless otherwise specified, suitable substituents are selected from the substituents listed above for alkyl groups, except that hydroxyl and amino are not normally present on the carbon bonded directly to the oxygen of a substituted "alkyl-O" group.

[0019] Similarly, each alkyl portion of other groups such as "alkylaminocarbonyl," "alkoxyalkyl," "alkoxycarbonyl," "alkoxy-carbonylalkyl," "alkylsulfonyl," "alkylsulfoxyl," "alkylamino," and "haloalkyl" shall have the same meaning as set forth in the definition of "alkyl" above. When used in this manner, unless otherwise indicated, alkyl groups are often alkyls of 1 to 4 carbons and are not further substituted with groups other than the recited components. Unless otherwise specified, when such alkyl groups are substituted, suitable substituents are those recited above for alkyl groups.

[0020] As used herein, the term "haloalkoxy" refers to haloalkyl-O-, where haloalkyl is defined above. Representative examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, and 1,1,1,3,3,3-hexafluoro-2-propoxy. Typically, a haloalkyl group has 1 to 4 carbon atoms.

[0021] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic, bicyclic, tricyclic, or spirocyclic hydrocarbon group of 3 to 12 carbon atoms; a cycloalkyl group can be unsubstituted and can be fused to another ring, which can be saturated, unsaturated, or aromatic, provided that the ring atom of the cycloalkyl group attached to the molecular formula in question is not an aromatic ring carbon. Unless otherwise provided, cycloalkyl refers to a cyclic hydrocarbon group having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms. Unless otherwise specified, a cycloalkyl group is preferably a saturated monocyclic ring having 3 to 7 ring atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] A saturated cycloalkyl may have one, two, three, or more than three water groups on the unsaturated group. and cycloalkyl groups substituted with up to a prime number of substituents. Typically, substituted cycloalkyls will have 1 to 4 substituents, unless otherwise specified. Suitable substituents, unless otherwise specified, include 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, carboxy, C1-C4-alkoxycarbonyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, C1-C4-alkylamino, C1-C4-alkylamino, and C1-C4-alkylamino. and independently selected from the group consisting of cyclocarbonyl, di-C1-C4-alkylaminocarbonyl, C1-C4-alkylcarbonylamino, C1-C4-alkylcarbonyl(C1-C4-alkyl)amino, C1-C4-alkylsulfonyl, C1-C4-alkylsulfamoyl, and C1-C4-alkylaminosulfonyl, wherein each of the foregoing hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted with one or more groups independently selected at each occurrence from the list of substituents for the "alkyl" group herein. Preferred substituents for cycloalkyl groups include C1-C4 alkyl and those listed above as suitable substituents for alkyl groups.

[0023] Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, 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.

[0024] Similarly, each cycloalkyl portion of other groups such as "cycloalkyloxy," "cycloalkoxyalkyl," "cycloalkoxycarbonyl," "cycloalkoxy-carbonylalkyl," "cycloalkylsulfonyl," and "halocycloalkyl" is intended to have the same meaning as set forth in the definition of "cycloalkyl" above. As used in these terms, cycloalkyl is typically a monocyclic 3-7 carbon ring that is unsubstituted or substituted with 1-2 groups. When optionally substituted, the substituents are typically selected from C1-C4 alkyl and the substituents described above as appropriate for an alkyl group.

[0025] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl (e.g., phenyl or naphthyl) having 6 to 14 carbon atoms, often 6 to 10 carbon atoms. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl (provided that the tetrahydronaphthyl is connected to the depicted formula through a carbon atom in the aromatic ring of the tetrahydronaphthyl group). Unless otherwise specified, the preferred aryl group is phenyl.

[0026] Substituted aryl is 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, carboxy, C1-C4-alkoxycarbonyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino, C1- An aryl group substituted by 1 to 5 (such as 1, 2, or 3) substituents independently selected from the group consisting of C4-alkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, C1-C4-alkylcarbonylamino, C1-C4-alkylcarbonyl(C1-C4-alkyl)amino, C1-C4-alkylsulfonyl, sulfamoyl, C1-C4-alkylsulfamoyl, and C1-C4-alkylaminosulfonyl, wherein each of the foregoing hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted by one or more groups independently selected at each occurrence from the groups listed above as suitable substituents for an alkyl group. Preferred substituents for the substituted aryl group are C 1~4 Alkyl and the groups listed above as suitable substituents for alkyl groups, excluding divalent groups such as oxo.

[0027] Similarly, each aryl portion of other groups such as "aryloxy," "aryloxyalkyl," "aryloxycarbonyl," and "aryloxy-carbonylalkyl" shall have the same meaning as described in the definition of "aryl" above.

[0028] As used herein, the term "heterocyclyl" refers to a heterocyclic radical that is saturated or partially unsaturated, but not aromatic, and can be monocyclic or polycyclic (particularly bicyclic, tricyclic, or spirocyclic, if polycyclic); having 3 to 14, more usually 4 to 10, and most preferably 5 or 6, ring atoms; in which one or more, preferably 1 to 4, and particularly 1 or 2, ring atoms are heteroatoms independently selected from O, S, and N (and thus the remaining ring atoms are carbon). For example, even when described as a C5-6 atom ring, the heterocycle still contains at least one heteroatom as a ring atom, with the other ring atoms being carbon, and has the recited number of ring atoms (e.g., 5 or 6 in this example). Preferably, a heterocyclyl group has one or two such heteroatoms as ring atoms, and preferably the heteroatoms are not directly connected to each other. Unless otherwise specified, the linking ring (i.e., the ring connected to the formula) preferably has 4 to 12, especially 5 to 7, ring atoms. A heterocyclic group can be fused to an aromatic ring, provided that the atom of the heterocyclic group attached to the formula is not aromatic. A heterocyclic group can be attached to the formula through a heteroatom (typically nitrogen) or a carbon atom of the heterocyclic group. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group need 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, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, and thiomorpholine.

[0029] Substituted heterocyclyl is a heterocyclyl group independently substituted with from 1 to 5 (such as 1, 2, or 3) substituents selected from the substituents described above for cycloalkyl groups.

[0030] Similarly, each heterocyclyl portion of other groups such as "heterocyclyloxy," "heterocyclyloxyalkyl," "heterocyclyloxycarbonyl," etc., is intended to have the same meaning as set forth in the definition of "heterocyclyl" above.

[0031] As used herein, the term "heteroaryl" refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms as ring members, the remaining ring atoms being carbon, with the heteroatoms being selected from N, O, and S. Typically, heteroaryl refers to a 5- to 10-membered ring system, particularly a 5- to 6-membered monocyclic group or an 8- to 10-membered bicyclic group. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 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-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, 1- or 2-tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

[0032] The term "heteroaryl" also refers to a group in which an aromatic heterocycle is fused to one or more aryl, cycloalkyl, or heterocyclyl rings. 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]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.

[0033] Substituted heteroaryl is a heteroaryl group that contains one or more substituents, typically one or two substituents, selected from those described above as suitable for aryl groups.

[0034] Similarly, each heteroaryl portion of other groups such as "heteroaryloxy," "heteroaryloxyalkyl," and "heteroaryloxycarbonyl" is intended to have the same meaning as described in the definition of "heteroaryl" above.

[0035] Various embodiments of the present invention are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. The following numbered embodiments are representative of aspects of the present invention:

[0036] In one embodiment, the present invention provides a compound of formula (A): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is the formula [ka] is the basis of wherein the dashed line represents the bond connecting Y to the tricyclic core of formula (A); G, H, or R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , -C(R G )2-OC(O)-OR 0 , -C(O)-N(R 0 )2, and -C(R G )2-OC(O)N(R 0 )2, Here, each R 0is independently H or a group selected from C1-C6 alkyl, phenyl, pyridyl, C3-C7 cycloalkyl, and a 3-6 membered heterocycle containing one or two heteroatoms selected from N, O, and S as ring members; each R that is not H 0 are halo, CN, -OH, amino, C 1~4 Alkyl, phenyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 and optionally substituted with one or two groups selected from haloalkoxy and a 3- to 6-membered heterocycle containing one or two heteroatoms selected from N, O, and S as ring members, wherein said one or two groups are halo, CN, —OH, oxo, amino, C 1~4 Alkyl, phenyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 or 2 groups selected from haloalkoxy; Each R G is H and C 1~4 independently selected from alkyl; R 1 H, Halo, CN, COOR * , -CONR * 2, OR * and -NR * C1-C6 alkyl, C1-C4 haloalkyl optionally substituted with 1 or 2 groups selected from 2; R * is independently at each occurrence H or C1-C6 alkyl optionally substituted with -OR or -NR2; Z 1 is N and Z 2 Is C(R)2? Or Z 1 is CH and Z 2 is NR, O, S, or CH2; Z 3is CH2, Q, -CH2-CH2-, -Q-CH2-, -CH2-Q-, -CH2-Q-CH2-, -CH2-CH2-CH2-, or CX2, where X is halo, e.g., F; Q is selected from -NR-, O, S, SO, and SO2; R 2 H, halo, CN, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 alkyl; Each R 3 is Z 2 and Z 3 is an optional substituent on any carbon atom of the ring, including -OR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, oxo, CN, -NR2, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 independently selected from alkyl; n is 0 to 2; Ar 1 and Ar 2 each independently represents phenyl or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S as ring members; Ar 1 and Ar 2 Ha, Halo, 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 is the formula -C(R L) optionally interconnected by 2-L- bridges to form a tricyclic group, wherein Ar 1 and Ar 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 each optionally substituted with up to three groups independently selected from alkyne, and CN; R is independently at each occurrence H, or halo, OH, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, and C 1~4 C1-C4 alkyl optionally substituted with up to 3 groups independently selected from haloalkyl; L is S, S=O, SO2, O, NR, C(R L )2, and CF2; Each R L are independently H or C 1~2 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, the compound of formula (A) comprises: 1 12-Benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-12 H-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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 3 12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,1 O-Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 4 12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,1 O-Tetrahydro-12H-dipyridazino[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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 6 13-Benzhydryl-4-hydroxy-8,9,10,11-tetrahydro-7 H,13H-Pyridazino[1',6':4,5][1,2,4]triazino[1,2-a][1,2]diazepine-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]diazepine-3,5-dione; 8 (R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7, 8,9,10-tetrahydro-12H-dipyridazino[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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 10 (9aR,10S)-10-benzhydryl-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-benzhydryl-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-benzhydryl-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-benzhydryl-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]pyra dino[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-benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione; 19A 12-Benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro -2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione; 19B 12-Benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro -2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazine-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]triazine-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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 23A 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydrobenzoate trihydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 23B 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydrobenzoate trihydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 24 12-Benzhydryl-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-Benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,1 O-Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 25B 12-Benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,1 O-Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 26A 12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4- Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 26B 12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4- Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 27A 12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4 -Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 27B 12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4 -Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 28A 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin -11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 28B 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin -11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 29 (S)-12-Benzhydryl-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-dipyridazino[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-dipyridazino[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 ethyl)-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]pyrazino[1,2-b]pyridazine-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) (nyl)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) (nyl)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-8,9,9 a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 107 4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxyphenyl) ci-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzonitrile; 108 (9aR,10S)-10-((S)-(4-chlorophenyl)(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; 109 (9aR,10S)-10-((R)-(3-chlorophenyl)(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; 110 (9aR,10S)-10-((S)-(2-bromophenyl)(4-fluoro Phenyl)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) Phenyl)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) Phenyl)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) Phenyl)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) (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) (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-Benzhydryl-4-hydroxy-7,8,10 a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione; 124A 11-Benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 124B 11-Benzhydryl-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-Benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro -10H-Pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione; 127 11-Benzhydryl-4-hydroxy-7-methyl-7,8,9,10,10 a,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-methylbutanoate; 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-methylbutanoate; 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]pyridazin-4-yl acetate; 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]pyridazin-4-yl isopropyl 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]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethyl ethyl Carbonate; 134 (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxa so-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]pyrazino[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)methyl methyl 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)methyl ethyl 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)methyl methyl 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)methyl ethyl 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)methyl isopropyl carbonate; 142 (((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl) (I)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 methyl 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 pivalate; 144 (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxa so-3,5,7,8,9,10-hexahydro-12H-dipyridazino[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-valinate; 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 Methyl 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)acetate; and 149 Methyl 2-((((((9aR,10S)-10-(bis(4-fluorophenyl) (yl)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-methylpropanoate; and pharmaceutically acceptable salts of these compounds.

[0038] Compounds of formula (A) in which G is not H can act as prodrugs that are readily converted to compounds in which G is H in vivo.

[0039] In one embodiment of the compounds of Formula (A), G is H.

[0040] In another embodiment of the compound of Formula (A), G is R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , -C(R G )2-OC(O)-OR 0 , -C(O)-N(R 0 )2, and -C(R G )2-OC(O)N(R 0 )2, where each R 0 is independently H or a group selected from C1-C4 alkyl, phenyl, pyridyl, C3-C7 cycloalkyl, and a 3-6 membered heterocycle containing one or two heteroatoms selected from N, O, and S as ring members; each R that is not H is halo, CN, —OH, amino, C 1~4 Alkyl, phenyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Optionally substituted with one or two groups selected from haloalkoxy and 3-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members.

[0041] In certain of the foregoing embodiments, G is R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , and -C(R G )2-OC(O)-OR 0where each R 0 are independently H or C1-C4 alkyl, and each R G is H or C1-C4 alkyl. In some of these embodiments, each R G is H and R 0 is C1-C4 alkyl.

[0042] In certain of the foregoing embodiments, the compound of Formula (A) has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0043] For certain compounds of this formula, Z 2 is CH2 and Z 3 is CH or CX, where X is halo (e.g., F), n is 0, 1, or 2, and each R 3 is Me.

[0044] In another embodiment (embodiment 1), the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 H, Halo, CN, COOR * , -CONR * 2, OR * and -NR * C1-C6 alkyl, C1-C4 haloalkyl optionally substituted with 1 or 2 groups selected from 2; R * is independently at each occurrence H or C1-C6 alkyl optionally substituted with -OR or -NR2; Z 1 is N and Z 2 Is C(R)2? Or Z 1 is CH and Z2 is NR, O, S, or CH2; Z 3 is CH2, Q, -CH2-CH2-, -Q-CH2-, -CH2-Q-, -CH2-Q-CH2-, -CH2-CH2-CH2-, or CX2, where X is halo, e.g., F; Q is selected from -NR-, O, S, SO, and SO2; R 2 H, halo, CN, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 alkyl; Each R 3 is Z 2 and Z 3 is an optional substituent on any carbon atom of the ring, including -OR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, oxo, CN, -NR2, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 independently selected from alkyl; n is 0 to 2; Ar 1 and Ar 2 each independently represents phenyl or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S as ring members; halo, 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 is the formula -C(R L) optionally interconnected by 2-L- bridges to form a tricyclic group, wherein Ar 1 and Ar 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 each optionally substituted with up to three groups independently selected from alkyne, and CN; R is independently at each occurrence H, or halo, OH, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, and C 1~4 independently selected from haloalkyl C1-C4 alkyl optionally substituted with up to three groups; L is S, S=O, SO2, O, NR, C(R L )2, and CF2; Each R L are independently H or C 1~2 is alkyl, The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0045] In a preferred embodiment of any of the compounds of formula (G) or formula (I) in the foregoing embodiments, Z 2 is NR, O, or S, then Z 3 is CH2, CH2CH2, CH2CH2CH2, or CX2, where X is halo (e.g., F).

[0046] The following numbered embodiments describe and illustrate certain aspects of the present invention.

[0047] 2.Z 1 is CH, or a pharmaceutically acceptable salt thereof.

[0048] 3.Z 1is N, or a pharmaceutically acceptable salt thereof.

[0049] 4.Z 2 is CH2 or -CH2-CH2-, or a pharmaceutically acceptable salt thereof.

[0050] 5.Z 3 is CH2, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-, O-, O, or CX2, where X is halo (e.g., F), or a pharmaceutically acceptable salt thereof.

[0051] 6.R 1 is H, or a pharmaceutically acceptable salt thereof.

[0052] 7.R 2 is H, or a pharmaceutically acceptable salt thereof.

[0053] 8.Ar 1 and Ar 2 Both are phenyl and halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 The compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, each independently substituted with up to three groups selected from alkyne, and CN.

[0054] 9.Formula: [ka] is a compound of During the ceremony, Y is [ka] represents a group selected from Here, each R y H, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 The compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, independently selected from: an alkyne, and CN.

[0055] 10. Expression [ka] is a compound of During the ceremony, Z 1 is N or CH; Z 3 is CH2, -CH2-CH2- or CX2, where X is halo, for example F, or a pharmaceutically acceptable salt thereof.

[0056] 11.G is: [ka] [ka] [ka] [ka] [ka] or any of the embodiments of Formula (A) and pharmaceutically acceptable salts of these compounds.

[0057] 12. The compound is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] or any of the embodiments of Formula (A) and pharmaceutically acceptable salts of these compounds.

[0058] 13. A compound according to embodiment 1 or any of the embodiments of Formula (A) selected from the group consisting of Examples 1 to 116, or a pharmaceutically acceptable salt thereof. Each compound of the Examples is a specific embodiment of the invention, and therefore the present invention provides: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0059] 14. A pharmaceutical composition comprising a compound according to any of the preceding embodiments or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0060] 15. A combination comprising a therapeutically effective amount of a compound according to any one of embodiments 1-13 or any of the embodiments of Formula (A) or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.

[0061] 16. A method of treating influenza, comprising administering a therapeutically effective amount of a compound according to any of embodiments 1-13, or any of the embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, to a subject in need of said treatment.

[0062] 17. A compound according to any one of embodiments 1 to 13 or any of the embodiments of formula (A), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0063] 18. A compound according to any one of embodiments 1-13 or any of the embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, for use in the treatment of influenza.

[0064] 19. Use of a compound according to any one of embodiments 1-13 or any of the embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of influenza.

[0065] In some embodiments, the compound of Formula (A) has the following formula: [ka] and During the ceremony, G is H or G is R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , and -C(R G )2-OC(O)-OR 0 where each R 0 are independently H or C1-C4 alkyl, and each R G is H or C1-C4 alkyl. In some of these embodiments, each R G is H and R 0 is C1-C4 alkyl; n is 0, 1, or 2; Each R 3 represents Me, OH, OMe, or halo; Y represents [ka] represents Here, each R y is independently selected from F, Cl, Me, OMe, CF3, OCF3, and CN; and each q is independently 0, 1, 2, or 3.

[0066] In some embodiments, the compound of formula (I) has the following formula: [ka] and During the ceremony, n is 0, 1, or 2; Each R 3 represents Me, OH, OMe, or halo; Y represents [ka] represents Here, each R y is a compound independently selected from H, F, Cl, Me, OMe, CF3, OCF3, and CN.

[0067] As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist for a given compound of the present invention, including geometric isomers. It is understood that substituents can be attached to chiral carbon atoms at chiral centers. The term "chiral" refers to a molecule that has the property of not being superimposable with its mirror image partner, while the term "achiral" refers to a molecule that is superimposable with its mirror image partner. Thus, the present invention includes enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of an enantiomeric pair is a "racemic" mixture. This term is used to designate racemic mixtures where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog "RS" system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be named (+) or (-) according to the direction (dextrorotatory or levorotatory) that they rotate plane-polarized light of the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and, therefore, can be designated as enantiomers. Enantiomers, diastereomers, and other stereoisomers may occur and may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0068] Depending on the selection of starting materials and synthetic procedures, compounds may exist in one of the possible isomeric forms or as a mixture thereof (e.g., as pure optical isomers or as isomeric mixtures, such as racemic and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. The present invention is meant to encompass 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 a compound contains a double bond, the substituent may be in either the E or Z configuration, unless otherwise specified. If a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have either the cis or trans configuration, unless otherwise specified. All tautomeric forms are also intended to be included.

[0069] In many cases, the compounds of the present invention can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salts" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically or otherwise undesirable.

[0070] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids (e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate). (Such salts include, but are not limited to, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.) Further lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0071] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0072] Organic acids from which salts can be derived 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, and sulfosalicylic acid.

[0073] Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases. These base addition salts can have inorganic or organic counterions.

[0074] Inorganic counterions for such base salts include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, the counterions are selected from sodium, potassium, ammonium, alkylammonium having 1 to 4 C1-C4 alkyl groups, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0075] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc. Suitable organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0076] The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or in a mixture of the two. Generally, it is desirable to use non-aqueous media such as ether, ethyl acetate, tetrahydrofuran, toluene, chloroform, dichloromethane, methanol, ethanol, isopropanol, or acetonitrile, if applicable.

[0077] Any formula given herein is also intended to represent unlabeled forms of the compounds (i.e., compounds in which all atoms are present at natural isotopic abundance and are not isotopically enriched) and isotopically enriched or labeled forms. Isotopically enriched or labeled compounds have structures depicted by the formulas given herein, except that at least one atom of the compound is replaced with an atom having an atomic mass or mass number different from the naturally occurring atomic mass or atomic mass distribution. Examples of isotopes that can be incorporated into enriched or labeled compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine (H, H, C, 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 The present invention includes various isotopically labeled compounds as defined herein (e.g., radioisotopes ( 3 H and 14 C) or non-radioactive isotopes ( 2 H and 13 These isotopically labeled compounds include compounds in which isotopes such as C are present at levels significantly above the natural abundance of these isotopes. These isotopically labeled compounds are useful for metabolic studies (e.g., 14 C), reaction rate studies (e.g., 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the examples of the present invention, substituting an appropriate isotopically labeled reagent for the non-labeled reagent that would otherwise be used.

[0078] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can confer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life, reduced required dosage, or improved therapeutic index). The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. When deuterium is designated as a substituent in a compound of the present invention, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation of each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0079] Pharmaceutically acceptable solvates of the present invention include solvates in which the solvent of crystallization may be isotopically substituted (e.g., DO, d6-acetone, d6-DMSO) as well as solvates with non-enriched solvents.

[0080] The compounds of the present invention (i.e., compounds of formula (I) containing groups capable of acting as donors and / or acceptors for hydrogen bonds) may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting a compound of formula (I) with a co-crystal former in solution under crystallization conditions and isolating the formed co-crystal. Suitable co-crystal formers include those described in WO 2004 / 078163. Thus, the present invention further provides co-crystals comprising compounds of formula (I).

[0081] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring substances, dyes, and the like, and combinations thereof, known to those of skill in the art for use in pharmaceutical compositions for administration to human subjects (see, e.g., Remington: The Science and Practice of Pharmacy, 22nd ed.). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0082] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that elicits a biological or medical response in a subject (e.g., an amount sufficient to alleviate one or more symptoms, mitigate a pathological condition, slow or delay the progression of a disease, or prevent a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject, is effective to alleviate one or more symptoms associated with influenza virus infection, reduce the duration of the symptomatic phase of influenza virus infection, slow the progression of influenza virus infection, or reduce or stop the progression of an underlying pathology due to influenza virus infection.

[0083] In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell, tissue, non-cellular biological material, or medium, is effective to cause a statistically significant decrease in the replication or proliferation rate of an Orthomyxovirus strain.

[0084] As used herein, the term "subject" refers to an animal. Typically, the subject is a human.

[0085] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refers to the alleviation or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0086] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer, in one embodiment, to amelioration of the disease or disorder (i.e., slowing, halting, or alleviating the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to the alleviation or amelioration of at least one physical parameter (including one that may not be discernible to the patient). In yet another embodiment, "treat," "treating," or "treatment" refers to the physical (e.g., stabilization of a discernible symptom), physiological (e.g., stabilization of a physical parameter), or both, modulation of the disease or disorder. In yet another embodiment, "treat," "treating," or "treatment" refers to the prevention or delay of the onset or progression of the disease or disorder.

[0087] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or quality of life from such treatment.

[0088] As used herein, unless otherwise indicated herein or clearly contradicted by context, the terms "a," "an," "the," and similar terms as used in the context of the present invention (particularly in the context of the claims) shall be construed to cover both the singular and the plural.

[0089] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any and all examples provided herein, or the use of illustrative language (e.g., "etc.") are intended merely to further clarify the invention and do not limit the scope of the invention as originally claimed.

[0090] Any asymmetric atom (e.g., carbon, etc.) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched form, for example, in the (R), (S), or (R,S) form. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in either the (R) or (S) form; that is, for optically active compounds, it is often preferable to use one enantiomer to the substantial exclusion of the other enantiomer, and therefore, an enantiomeric purity of at least 95% is typically preferred. Substituents on atoms with unsaturated double bonds can, if possible, exist in the cis-(Z) or trans-(E) form.

[0091] Thus, as used herein, the compounds of the present invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as 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%, preferably less than 2%, of other isomers relative to the amount of the preferred isomer by weight.

[0092] The resulting mixture of isomers can typically be separated on the basis of the physical chemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0093] Racemic final products or intermediates can typically be resolved into their optical antipodes by known methods, such as by separation of diastereomeric salts thereof obtained with optically active acids or bases to liberate the optically active acidic or basic compounds. Thus, in particular, basic moieties can be used to resolve the compounds of the present invention into their optical antipodes by fractional crystallization of salts formed, for example, with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid). Racemic products can also be resolved by chiral chromatography, such as high-pressure liquid chromatography (HPLC) using a chiral stationary phase.

[0094] Furthermore, the compounds of the present invention (including their salts) can be obtained in the form of their hydrates or can include other solvents used for their crystallization. The compounds of the present invention can inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the present invention encompasses both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are solvent molecules commonly used in the pharmaceutical field (such as water and ethanol) that are known to be harmless to recipients. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0095] 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 may be selected, for example, from carriers and excipients used in approved (registered) prescription therapeutics administered via similar administration routes. Pharmaceutical compositions can be formulated for specific administration routes, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be processed into solid forms (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid forms (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers and adjuvants (such as preservatives, stabilizers, wetting agents, emulsifiers, and buffering agents).

[0096] In one embodiment, the compounds of the invention are formulated for oral delivery. Typically, these pharmaceutical compositions contain the following: a) diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine); b) lubricants (e.g., silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol); for tablets, additionally: c) binders (e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone); optionally, d) disintegrating agents (e.g., starch, agar, alginic acid or its sodium salt, or effervescent mixtures); and / or e) Absorbents, colorants, flavors, and sweeteners and / or a gelatin capsule containing the active ingredient (at least one compound of formula (I)) together with one or more excipients selected from the group consisting of:

[0097] Tablets may be film coated or enteric coated according to methods known in the art. It can be done.

[0098] Compositions suitable for oral administration include an effective amount 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 intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients include, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrating agents (e.g., corn starch or alginic acid); binders (e.g., starch, gelatin, or acacia); and lubricants (e.g., magnesium stearate, stearic acid, or talc). The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a long period of time. For example, a time-delay material (such as glyceryl monostearate or glyceryl distearate) can be used. Oral preparations can be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0099] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may contain stabilizers and / or adjuvants (such as preservatives, stabilizers, wetting agents, or emulsifiers, solution enhancers, salts for regulating osmotic pressure, and / or buffers). Additionally, the compositions may also contain other therapeutically beneficial substances. The compositions are prepared according to conventional blending, granulating, or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient.

[0100] The composition suitable for transdermal application comprises an effective amount of the compound of the present invention together with suitable carrier.The carrier suitable for transdermal delivery comprises absorbable pharmacologically acceptable solvent to support the passage through the host's skin.For example, transdermal device is in the form of a bandage, which comprises a backing member, a reservoir containing the compound together with a carrier if necessary, a rate-controlling barrier for delivering the compound to the host's skin at a controlled and constant rate if necessary over a long period of time, and a means for fixing the device to the skin.

[0101] Compositions suitable for topical administration (e.g., to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations for delivery, e.g., by aerosol. Such topical delivery systems may be associated with inhalation or intranasal applications, which may be suitable for use in treating influenza, and may include, for example, solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives. The compositions may conveniently be delivered as a dry powder from a dry powder inhaler (either alone or in admixture (e.g., dry blends with lactose, or particles in which the ingredients are mixed with, e.g., phospholipids)) or in an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without a suitable propellant.

[0102] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds.

[0103] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture ingredients and low moisture or The anhydrous pharmaceutical composition can be prepared using conditions of low humidity or low humidity. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Therefore, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0104] The present invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate at which a compound of the invention as an active ingredient decomposes. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers, etc.

[0105] The compounds of formula (I), in free or salt form, exhibit beneficial pharmacological properties (e.g., they inhibit or prevent orthomyxovirus replication), as indicated by the test data provided in the next section. Accordingly, the compounds are indicated for use as therapeutic or research chemicals (e.g., tool compounds for studying the replication of orthomyxoviruses, particularly influenza A, B, or C). Accordingly, the compounds of the present invention are useful, particularly in the treatment of infections caused by orthomyxoviruses, particularly influenza A, B, or C, in human subjects. In some embodiments, the subject to be treated is a human infected with or at risk for influenza virus infection. For example, subjects with pre-existing conditions, such as asthma or COPD, that can be significantly exacerbated by influenza infection, can be treated with the methods or compounds of the present invention before they exhibit symptoms of influenza infection, particularly if the subject is at risk for influenza infection due to close contact with a family member or other individual who is infected or believed to be infected with influenza. In other embodiments, the subject treated by the methods and compositions of the present invention is a subject diagnosed with symptoms consistent with influenza infection. In other embodiments, the subject may be a human who has been tested using known diagnostic methods, such as a rapid influenza diagnostic test (RIDT) or reverse transcriptase PCR (RT-PCR), which detect the presence of influenza virus and detect influenza infection regardless of the presence of typical influenza symptoms.

[0106] In a further embodiment, the present invention provides for the use in therapy of a compound of formula (I) or any embodiment within formula (I) as described herein. In particular, the compounds are suitable for use in treating subjects infected with, or at particular risk of infection with, an orthomyxovirus virus, particularly influenza A, influenza B, or influenza C.

[0107] In another embodiment, the present invention provides a method for treating a disease caused by an orthomyxovirus, comprising administering a therapeutically effective amount of a compound of Formula (I) or any embodiment within the scope of Formula (I) described herein to a subject in need of such treatment. In some embodiments, the compound of Formula (I) is administered orally. In further embodiments, the disease is selected from influenza A, influenza B, and influenza C. The method typically comprises administering an effective amount of a compound described herein or a pharmaceutical composition containing an effective amount of such a compound to a subject in need of such treatment. The compound can be administered by any suitable method, such as the methods described herein, and administration can be repeated at intervals that can be selected by the treating physician. In some embodiments, the compound or pharmaceutical composition is administered orally.

[0108] Thus, in a further embodiment, the present invention relates to a method for the manufacture of a medicament comprising administering to a subject a compound as described herein. The present invention provides the use of a compound of formula (I) or any embodiment of such a compound, in certain embodiments, the medicament is for the treatment of an orthomyxovirus infection, particularly an influenza A, influenza B, or influenza C infection.

[0109] The compounds of the present invention can be administered simultaneously with, before, or after one or more therapeutic adjuncts.The compounds of the present invention can be administered separately by the same or different administration route, or can be administered together with the adjunct(s) in the same pharmaceutical composition.Suitable adjuncts for use with the compounds of the present invention include antiviral agents active against influenza viruses, such as neuraminidase inhibitors (including oseltamivir, peramivir, zanamivir, and laninamivir, laninamivir octanoate) and adamantanes (such as amantadine and rimantadine). Additional adjuvants for use in these methods include M2 ​​protein inhibitors, polymerase inhibitors, PB2 inhibitors, favipiravir, fludase, ADS-8902, beraprost, Neugene®, ribavirin, CAS Reg. No. 1422050-75-6, VX-787, Flu Mist Quadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax®, and FluBlok®.

[0110] In one embodiment, the present invention provides a product comprising a compound of Formula (I) and at least one other auxiliary therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C. Products provided as combined preparations include compositions comprising the compound of Formula (I) and at least one other auxiliary therapeutic agent(s) together in the same pharmaceutical composition, or the compound of Formula (I) and at least one other auxiliary therapeutic agent(s) in separate forms, for example, in the form of a kit used to treat a subject by the methods described herein.

[0111] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic auxiliary agent(s). Suitable auxiliary agents include antiviral agents active against influenza viruses, such as neuraminidase inhibitors (including oseltamivir, peramivir, zanamivir, and laninamivir) and adamantanes (such as amantadine and rimantadine). If necessary, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described above.

[0112] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I). The other pharmaceutical compositions may comprise one of suitable auxiliary agents. In one embodiment, the kit comprises a means for separately holding the compositions (such as a container, a divided bottle, or a divided foil vesicle). An example of such a kit is a blister pack (typically used for packaging tablets, capsules, etc.).

[0113] The kits of the invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer the individual compositions at different dosage intervals, or to titrate the individual compositions relative to one another. To aid in compliance, the kits of the invention typically include administration instructions.

[0114] In the combination therapy of the present invention, the compound of the present invention and the therapeutic auxiliary can be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the therapeutic auxiliary can be (i) manufactured and / or formulated by the same or different manufacturers before being sold to physicians as a combination product (e.g., a compound of the present invention and another therapeutic auxiliary). (ii) by the physician (or under the guidance of the physician) immediately prior to administration; or (iii) by the patient themselves (e.g., during sequential administration of the compound of the present invention and a therapeutic adjunct).

[0115] Thus, the present invention provides the use of a compound of formula (I) for treating a viral infection caused by an orthomyxovirus, particularly influenza, which may be influenza A, influenza B, or influenza C, where the medicament is prepared to be administered together with a therapeutic adjunct. Typically, in the method of using the compound of the present invention, the serotype of the influenza is not identified prior to treatment. The present invention also provides the use of a therapeutic adjunct for treating a disease or condition, where the medicament is administered together with a compound of formula (I).

[0116] The present invention also provides a compound of formula (I) for use in a method for treating a viral infection caused by an orthomyxovirus, particularly influenza A, B, or C, wherein the compound of formula (I) is prepared for administration with a therapeutic adjunct. The present invention also provides another therapeutic adjunct for use in a method for treating a viral infection caused by an orthomyxovirus, particularly influenza (e.g., influenza A, B, or C), wherein the therapeutic adjunct is prepared for administration with a compound of formula (I). The present invention also provides a compound of formula (I) for use in a method for treating a viral infection caused by an orthomyxovirus, particularly influenza A, B, or C, wherein the compound of formula (I) is administered with a therapeutic adjunct. The present invention also provides a therapeutic adjunct for use in a method for treating a viral infection caused by an orthomyxovirus, particularly influenza A, B, or C, wherein the therapeutic adjunct is administered with a compound of formula (I).

[0117] The present invention also provides the use of a compound of formula (I) for treating a viral infection caused by an orthomyxovirus, particularly influenza, e.g., influenza A, influenza B, or influenza 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 a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C, wherein the patient has previously (e.g., within 24 hours) been treated with a compound of formula (I).

[0118] In one embodiment, the therapeutic adjunct is selected from antiviral agents known to be useful in treating infections caused by influenza viruses, such as neuraminidase inhibitors (including oseltamivir, peramivir, zanamivir, and laninamivir) and adamantanes (such as amantadine and rimantadine).

[0119] Pharmaceutical compositions or combinations of the present invention may be present in unit dosage amounts containing about 1-1000 mg of active ingredient(s), 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(s) for a human subject weighing about 50-70 kg. The therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof will depend on the subject's species, weight, age, and particular condition, disorder or disease being treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of the disorder or disease.

[0120] The properties of the above dosages can be demonstrated in in vitro and in vivo tests, advantageously using mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and preparations. The compounds of the invention can be administered in vitro in solutions (e.g., In vivo, it can be administered either enterally, parenterally or advantageously intravenously in the form of a suspension or in aqueous solution, for example. The in vitro dosage is about 10 -3 Molar concentration and 10 -9 The therapeutically effective amount in vivo may range from about 0.1 to 500 mg / kg or from about 0.1 to 50 mg / kg, depending on the route of administration.

[0121] The present invention further relates to the process for making the compounds of formula (I) disclosed herein and any variant of this process, including processes in which intermediate products obtainable at any stage thereof are used as starting materials to carry out the remaining steps, or in which the starting materials are insoluble under the reaction conditions. These include processes in which the reactants are formed in situ or in the form of their salts or optically pure materials.

[0122] The compounds and intermediates of the present invention may also be interconverted according to methods generally known to those skilled in the art.

[0123] Methods for synthesizing compounds of Formula (I) are shown in Schemes A-D and illustrated in the Examples herein. Scheme A illustrates the preparation of a compound in which Z1 is N, Z2 is C(R)2, and Z3 is -CR2-CR2-; compounds with other Z3 bonds should also be synthesizable. Scheme A starts with a 5-hydroxypyridazin-4-one-3-carboxylic acid compound in which both the 5-hydroxy and ring NH are protected with suitable, easily removable protecting groups. The carboxylic acid is condensed with the cyclic hydrazine bond to yield two outer rings. After deprotection of the ring nitrogen, a central ring is formed by condensation with an aldehyde. Scheme A. [ka] Scheme B shows an alternative method for making the intermediate after step 1 of Scheme A. Scheme B. [ka] Schemes C and D show Z 1 is CR and Z 2 is CR2 and Z 3 A method for preparing a compound of formula (I) is shown, wherein Scheme C. [ka] Scheme D. [ka]

[0124] Using these synthetic schemes and examples provided, one of ordinary skill in the art can prepare compounds of formula (I). [Example]

[0125] The following examples are intended to illustrate the present invention and are not to be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations are typically carried out under reduced pressure between about 15 mmHg and 100 mmHg (about 20-133 mbar). The structure of the products, intermediates, and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR). The abbreviations used are those conventional in the art.

[0126] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention can be commercially available or prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art in light of the following examples. Abbreviation ATP adenosine 5'-triphosphate Bn Benzyl BOC tertiary butyl carboxylate br Broad BSA Bovine serum albumin d doublet dd Doublet of Doublets DCM dichloromethane DEAD Diethyl azodicarboxylate DBAD Di-tert-butyl azodicarboxylate 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 Flash Column Chromatography h hour(s) HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazolium hexafluorophosphate(1-)3-oxide HOBt 1-hydroxy-7-azabenzotriazole HPLC High Pressure Liquid Chromatography IR Infrared Spectroscopy LCMS Liquid Chromatography and Mass Spectrometry MeOH Methanol MS mass spectrometry MW Microwave m multiplet min mL milliliter(s) m / z mass-to-charge ratio NBS N-Bromosuccinimide NCS N-chlorosuccinimide NMP N-methylpyrrolidinone NMR nuclear magnetic resonance ppm parts per million PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate rac racemic rt room temperature s singlet SEM(2-(trimethylsilyl)ethoxy)methyl t triplet TBDMS t-butyldimethylsilyl TBDPS t-butyldiphenylsilyl TFA trifluoroacetic acid THF tetrahydrofuran Tris·HCl Aminotris(hydroxymethyl)methane hydrochloride Compound 1. 1-Benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid hydrochloride [ka]

[0127] To a suspension of ethyl 5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carboxylate hydrochloride (50 g, 161 mmol; see U.S. Patent Application Publication No. 2015 / 0072982 A1) in MeOH (800 mL) at room temperature, NaOH (26.4 g, 660 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Benzyl bromide (99 g, 579 mmol) was added, and the mixture was stirred for 2 hours. The reaction was concentrated, and then water was added to the residue. The mixture was then acidified to pH 2 with 2 M HCl, which resulted 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-carboxylic acid hydrochloride (57.5 g, 154 mmol, 96% yield), which was used without further purification. MS m / z 337.3 (M+1). General synthesis of chiral N-CBZ amino alcohols [ka] Step G-1: tert-butyl (R,E)-2-(4-fluorostyryl)pyrrolidine -1-carboxylate

[0128] A solution of lithium bis(trimethylsilyl)amide (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. After stirring at 0° C. for 20 minutes, a solution of (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (15 g, 75 mmol) in THF (40 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then slowly warmed to room temperature over 1 hour, and then stirred at room temperature for an additional 2 hours. 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) gave tert-butyl (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylate (11.65 g, colorless oil) in 53% yield. MS m / z 236.3 (M-tBu+H). Step G-2: (R,E)-2-(4-fluorostyryl)pyrrolidine hydrochloride

[0129] A solution of HCl (4.0 M in dioxane, 29.6 ml, 118 mmol) was added to tert-butyl (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylate (11.5 g, 39.5 mmol) at room temperature and stirred for 1 hour. The reaction mixture was then concentrated to give crude (R,E)-2-(4-fluorostyryl)pyrrolidine hydrochloride, which was used in the next step without further purification. MS m / z 192.1 (MH + ). Step G-3: Benzyl (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylate

[0130] Benzyl chloroformate (6.8 mL, 47.4 mmol) was added dropwise 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) at 0 °C, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was then diluted with more DCM, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylate (11.6 g, colorless oil) in 90% yield over two steps. MS m / z 348.2 (M+Na). + . Step G-4: benzyl (R)-2-((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2-((2R,3R)-3-(4-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate

[0131] To a solution of benzyl (R,E)-2-(4-fluorostyryl)pyrrolidine-1-carboxylate (3.5 g, 10.8 mmol) in DCM (200 mL) was added sodium bicarbonate (4.52 g, 53.8 mmol) and mCPBA (70%, 13.3 g, 53.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. Additional DCM (50 mL) was added and stirred for an additional hour. The reaction was quenched with water and extracted with DCM (twice). The combined organic extracts were washed sequentially with saturated aqueous NaSO, saturated aqueous NaHCO, and brine. The organic layer was then dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded an inseparable mixture of benzyl (R)-2-((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2-((2R,3R)-3-(4-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (2.25 g, colorless oil) in 61% yield. The mixture was not further purified. was used in the next step. MS m / z 342.4 (MH + ). Step G-5: benzyl (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate and benzyl (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate

[0132] Copper(I) bromide-dimethyl sulfide complex (452 ​​mg, 2.20 mmol) was added to a mixture of benzyl (R)-2-((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2-((2R,3R)-3-(4-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (750 mg, 2.20 mmol) in THF (12 mL) at room temperature. The mixture was cooled to between -20 and -30 °C in an acetone bath with periodic addition 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 min and warmed to 0 °C. Two more equivalents of (3-(trifluoromethyl)phenyl)magnesium bromide were added and stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (twice). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (195 mg, colorless oil, first eluted) in 18% yield and benzyl (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (440 mg, second eluted) in 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 [ka] Step 1: Benzyl (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate

[0133] Benzyl (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxamide To a solution of the silane (195 mg, 0.400 mmol) in pyridine (6 mL) was added methanesulfonyl chloride (0.47 mL, 6.0 mmol) at 0 °C. After 5 min, 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 1 N aqueous HCl, saturated aqueous NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (130 mg) in 58% yield. MS m / z 566.4 (MH + ). Step 2: (1R,2S)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate hydrochloride

[0134] A solution of benzyl (R)-2-((1R,2S)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (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 evacuated and refilled with hydrogen (3 times), then vigorously stirred at room temperature under a hydrogen balloon. After 2 h, the reaction mixture was filtered through Celite and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate 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-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate

[0135] Huenig's 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. Stirring was continued for 15 minutes at room temperature, followed by the addition of a solution of crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate hydrochloride (98 mg, 0.23 mmol) in DCM (2 mL) and two equivalents of Huenig's base. The mixture was stirred at room temperature for 30 minutes. The reaction 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) gave (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate (150 mg) in 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)pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate

[0136] (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethylmethane A solution of the sulfonate (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 evacuated and refilled with hydrogen (three times), then vigorously stirred under a hydrogen balloon at room temperature for 2 hours. The reaction mixture was filtered through Celite and the filter cake was washed with MeOH. The filtrate was concentrated to give crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate, 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

[0137] To a solution of crude (1R,2S)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate (110 mg, 0.19 mmol) in DMF (3 mL) was added potassium carbonate (107 mg, 0.773 mmol) and the mixture was stirred at room temperature overnight. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and lyophilized to give (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 formate salt (56 mg, 0.11 mmol, white solid) in 55% yield over two steps. 1 H NMR (400 MHz, MeOD) δ ppm 7.63 (dd, J=8.63, 5.21 Hz, 2 H) 7.37 (br d, J=7.24 Hz, 1 H) 7.23 - 7.33 (m, 4 H) 7.18 (t, J=8.68 Hz, 2 H) 5.77(dd, J=9.59, 3.62 Hz, 1 H) 4.72 (d, J=9.63 Hz, 1 H) 4.44 - 4.58 (m, 1 H) 3.82 - 3.95 (m, 1 H) 3.62 - 3.76 (m, 1 H) 2.02 - 2.13 (m, 2 H) 1.73 - 1.96(m, 2 H) 1.54 - 1.71 (m, 1 H). MS m / z 474.4 (MH + ). [Table 1A-1] [Table 1A-2] [Table 1A-3] [Table 1A-4] [Table 1A-5] [Table 1A-6] [Table 1A-7] 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 [ka]

[0138] Prepared by the general method of Example 1 using commercially available reagents. 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 = 10.0 Hz, 1H), 4.46 (dd, J = 10.7, 5.2 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.62 - 3.50 (m, 1H), 1.89 (dd, J = 12.6, 6.4 Hz, 1H), 1.79 (dt, J = 12.3, 5.9 Hz, 1H), 1.73 - 1.59 (m, 1H), 1.31 (qd, J = 11.5, 6.6 Hz, 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 [ka] Step 1: Benzyl (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate

[0139] To a solution of benzyl (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (440 mg, 0.90 mmol) in pyridine (8 mL) at 0 °C was added methanesulfonyl chloride (1.1 mL, 13.5 mmol). After 5 min, 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 1 N aqueous HCl, saturated aqueous NaHCO, and brine. The organic layer was dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) gave benzyl (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (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

[0140] A solution of benzyl (R)-2-((1S,2R)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidine-1-carboxylate (450 mg, 0.796 mmol) in pyridine (8 mL) was heated in a microwave reactor at 155° C. for 3 hours. Silica gel column chromatography (EtOAc / heptane) afforded (1R,7aR)-1-((R)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (175 mg) in 58% yield. MS m / z 380.5 (MH + ). Step 3: (1R,2R)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethan-1-ol hydrochloride

[0141] 6N aqueous HCl was added to 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), and the mixture was heated in a sealed vial 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)ethan-1-ol hydrochloride, which was used in 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)pyridazin-4(1H)-one

[0142] Huenig's 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. After stirring at room temperature for 15 minutes, a solution of crude (1R,2R)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethan-1-ol hydrochloride (160 mg, 0.453 mmol) in DCM (4 mL) and Huenig's base (0.32 mL, 1.8 mmol) were added. The mixture was stirred at room temperature for 60 minutes. 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) gave 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 (290 mg, 0.432 mmol) in 95% yield. MS m / z 672.7 (MH + ). Step 5: (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate

[0143] 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-lutidine (6 mL) in an ice bath was added methanesulfonyl chloride (0.52 mL, 6.7 mmol). After 5 min, the 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 1 N aqueous HCl, saturated aqueous NaHCO, and brine. The DCM layer was then dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) gave (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate (280 mg, 0.373) in 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 methanesulfonate

[0144] To a solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(4-fluorophenyl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate (280 mg, 0.373 mmol) in methanol (10 mL) was added HCl (4.0 M in dioxane, 0.19 mL, 0.75 mmol), 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 evacuated and refilled with hydrogen (3 times), then stirred vigorously under a hydrogen balloon at room temperature for 2 hours. Additional palladium on carbon (199 mg) was added and stirred at room temperature for an additional 3 hours. The reaction mixture was filtered through Celite, 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)pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate, 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

[0145] To a solution of crude (1R,2R)-2-(4-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(3-(trifluoromethyl)phenyl)ethyl methanesulfonate (210 mg, 0.369 mmol) in DMF (6 mL) was added potassium carbonate (204 mg, 1.48 mmol) and the mixture was stirred at room temperature overnight. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and lyophilized to give (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 formate salt (30 mg, 0.112 mmol, white solid) in 30% yield over two steps. 1 H NMR (400 MHz, MeOD) δppm 7.88 (br s, 2 H) 7.62 (br s, 2 H) 7.36 - 7.48 (m, 1 H) 6.89 - 7.05 (m, 2 H) 6.82 (br t, J=8.41 Hz, 2 H) 5.83 (br d,J=8.02 Hz, 1 H) 4.52 (br s, 1 H) 3.80 - 3.92 (m, 1 H) 3.62 - 3.74 (m, 1 H) 2.03 - 2.12 (m, 1 H) 1.78 - 1.98 (m, 2 H) 1.49 - 1.66 (m, 1 H). MS m / z 474.4 (MH + ). [Table 1B-1] [Table 1B-2] [Table 1B-3] [Table 1B-4] Compound E-1: benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and E-2: benzyl (R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate [ka] Step 1: Diethyl (2,3-difluorobenzyl)phosphonate

[0146] 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 and then cooled to room temperature. Toluene (approximately 50 mL) was added, and the mixture was then concentrated to give crude diethyl (2,3-difluorobenzyl)phosphonate (41 g, colorless oil), which was used in the next step without further purification. MS m / z 265.3 (MH + ). Step 2: tert-butyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate

[0147] A solution of lithium bis(trimethylsilyl)amide (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. After stirring at 0° C. for 1 hour, (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (5.0 g, 25.1 mmol) was added dropwise. The reaction mixture was stirred in an ice bath for 1 hour, then slowly warmed to room temperature over 1 hour, and then stirred at room temperature for an additional 2 hours. 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) gave tert-butyl ( R,E)-2-(2,3-Difluorostyryl)pyrrolidine-1-carboxylate (6.87 g, white solid) was obtained in 88% yield. MS m / z 254.3 (M-tBu+H). Step 3: (R,E)-2-(2,3-difluorostyryl)pyrrolidine hydrochloride

[0148] A solution of HCl (4.0 M in dioxane, 19.6 ml, 78 mmol) was added to tert-butyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (6.07 g, 19.6 mmol) at room temperature and stirred for 1 hour. The reaction mixture was then concentrated to give crude (R,E)-2-(2,3-difluorostyryl)pyrrolidine hydrochloride, which was used in the next step without further purification. MS m / z 210.2 (MH + ). Step 4: Benzyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate

[0149] Benzyl chloroformate (3.1 mL, 21.6 mmol) was added dropwise 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) at 0 °C, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was then diluted with more DCM, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (6.67 g, colorless oil) in 99% yield over two steps. MS m / z 344.3 (MH + ). Step 5: E-1: benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and E-2: benzyl (R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate

[0150] To a solution of benzyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carboxylate (5.9 g, 17.2 mmol) in DCM (286 mL) was added mCPBA (21.2 g, 86 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM (twice). The combined organic extracts were washed sequentially with saturated aqueous NaSO, saturated aqueous NaHCO, and brine. The organic layer was then dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded an inseparable mixture of benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (E-1) and benzyl (R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (E-2) (5.16 g, colorless oil) 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 [ka] Step 1: Benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

[0151] Copper(I) bromide-dimethyl sulfide complex (286 mg, 1.39 mmol) was added to a mixture of benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.39 mmol) in THF (8 mL) at room temperature. The mixture was cooled to between −20 and −30° C. in an acetone bath with periodic addition 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 warmed to 0° C. Two additional equivalents of (4-fluorophenyl)magnesium bromide were added and stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (88 mg, colorless oil, first eluted) in 14% yield and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (350 mg, second eluted) in 55% yield. MS m / z 456.4(MH + ). Step 2: Benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate

[0152] To a solution of benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (88 mg, 0.19 mmol) in pyridine (2.5 mL) at 0 °C was added methanesulfonyl chloride (0.23 mL, 2.9 mmol). After 5 min, 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 1 N aqueous HCl, saturated aqueous NaHCO, and brine. The organic layer was dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) gave benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (85 mg) in 82% yield. MS m / z 534.5 (MH + ). Step 3: (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride

[0153] A solution of benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (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 evacuated and refilled with hydrogen (3 times), then vigorously stirred at room temperature under a hydrogen balloon. After 2 h, the reaction mixture was filtered through Celite 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)-pyrrolidin-2-yl)ethyl methanesulfonate 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-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)ethyl methanesulfonate

[0154] Huenig's 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. After stirring at room temperature for 15 minutes, a solution of crude (1R,2R)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride (62 mg, 0.16 mmol) in DCM (2 mL) and two equivalents of Huenig's base were added. The mixture was stirred at room temperature for 30 minutes. The reaction 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) gave (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-(4-fluorophenyl)ethyl methanesulfonate (100 mg) in 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)pyrrolidin-2-yl)ethyl methanesulfonate

[0155] (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2- A solution of (2,3-difluorophenyl)-2-(4-fluorophenyl)ethyl methanesulfonate (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 evacuated and refilled with hydrogen (three times), then vigorously stirred under a hydrogen balloon at room temperature for 1 hour. The reaction mixture was filtered through Celite, 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)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate, 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

[0156] 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)pyrrolidin-2-yl)ethyl methanesulfonate (74 mg, 0.138 mmol) in DMF (3 mL) was added potassium carbonate (76 mg, 0.551 mmol) and the mixture was stirred at room temperature overnight. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and lyophilized to give (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 formate salt (24 mg, 0.049 mmol, white solid) in 36% yield over two steps. 1H NMR (400 MHz, CD3OD) δ ppm 7.79 - 7.65 (m, 1H), 7.42 (s, 1H), 7.37 - 7.21 (m, 2H), 7.02 (dd, J = 8.6, 5.3 Hz, 2H), 6.85 (t, J = 8.7 Hz, 2H), 5.79 (dd, J = 9.6, 3.7 Hz, 1H), 4.74 (d, J = 9.6 Hz, 1H), 4.62 (s, 1H), 4.53 (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). + ). 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]pyridazine-3,5-dione [ka] Step 1: Benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate

[0157] Copper(I) bromide-dimethyl sulfide complex (3.65 g, 17.7 mmol) was added to a mixture of benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (5.8 g, 16.1 mmol) in THF (161 mL) at room temperature. The mixture was cooled to between -20 °C and -30 °C in an acetone bath with periodic addition of dry ice. A solution of phenylmagnesium bromide (1.0 M in THF, 97 mL, 97 mmol) was added dropwise. The mixture was stirred for 10 min, warmed to 0 °C, and stirred for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 times). The combined organic extracts were dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate (1.5 g, colorless oil, first eluted) in 13% yield and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate (2.5 g, second eluted) in 35% yield. MS m / z 438.5 (MH + ). Step 2: Benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate

[0158] To a solution of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate (900 mg, 2.06 mmol) in pyridine (21 mL) was added methanesulfonyl chloride (1. To the resulting solution was added 92 mL of HCl (24.7 mmol). After 5 min, 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 successively with 1 N aqueous HCl, saturated aqueous NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate (700 mg) in 66% yield. MS m / z 516.5 (MH + ). Step 3: (1R,2R)-2-(2,3-difluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride

[0159] A solution of benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxylate (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 evacuated and refilled with hydrogen (three times) and then vigorously stirred at room temperature under a hydrogen balloon. After 30 min, the reaction mixture was filtered through Celite 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)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride, which was used in 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-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-phenylethyl methanesulfonate

[0160] Huenig's 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. After stirring at room temperature for 15 minutes, a solution of crude (1R,2R)-2-(2,3-difluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride (570 mg, 1.36 mmol) in DCM (2 mL) and 1.1 equivalents of Huenig's base were added. The mixture was stirred at room temperature for 1 hour. The reaction 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) gave (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-phenylethyl methanesulfonate (900 mg) in 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)pyrrolidin-2-yl)-2-phenylethyl methanesulfonate

[0161] A solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-phenylethyl methanesulfonate (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 evacuated and refilled with hydrogen (3 times), then vigorously stirred under a hydrogen balloon at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filter cake was washed with MeOH. The filtrate was concentrated to give crude ( 1R,2R)-2-(2,3-difluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethyl methanesulfonate was obtained, 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

[0162] To a solution of crude (1R,2R)-2-(2,3-difluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-phenylethyl methanesulfonate (670 mg, 1.29 mmol) in DMF (13 mL) was added potassium carbonate (535 mg, 3.87 mmol) and the mixture was stirred at room temperature overnight. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and 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 47% yield over two steps. (400 MHz, DMSO-d6) δ 7.84 (t, J = 7.1 Hz, 1H), 7.37 (ddt, J = 16.0, 13.4, 8.1 Hz, 2H), 7.21 (s, 1H), 7.14 - 7.03 (m, 3H), 6.98 - 6.85 (m, 2H), 5.77 (dd, J = 9.6, 3.7 Hz, 1H), 4.64 (d, J = 9.6 Hz, 1H), 4.50 (dt, J = 10.0, 5.1 Hz, 1H), 3.73 (dd, J = 12.0, 8.4 Hz, 2H), 1.92 (ddt, J = 30.6, 12.3, 6.1 Hz, 2H), 1.74 (q, J = 8.3, 6.0 Hz, 1H), 1.34 (qd, J = 11.6, 6.6 Hz, 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 [ka] Step 1: Benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate

[0163] Copper(I) bromide-dimethyl sulfide complex (2.83 g, 13.8 mmol) was added to a mixture of benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (4.95 g, 13.8 mmol) in THF (120 mL) at room temperature. The mixture was cooled to between -20 and -30 °C in an acetone bath with periodic addition of dry ice. 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 min, warmed to 0 °C, and stirred for an additional 15 min. Two more equivalents of (3-fluorophenyl)magnesium bromide were added and stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (twice). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) afforded benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (1.4 g, colorless oil, first eluting) in 10% yield and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (3.2 g, second eluting) in 51% yield. MS m / z 456.4 (MH + ). Step 2: Benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate

[0164] To a solution of (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (1.4 g, 1.38 mmol) in pyridine (20 mL) at 0 °C was added methanesulfonyl chloride (1.62 mL, 20.7 mmol). After 5 min, 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 1 N aqueous HCl, saturated aqueous NaHCO, and brine. The organic layer was dried over NaSO, filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) gave benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (575 mg) in 78% yield. MS m / z 534.4 (MH + ). Step 3: (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride

[0165] A solution of benzyl (R)-2-((1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate (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 evacuated and refilled with hydrogen (3 times), then vigorously stirred at room temperature under a hydrogen balloon. After 2 h, the reaction mixture was filtered through Celite 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)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride was obtained, 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-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)ethyl methanesulfonate

[0166] Huenig's 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. After stirring at room temperature for 15 minutes, a solution of crude (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride (430 mg, 1.08 mmol) in DCM (6 mL) and 1.1 equivalents of Huenig's base were added. The mixture was stirred at room temperature for 1 hour. The reaction 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) gave (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)ethyl methanesulfonate (735 mg) in 95% yield. MS m / z 718.6 (MH + ). Step 5: (1R,2R)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate

[0167] A solution of (1R,2R)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2,3-difluorophenyl)-2-(3-fluorophenyl)ethyl methanesulfonate (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 evacuated and refilled with hydrogen (3 times), then vigorously stirred under a hydrogen balloon at room temperature for 1 hour. The reaction mixture was filtered through Celite, 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)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate, 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

[0168] 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)pyrrolidin-2-yl)ethyl methanesulfonate (550 mg, 1.02 mmol) in DMF (20 mL) was added potassium carbonate (566 mg, 4.09 mmol) and the mixture was stirred at room temperature overnight. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7,9-diol. H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (252 mg, 0.571 mmol, white solid) was obtained in 56% yield over two steps. (400 MHz, MeOD) δ ppm 7.74 (br t, J=6.99 Hz, 1 H) 7.40 (s, 1 H) 7.37 (br s, 1 H) 7.23 - 7.36 (m, 1 H) 7.06 - 7.16 (m, 1 H) 6.82 - 6.91(m, 1 H) 6.72 - 6.81 (m, 2 H) 5.81 (dd, J=9.61, 3.59 Hz, 1 H) 4.76 (d, J=9.63 Hz, 1 H) 4.61 (br s, 1 H) 4.48 - 4.55 (m, 1 H) 3.84 - 3.94 (m, 1 H) 3.65(td, J=11.25, 7.38 Hz, 1 H) 2.04 - 2.14 (m, 1 H) 1.95 - 2.03 (m, 1H) 1.80 - 1.92 (m, 1 H) 1.50 (qd, J=11.67, 6.80 Hz, 1 H). 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)methyl methyl carbonate [ka] Step 1. Iodomethyl methyl carbonate

[0169] 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 at 40° C. overnight. The reaction was cooled to room temperature and concentrated. The residue was diluted with water and aqueous sodium thiosulfate solution 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)methyl methyl carbonate

[0170] 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 and then at room temperature for an additional hour. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product The fractions were combined, frozen, 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 methyl carbonate (367 mg, 0.710 mmol, white solid) in 59% yield. 1 H 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 = 2.2 Hz, 3H), 3.78 (t, J = 10.3 Hz, 1H), 3.63 (q, J = 10.4 Hz, 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 [ka]

[0171] 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) was added triethylamine (0.040 mL, 0.28 mmol), followed by isobutyryl chloride (0.020 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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 isobutyrate (26 mg, 0.052 mmol, white solid) in 55% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (t, J = 7.1 Hz, 1H), 7.37 (dddd, J = 21.7, 15.9, 11.5, 4.8 Hz, 3H), 7.20 - 7.02 (m, 3H), 6.88 (s, 2H), 5.78 (d, J = 10.1 Hz, 1H), 4.52 (dd, J = 10.1, 4.9 Hz, 2H), 3.62 (dd, J = 12.1, 8.0 Hz, 1H), 3.48 (td, J = 11.0, 6.6 Hz, 1H), 2.77 (hept, J = 7.1 Hz, 1H), 1.84 (dd, J = 11.8, 6.1 Hz, 2H), 1.66 (s, 1H), 1.22 (dd, J = 7.2, 3.9 Hz, 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 [ka]

[0172] Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (141 mg, 0.85 mmol), and chloromethyl 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 was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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) in 25% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (t, J = 7.1 Hz, 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 = 11.3 Hz, 1H), 1.45 - 1.17 (m, 1H), 1.09 (dd, J = 7.0, 1.1 Hz, 6H). MS m / z 524.3 (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 [ka]

[0173] Potassium carbonate (98 mg, 0.71 mmol), potassium iodide (118 mg, 0.71 mmol), 18-crown-6 (12 mg, 0.05 mmol), and 1-chloro Ethyl methyl carbonate (98 mg, 0.71 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, 0.118 mmol) in DMF (volume: 1 mL) at room temperature. The mixture was stirred at 60°C for 4 hours. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and 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) in 19% yield. 1 H NMR (500 MHz, chloroform-d) δ 7.40 (t, J = 6.9 Hz, 1H), 7.34 (s, 1H), 7.28 - 7.12 (m, 5H), 7.01 (d, J = 7.0 Hz, 2H), 6.70 (q, J = 5.3 Hz, 1H), 5.37 (dd, J = 10.5, 3.4 Hz, 1H), 4.59 (d, J = 10.5 Hz, 1H), 4.37 (ddd, J = 10.1, 6.3, 3.4 Hz, 1H), 3.93 - 3.85 (m, 4H), 3.64 (td, J = 11.2, 6.6 Hz, 1H), 2.00 (dt, J = 13.0, 6.8 Hz, 1H), 1.92 (dt, J = 12.9, 6.4 Hz, 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-yl isopropyl carbonate [ka]

[0174] 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 DCM (2 mL) was added Huenig's base (0.074 mL, 0.43 mmol), followed by isopropyl chloroformate (0.18 mL, 0.18 mmol). The reaction mixture was stirred at room temperature for 2 hours 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 reverse-phase HPLC. The product fractions were combined, frozen, 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 isopropyl carbonate (17 mg, 0.032 mmol, white solid) in 23% yield. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.86 (br t, J=6.92 Hz, 1 H) 7.34 - 7.49 (m, 3 H) 7.10 - 7.17 (m, 3 H) 6.88 - 6.95 (m, 2 H) 5.82 (dd, J=10.23, 3.37 Hz, 1 H) 4.90 (dt, J=12.44, 6.13 Hz, 1 H) 4.54 - 4.59 (m, 2 H) 3.63 - 3.70 (m, 1 H) 3.45 - 3.63 (m, 1 H) 1.84 - 1.94 (m, 2 H) 1.65 - 1.83 (m, 1 H) 1.18 - 1.37 (m, 7 H). 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 [ka]

[0175] 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) was added triethylamine (0.13 mL, 0.95 mmol), followed by DMAP (7 mg, 0.06 mmol) and dimethylcarbamyl chloride (0.065 mL, 0.71 mmol). The reaction mixture was stirred overnight at room temperature, filtered, and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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-yldimethylcarbamate (32 mg, 0.064 mmol, white solid) in 54% yield. 1 H NMR (500 MHz, meta Nol-d4) δ 7.72 (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). MS m / 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-carboxylate [ka] Step 1. Chloromethyl 4-methylpiperazine-1-carboxylate

[0176] To a solution of 1-methylpiperazine (0.51 mL, 4.6 mmol) in DCM (10 mL) at 0 °C, chloromethyl carbonochloridate (0.2 mL, 2.25 mmol) was added, and the mixture was stirred at 0 °C for 3 h. The reaction was quenched with 5% aqueous NaHCO and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated to give crude chloromethyl 4-methylpiperazine-1-carboxylate, 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-carboxylate

[0177] Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (94 mg, 0.57 mmol), and chloromethyl 4-methylpiperazine-1-carboxylate (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 at room temperature for 3 hours. Additional chloromethyl 4-methylpiperazine-1-carboxylate (109 mg, 0.57 mmol) was added, and the mixture was stirred overnight. The reaction was filtered through a 1 micron filter and purified by SFC (CO / MeOH). The product fractions were combined, frozen, 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-carboxylate (8 mg, 0.013 mmol, white solid) in 9% yield. 1 H NMR (500 MHz, DMSO-d6) δ 7.87 (t, J = 7.0 Hz, 1H), 7.47 - 7.31 (m, 3H), 7.21 - 7.07 (m, 3H), 7.01 - 6.85 (m, 2H), 5.83 - 5.70 (m, 2H), 5.61 (d, J = 6.4 Hz, 1H), 4.50 (dd, J = 13.9, 7.2 Hz, 2H), 3.70 - 3.59 (m, 1H), 3.54 (td, J = 11.2, 6.6 Hz, 1H), 3.38 (d, J = 5.6 Hz, 4H), 2.30 (s, 4H), 2.20 (s, 3H), 1.98 - 1.82 (m, 2H), 1.70 (d, J = 15.9 Hz, 1H), 1.30 (ddd, J = 17.8, 15.4, 9.0 Hz, 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]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl L-valinate [ka] 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-valinate

[0178] 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) was added K2CO3 (78 mg, 0.57 mmol) and KI (94 mg, 0.57 mmol). The mixture was cooled to 0 °C, and chloromethyl(tert-butoxycarbonyl)-L-valinate (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) gave (((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-valinate (90 mg) in 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-valinate

[0179] 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-valinate (90 mg, 0.138 mmol) in dioxane (volume: 460 μL) at 0° C. was added dropwise HCl (4.0 M in dioxane, 0.7 mL, 2.8 mmol). 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 reverse phase HPLC 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 L-valinate formate. The salt (14 mg) was obtained in 14% yield. 1 H NMR (500 MHz, methanol-d4) δ 7.74 (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 = 6 Hz, 1H), 5.78 (m, 1H), 5.73 (m, J = 6 Hz, 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 = 7 Hz, 3H), 0.98 (d, J = 7 Hz, 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 [ka]

[0180] 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. Stirring was continued overnight at room temperature. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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) in 39% yield. 1 H 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 = 10.1, 6.5, 3.4 Hz, 1H), 4.04 (s, 3H), 3.94 - 3.85 (m, 1H), 3.73 (td, J = 11.3, 6.7 Hz, 1H), 2.11 (dt, J = 13.2, 6.9 Hz, 1H), 2.00 (dt, J = 12.8, 6.6 Hz, 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-methylbutanoate [ka]

[0181] Huenig's base (0.10 mL, 0.57 mmol) and HATU (70 mg, 0.18 mmol) were added to a solution of 3-methoxy-3-methylbutanoic acid (21 mg, 0.16 mmol) in DMF (1 mL) at room temperature. After stirring at room temperature for 15 minutes, 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) and Huenig's 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 reverse-phase HPLC. The product fractions were combined, frozen, 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 3-methoxy-3-methylbutanoate (5 mg, 0.008 mmol, white solid) in 6% yield. 1 HNMR (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, overlapping), 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 + ).

[0182] 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-methylpropanoate [ka]

[0183] A mixture of 2-methoxy-2-methylpropanoic acid (56 mg, 0.47 mmol) and oxalyl chloride (115 μl, 1.31 mmol) was slowly heated at 50° C. for 5 minutes. The mixture was maintained at room temperature for 1 hour and then at 40°C for 30 minutes. 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]pyridazine-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 reverse-phase HPLC. The product fractions were combined, frozen, 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 2-methoxy-2-methylpropanoate (28 mg, 0.052 mmol, white solid) in 56% yield.1 HNMR (400 MHz, DMSO-d6) δ 7.83 (t, J = 7.1 Hz, 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 MS m / z 524.3 (MH + ).

[0184] 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-methylpropanoate [ka] Step 1. Chloromethyl 2-methoxy-2-methylpropanoate

[0185] A mixture of 2-methoxy-2-methylpropanoic acid (1 g, 8.5 mmol), NaHCO (2.84 g, 33.9 mmol), tetrabutylammonium hydrogen sulfate (0.287 g, 0.847 mmol), and chloromethyl sulfochloridate (0.942 mL, 9.31 mmol) in 20 mL of water:dichloromethane (1:1) was stirred at room temperature for 1 h. The organic phase was separated and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to give crude chloromethyl 2-methoxy-2-methylpropanoate (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-methylpropanoate

[0186] Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (141 mg, 0.85 mmol), and chloromethyl 2-methoxy-2-methylpropanoate (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 was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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 2-methoxy-2-methylpropanoate (8 mg, 0.015 mmol, white solid) in 10% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (t, J = 7.0 Hz, 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 = 6.3 Hz, 1H), 4.58 - 4.32 (m, 2H), 3.68 - 3.41 (m, 2H), 3.15 (s, 3H), 1.86 (dt, J = 12.3, 6.5 Hz, 2H), 1.64 (q, J = 17.2, 13.7 Hz, 1H), 1.31 (s, 6H). MS m / z 554.3 (MH + ). Example 42. 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]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropanoate [ka] Step 1. Methyl 2-(((chloromethoxy)carbonyl)oxy)-2-methylpropanoate

[0187] To a solution of chloromethyl carbonochloridate (600 mg, 4.65 mmol) in DCM (10 mL) at 0 °C, pyridine (0.5 mL, 1.3 mmol) and methyl 2-hydroxy-2-methylpropanoate (600 mg, 5.08 mmol) were added, and the mixture was stirred at 0 °C for 1 h and then at room temperature for 2 h. The reaction was quenched with 2 N aqueous HCl. The mixture was quenched with HCl and extracted with DCM. The organic layer was dried over NaSO, filtered, and concentrated to give crude methyl 2-(((chloromethoxy)carbonyl)oxy)-2-methylpropanoate, which was used in the next step without further purification. Step 2. 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]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropanoate

[0188] Potassium carbonate (118 mg, 0.85 mmol), potassium iodide (94 mg, 0.57 mmol), and methyl 2-(((chloromethoxy)carbonyl)oxy)-2-methylpropanoate (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 at room temperature for 4 hours. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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]pyrazino[1,2-b]pyridazin-4-yl)oxy)methoxy)carbonyl)oxy)-2-methylpropanoate (9 mg, 0.015 mmol, white solid) in 11% yield. 1 H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.39 (d, J = 23.5 Hz, 3H), 7.12 (d, J = 4.0 Hz, 3H), 6.94 (d, J = 7.8 Hz, 2H), 5.84 - 5.58 (m, 3H), 4.50 (d, J = 10.0 Hz, 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-dioxol-4-yl)methoxy)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione [ka] Step 1. 4-(iodomethyl)-5-methyl-1,3-dioxol-2-one

[0189] To a room temperature solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (500 mg, 3.37 mmol) in butanone (10 mL) was added sodium iodide (1 0.51 g, 10.1 mmol) was added and the mixture was stirred at 60° C. for 90 min. The reaction was filtered and concentrated. Silica gel column chromatography (EtOAc / heptane) gave 4-(iodomethyl)-5-methyl-1,3-dioxol-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-dioxol-4-yl)methoxy)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione

[0190] Potassium carbonate (41 mg, 0.30 mmol) and 4-(iodomethyl)-5-methyl-1,3-dioxol-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 was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and lyophilized to give (9aR,10S)-10-((R)-(2,3-difluorophenyl)(phenyl)methyl)-4-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (32 mg, 0.059 mmol, white solid) in 50% yield. 1 H NMR (400 MHz, chloroform-d) δ 7.49–7.40 (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, 3.3 Hz, 1H), 5.18 (d, J = 13.3 Hz, 1H), 5.10 (d, J = 13.3 Hz, 1H), 4.60 (d, J = 9.3 Hz, 1H), 4.38 (ddd, J = 10.0, 6.4, 3.3 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.68 (td, J = 12.1, 11.3, 6.7 Hz, 1H), 2.17 (s, 3H), 2.08 (dt, J = 13.1, 6.7 Hz, 1H), 1.97 (dt, J = 13.5, 6.2 Hz, 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]pyridazin-4-yl 4-methylpiperazine-1-carboxylate [ka]

[0191] Potassium carbonate (98 mg, 0.71 mmol) and 4-methylpiperazine-1-carbonyl chloride (58 mg, 0.35 mmol) were dissolved in (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) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, 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-carboxylate (63 mg, 0.11 mmol, white solid) in 81% yield. 1 H NMR (400 MHz, MeOD) δ ppm 7.70 (br s, 1 H) 7.45 (br s, 1 H) 7.23 - 7.38 (m, 2 H) 7.04 - 7.20 (m, 3 H) 6.90 - 7.04 (m, 2 H) 5.81 (br s, 1 H)4.64 (d, J=10.17 Hz, 1 H) 4.56 (br s, 1 H) 3.68 - 3.89 (m, 3 H) 3.43 - 3.66 (m, 3 H) 2.70 (br s, 4 H) 2.44 (br s, 3 H) 1.92 - 2.08 (m, 2 H) 1.75 - 1.89 (m, 1 H) 1.47 (br s, 1 H). MS m / z 550.5 (MH + ).

Table 1C-1

Table 1C-2

Table 1C-3

Table 1C-4

Table 1C-5

Table 1C-6

Table 1C-7

Table 1C-8

Table 1C-9

Table 1C-10

Table 1C-11

Table 1C-12

Table 1C-13

Table 1C-14

Table 1C-15

Table 1C-16

Table 1C-17

Table 1C-18

Table 1C-19

Table 1C-20

Table 1C-21

Table 1C-22

Table 1C-23

Table 1C-24

Table 1C-25

Table 1C-26

Table 1C-27

Table 1C-28

Table 1C-29

Table 1C-30

[0192] The activity of the compounds of the present invention can be evaluated by the following in vitro and in vivo methods. Using the test assays described herein, the compounds of the present invention exhibit the inhibitory potencies shown in Table 2. In Table 2, + means 1□M or more; ++ means less than 1□M and 0.1□M or more; +++ means less than 0.1□M. Influenza virus minigenome assay (RNP assay)

[0193] For influenza A virus minigenome reporter assays, 293T cells were transfected with expression vectors encoding the PB2, PB1, PA, and NP proteins and an influenza A luciferase reporter plasmid. Cells were harvested in phenol red-free Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% inactivated fetal bovine serum (FBS), 1% sodium pyruvate, and 1% L-glutamine (Cellgro, Manassas, VA). The five plasmids were cotransfected using Fugene 6 transfection reagent (Promega, Madison, WI) at a DNA (μg):Fugene 6 (μl) ratio of 1:3 in OptiMEM® (Gibco, Carlsbad, CA). Transfections were performed in a 384-well format at a cell density of 1.8 × 10 cells. 4 Compounds were added 2 hours after transfection and plates were incubated at 37°C, 5% CO for 48 hours. After incubation, cells were lysed and luciferase production was measured using Britelite CellTiter-Glo® (Promega, Madison, WI) was added to treated cells according to the manufacturer's instructions. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0194] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula (A): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Y is the formula [ka] is the basis of where the dashed line represents the bond connecting this group to formula (A); G, H, or R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , -C(R G )2-OC(O)-OR 0 , -P(=O)(OR 0 )2, -(CR G )2-OP(=O)(OR 0 )2, -C(O)-N(R 0 )2, and -C(R G )2-OC(O)N(R 0 )2, Here, each R 0 is independently H or one or more ring members selected from C1-C6 alkyl, phenyl, pyridyl, C3-C7 cycloalkyl, and N, O, and S as ring members. or a group selected from 3- to 6-membered heterocycles containing two heteroatoms; each R that is not H 0 are halo, CN, -OH, amino, C 1~4 Alkyl, COOR, Phenyl, C 1~4 Alkoxy, C1~4 Haloalkyl, C 1~4 and optionally substituted with one or two groups selected from haloalkoxy and a 3- to 6-membered heterocycle containing one or two heteroatoms selected from N, O, and S as ring members, wherein said one or two groups are halo, CN, —OH, oxo, amino, C 1~4 Alkyl, phenyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, and C 1~4 optionally substituted with 1 or 2 groups selected from haloalkoxy; Each R G H and C 1~4 independently selected from alkyl; R 1 H, Halo, CN, COOR * , -CONR * 2, or halo, -OR * , and -NR * C1-C6 alkyl optionally substituted with 1 or 2 groups selected from: R * is independently at each occurrence H or C1-C6 alkyl optionally substituted with -OR or -NR2; Z 1 is N and Z 2 Is C(R)2? Or Z 1 is CH and Z 2 is NR, O, S, or CH2; Z 3 is CH2, Q, -CH2-CH2-, -Q-CH2-, -CH2-Q-, -CH2-Q-CH2-, -CH2-CH2-CH2-, or CX2, where X is halo; Q is selected from -NR-, O, S, SO, and SO2; R 2 H, halo, CN, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl1~4 alkyl; Each R 3 is Z 2 and Z 3 and optionally present on any carbon atom of the ring, including halo, -OR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, oxo, CN, -NR2, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 independently selected from alkyl; n is 0 to 2; Ar 1 and Ar 2 each independently represents phenyl or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S as ring members; Ar 1 and Ar 2 Ha, Halo, 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 is the formula -C(R L ) optionally interconnected by 2-L- bridges to form a tricyclic group, wherein Ar 1 and Ar 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 each optionally substituted with up to three groups independently selected from alkyne, and CN; R is independently at each occurrence H, or halo, OH, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C1~4 Haloalkoxy, and C 1~4 C1-C4 alkyl optionally substituted with up to 3 groups independently selected from haloalkyl; L is S, S=O, SO2, O, NR, C(R L )2, and CF2; Each R L are independently H or C 1~2 alkyl; provided that said compound is selected from the group consisting of: 1 12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-12 H-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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 3 12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,1 O-Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 4 12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,1 O-Tetrahydro-12H-dipyridazino[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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 6 13-Benzhydryl-4-hydroxy-8,9,10,11-tetrahydro-7 H,13H-Pyridazino[1',6':4,5][1,2,4]triazino[1,2-a][1,2]diazepine-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]diazepine-3,5-dione; 8 (R)-12-(bis(3-fluorophenyl)methyl)-4-hydroxy-7, 8,9,10-tetrahydro-12H-dipyridazino[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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 10 (9aR,10S)-10-benzhydryl-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-benzhydryl-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-benzhydryl-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-benzhydryl-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-benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione; 19A 12-Benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro -2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazino thien-6,8-dione; 19B 12-Benzhydryl-7-hydroxy-3,4,12,12a-tetrahydro -2H-pyridazino[1',6':4,5]pyrazino[2,1-b][1,3]oxazine-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]triazine-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-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 23A 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydrobenzoate trihydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 23B 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydrobenzoate trihydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 24 12-Benzhydryl-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-Benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,1 O-Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 25B 12-Benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,1 O-Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 26A 12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4- Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 26B 12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4- Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 27A 12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4 -Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 27B 12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4 -Hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 28A 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin -11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 28B 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin -11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-dione; 29 (S)-12-Benzhydryl-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-dipyridazino[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-dipyridazino[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) (I)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]pyrazino[1,2-b]pyridazine-3,5-dione; 62 (9aR,10S)-10-((S)-(2,6-difluorophenyl)(3-fluorophenyl) (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;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) (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; 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) (nyl)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) (nyl)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-8,9,9 a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 107 4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxyphenyl) 3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzodi Trill; 108 (9aR,10S)-10-((S)-(4-chlorophenyl)(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; 109 (9aR,10S)-10-((R)-(3-chlorophenyl)(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; 110 (9aR,10S)-10-((S)-(2-bromophenyl)(4-fluoro Phenyl)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) Phenyl)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) Phenyl)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) Phenyl)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) (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) (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-Benzhydryl-4-hydroxy-7,8,10 a,11-tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione; 124A 11-Benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 124B 11-Benzhydryl-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-Benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro -10H-Pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-3,5-dione; 127 11-Benzhydryl-4-hydroxy-7-methyl-7,8,9,10,10 a,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-methylbutanoate; 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-methylbutanoate; 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]pyridazin-4-yl acetate; 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]pyridazin-4-yl isopropyl 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]pyrazino[1,2-b]pyridazin-4-yl)oxy)ethyl ethyl carbonate; 134 (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxa so-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]pyrazino[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)methyl methyl 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)methyl ethyl 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)methyl methyl 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)methyl ethyl 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)methyl isopropyl carbonate; 142 (((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl) (I)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 methyl 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 pivalate; 144 (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxa so-3,5,7,8,9,10-hexahydro-12H-dipyridazino[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-valinate; 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 Methyl 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)acetate; and 149 Methyl 2-((((((9aR,10S)-10-(bis(4-fluorophenyl) (I)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-methylpropanoate; and pharmaceutically acceptable salts of these compounds, A compound or a pharmaceutically acceptable salt thereof. (Section 2) Item 1. The compound according to item 1, wherein G is H, or a pharmaceutically acceptable salt thereof. (Section 3) G is R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , -C(R G )2-OC(O)-OR 0 , -C(O)-N(R 0 )2, and -C(R G )2-OC(O)N(R 0 )2, where each R 0 are independently H, or halo, CN, -OH, amino, C 1~4 Alkyl, phenyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4The compound according to item 1, wherein the C1-C4 alkyl is optionally substituted with one or two groups selected from haloalkoxy and a 3- to 6-membered heterocycle containing one or two heteroatoms selected from N, O, and S as ring members, or a pharmaceutically acceptable salt thereof. (Section 4) G is R 0 , -C(O)R 0 , -C(O)-OR 0 , -C(R G )2-OC(O)R 0 , and -C(R G )2-OC(O)-OR 0 where each R 0 are independently a group selected from H or C1-C4 alkyl, and each R G is H or C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. (Section 5) G is -C(O)R 0 , -C(O)-OR 0 , -CH2-OC(O)R 0 , and -CH2-OC(O)-OR 0 where each R 0 5. The compound according to any one of items 1 to 4 above, wherein is C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. (Section 6) formula: [ka] 6. The compound according to any one of items 1 to 5, wherein the compound is: or a pharmaceutically acceptable salt thereof. (Section 7) Z 2 is CH2 and Z 3 is CH2 or CX2, where X is halo and n is 0, 1, or 2; and each R 3 Item 7. The compound according to item 6 above, wherein is Me, or a pharmaceutically acceptable salt thereof. (Section 8) Formula (I): [ka] is a compound of During the ceremony, R 1 H, Halo, CN, COOR * , -CONR * 2, OR * and -NR * C1-C6 alkyl, C1-C4 haloalkyl optionally substituted with 1 or 2 groups selected from R * is independently at each occurrence H or C1-C6 alkyl optionally substituted with -OR or -NR2; Z 1 is N and Z 2 Is C(R)2? Or Z 1 is CH and Z 2 is NR, O, S, or CH2; Z 3 is CH2, Q, -CH2-CH2-, -Q-CH2-, -CH2-Q-, -CH2-Q-CH2-, -CH2-CH2-CH2-, or CX2, where X is halo; Q is selected from -NR-, O, S, SO, and SO2; R 2 H, halo, CN, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4 C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 alkyl; Each R 3 is Z 2 and Z 3 is an optional substituent on any carbon atom of the ring, including -OR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, oxo, CN, -NR2, and halo, CN, C 1~4 Alkyl, -OR, C 1~4 Haloalkoxy, -NR2, and C 1~4C optionally substituted with up to 3 groups independently selected from haloalkyl 1~4 independently selected from alkyl; n is 0 to 2; Ar 1 and Ar 2 each independently represents phenyl or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S as ring members; halo, 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 is the formula -C(R L ) optionally interconnected by 2-L- bridges to form a tricyclic group, wherein Ar 1 and Ar 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 each optionally substituted with up to three groups independently selected from alkyne, and CN; R is independently at each occurrence H, or halo, OH, oxo, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, and C 1~4 C1-C4 alkyl optionally substituted with up to 3 groups independently selected from haloalkyl; L is S, S=O, SO2, O, NR, C(R L )2, and CF2; Each R L are independently H or C 1~2 Item 1. The compound according to item 1, wherein R is alkyl, or a pharmaceutically acceptable salt thereof. (Section 9) Z 19. The compound according to any one of items 1 to 8, wherein is CH, or a pharmaceutically acceptable salt thereof. (Section 10) Z 1 The compound according to item 1 or 8, wherein is N, or a pharmaceutically acceptable salt thereof. (Section 11) Z 2 11. The compound according to any one of items 1 to 10 above, wherein is CH2, or a pharmaceutically acceptable salt thereof. (Section 12) Z 3 is CH2, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-O-, O, or CX2, where X is halo, or a pharmaceutically acceptable salt thereof. (Section 13) Z 3 Item 13. The compound according to item 12, or a pharmaceutically acceptable salt thereof, wherein X is CH2 or CX2, and X is halo. (Section 14) R 1 14. The compound according to any one of items 1 to 5 or 8 to 13, wherein is H, or a pharmaceutically acceptable salt thereof. (Section 15) R 2 is H, or a pharmaceutically acceptable salt thereof. (Section 16) Ar 1 and Ar 2 Both are phenyl and halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein each of the compound and the compound is independently substituted with up to three groups selected from alkyne, and CN. (Section 17) formula: [ka] is a compound of During the ceremony, Y is [ka] [ka] represents a group selected from Here, each R y Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 independently selected from an alkyne, and CN; 16. The compound according to any one of items 1 to 15 above, wherein each q is independently 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof. (Section 18) formula [ka] is a compound of During the ceremony, Z 1 is N or CH; Z 3 is CH2 or -CH2-CH2- or CX2, where X is halo Item 18. The compound according to item 17 above, or a pharmaceutically acceptable salt thereof. (Section 19) Ar 1 and Ar 2 Both of Ar and Ar are phenyl. 1 and Ar 2 is independently optionally substituted with 1 or 3 groups independently selected from F, Cl, and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. (Section 20) G is [ka] [ka] [ka] [ka] [ka] [ka] The compound according to any one of the preceding clauses, selected from the group consisting of: (Section 21) The compound is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts of these compounds. (Section 22) Compound: [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

Claims

[Claim 1] Properties of a compound for treating viral infections.

Images